Speciality
Spotlight

 




           

Clinical Pharmacology

       

     






  • Ian M. Thompson

    Pharmacologic Agents in Complementary Medicine in Prostatic Disease

    Drugs of Today Vol.37 (6), June 2001, Pg. 427-433 

           

    Summary : Use of alternative medicine has increased considerably in the last 10 years. The very high frequency of urologic diseases such as benign prostatic hyperplasia and prostate cancer makes these diseases natural targets of alternative medicine.

          

    As many as 80% of men at risk of prostate cancer are using alternative therapies. In the majority of cases, physicians were unaware of the fact that their patients were using these treatments.

          

    Treatment of Prostate Cancer :

         

    1) Vitamin E – Main function is its intracellular anti-oxidant activity. In preclinical models, vitamin E has been demonstrated to reduce growth rate of human LNCaP prostate cancer model.

            

    Higher vitamin E levels have been suggested in epidemiologic studies to be associated with lower cancer risk. In a clinical trial it was found that prostate cancer rates were
    1/3rd lower in men who had been randomized to receive vitamin E. Effect of vitamin E supplementation was seen almost at the inception of the study and persisted for its duration.

            

    2) Selenium – It is a naturally occurring micronutrient. Humans receive it from ingestion of both plants and animals. A dramatic almost
    2/3rds reduction in incidence of prostate cancer was observed among men receiving selenium. A large study is planned to determine relationship of this agent and prostate cancer risk.

            

    3) Soy and Isoflavenoids – Soy is a major source of a group of weak estrogens known as isoflavenoids. One of these agents, genistein may be the most abundant and clinically significant. The exact mode of action of these isoflavenoids is not known.

           

    Besides estrogenic effect, inhibition of epidermal growth factor receptor tyrosine kinase and inhibition of angiogenesis may be involved. Several prostate cancer cell lines have been found to have growth inhibition when exposed to genistein.

           

    4) Dietary Fat – It has been associated with prostate cancer consistently. The precise cause is not understood but may be related to total caloric intake. HMG-CoA reductase inhibitors which block synthesis of cholesterol have a small effect. These agents have been reported to induce apoptosis in prostate cancer cells as well as in stromal cells.



    5) PC-SPES – It has unquestionable activity against existing prostate cancer. It is a mixture of 8 herbs-chrysanthemum, isatis licorice, Ganoderma lucidum, Panax pseudo-ginseng, Rabdosia rubescens, saw palmetto and skullcap.



    6) COX Inhibitors – Highest concentrations of COX-1 and COX-2 are found within the prostate. A significant reduction of prostate cancer risk among men taking NSAIDS or aspirin has been demonstrated.

           

    Treatment of Benign Prostatic Hyperplasia
    – 

            

    (1) Saw palmetto (2) Pygeum africanum (3) Cernilton (4)
    b-Sitosterol have been discussed.

            

    There is compelling evidence that a variety of the above therapies for both prostate cancer (prevention and treatment) and lower urinary tract symptoms (BPH) may be effective. Ongoing clinical trials will address to a greater degree of precision, the effect and optimal use of these agents.

          

  • Gene-Jack Wang, Nora D. Volkow, et al

    Brain Dopamine and Obesity

    Lancet Vol.357, February 3, 2001, Pg. 354-357

           

    Summary : The cerebral mechanisms underlying the behaviours that lead to pathological overeating and obesity are poorly understood. Dopamine, a neurotransmitter that modulates rewarding properties of food, is likely to be involved. To test the hypothesis that obese individuals have abnormalities in brain dopamine activity, authors measured the availability of dopamine
    D2 receptors in brain. 

          

    Brain dopamine D2 receptor availability was measured with positron emission tomography [PET] and [C-11]raclopride (a radioligand for the dopamine
    D2 receptor). Striatal dopamine D2 receptor availability was significantly lower in the 10 obese individuals than in controls. The interpretation was that the availability of dopamine
    D2 receptor was decreased in obese individuals in proportion to their BMI (body-mass index). 

           

    Dopamine modulates motivation and reward circuits and hence dopamine deficiency in obese individuals may perpetuate pathological eating as a means to compensate for decreased activation of these circuits. Strategies aimed at improving dopamine function may be beneficial in the treatment of obese individuals.

           

  • Haruya
    Saji, Michiko Yamanaka, et al

    Losartan and Fetal Toxic Effects

    Lancet Vol.357, February 3, 2001, Pg. 363



    Summary : Authors report a case of maternal exposure to the antihypertensive drug losartan during weeks 20-31 of pregnancy. They saw the fetal toxic effects of oligohydramnios (decreased amniotic fluid), fetal pulmonary hypoplasia, fetal hypoplastic skull bones, and subsequent fetal death. 

           

    This pattern of abnormalities is similar to those seen in exposure to angiotensin-converting-enzyme (ACE) inhibitors during pregnancy, and were probably caused by
    losartan.

       

  • David M Coulter, Andrew Bate, et al (University of Otago, Dunedin, New Zealand)

    Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study.

    BMJ, 19 May 2001, pg.1207

           


    The objective of the study was to examine the relation between antipsychotic drugs and myocarditis and cardiomyopathy.

           


    The international database on adverse drug reactions run by WHO programme for international drug monitoring was used. Reports mentioning antipsychotic drugs, cardiomyopathy or myocarditis were included. 

          


    Results : A strong signal existed for an association between clozapine and cardiomyopathy and myocarditis. An association was also seen with other antipsychotics as a group. The association was based on sufficient cases with adequate documentation and apparent lack of confounding to constitute a signal. Associations between myocarditis or cardiomyopathy and lithium, chlorpromazine, fluphenazine, haloperidol, and risperidone need further investigation.

          


    Conclusion : Some antipsychotic drugs seem to be linked to cardiomyopathy and myocarditis. 

           

  • Andrew J Krentz, Sherine Mikhail, et al 

    Pseudophaeochromocytoma syndrome associated with clozapine.

    BMJ, vol.32, 19 May 2001,pg.1213.

          


    Clozapine has an established role in treatment of refractory schizophrenia. It produces serious adverse effects which include agranulocytosis. Paradoxical hypertension with increased concentrations of catecholamines has been reported rarely and in association with other antipsychotic treatment.

           


    Authors describe 4 patients with pseudophaeochromocytoma syndrome associated with clozapine. Profuse sweating, hypertension and obesity were common to all the patients. Urinary catecholamine concentrations, measured in 24 hour collections during clozapine treatment were increased in all 4 patients. Computed tomography and isotopic imaging were used to exclude phaeochromocytoma. In 2 cases, urinary catecholamine concentrations normalized and clinical features improved or resolved after withdrawal of the drug, and the patients also lost several kilograms in body weight.

             


    Clozapine has affinity for 5HT2 receptors and adrenergic receptors in vitro. It increases plasma noradrenaline concentrations, by inhibiting synaptic uptake mediated by µ2 adrenergic receptors.

           

  • Jean L Rouleau, Marc A Pfeffer et al

    Comparison of vasopeptidase inhibitor, omapatrilat and lisinopril on exercise tolerance and morbidity in patients with heart failure:
    IMPRESS randomized trial.

    Lancet, vol.356, Aug.19, 2000, pg.615

           


    Background: Authors aimed to assess in patients with congestive heart failure whether dual inhibition of neutral endopeptidase and angiotensin-converting enzyme (ACE) with the vasopeptidase inhibitor, omapatrilat is better than ACE inhibition alone with lisinopril on functional capacity and clinical outcome.

          


    Methods : Authors did a prospective, randomised, double-blind, parallel trial of 573 patients with New York Heart Association (NYHA) class II-IV congestive heart failure, left-ventricular ejection fraction of 40% or less, and receiving an ACE inhibitor. Patients were randomly assigned omapatrilat at a daily target dose of 40mg (n=289) or lisinopril at a daily target dose of 20 mg (n=284) for 24 weeks. The primary endpoint was improvement in maximum exercise treadmill test (ETT) at week 12. Secondary endpoints included death and comorbid events indicative of worsening heart failure.

           


    Omapatrilat improved NYHA class more than lisinopril in patients who had NYHA class III and IV, but not if patients with NYHA class II were included.

           


    Interpretation : Findings suggest that omapartilat could have some advantages over lisinopril in the treatment of patients with congestive heart failure. Thus use of vasopeptidase inhibitors could constitute a potentially important treatment for further improving the prognosis and well being of patients with this disorder.

            

  • Franz H Messerli, Jurg Nussberger

    Commentary – Vasopeptidase inhibition and angio-oedema

    Lancet, vol.356, Aug.19, 2000, pg.608

          


    Omapatrilat affects the cardiovascular system by inhibiting the ACE (and thereby interrupting the renin-angiotensin-aldosterone cascade), and by inhibiting the neutral endopeptidase (NEP) (and thereby increasing the concentration of natriuretic peptides). Both these enzymes also inactivate bradykinin, and ACE inhibitors alone have been shown to increase plasma kinin concentrations. Bradykinin is probably the mediator of the angio-oedema associated with ACE inhibitors. Plasma bradykinin concentrations can rise more than 10 fold during attacks of angio-oedema associated with an ACE inhibitor. The US FDA has raised concern about this adverse effect and the manufacturer withdrew the application temporarily.

             


    Angio-oedema is a well documented, but rare, adverse event in patients taking ACE inhibitors. It can first appear from a few hours to 8 years after an ACE inhibitor is first taken.

           


    Omapatrilat apart from conferring potential cardiovascular benefits, may be of advantage in CHF patients with renal impairment. But as a dual ACE and NEP inhibitor, omapatrilat also carries a higher risk of life-threatening angio-oedema than do ACE inhibitors alone. For omapatrilat, as for any therapy, the risk/benefit ratio must be quantified before it becomes generally
    available.

            

  • Simon Shorvon

    Pyrrolidone Derivatives

    Lancet, Vol. 358, December 2001, Pg. 1885-1892

           

    This is a review article of pyrrolidone derivatives – the so-called nootropic agents. The pyrrolidone (2-oxopyrrolidine) family of chemicals has been the subject of research for more than three decades. Experimental and clinical work first focused on their so-called nootropic effects; later came the possibilities for neuroprotection after stroke and use as an antiepileptic agents.

          

    Piracetam, first of the class, was developed by pioneering research by C Giurgea in the late 1960s, and it was he who coined the term “nootropic”, to mean enhancement of learning and memory.

          

    The term is sometimes extended to include other actions such as neuroprotection. These properties, together with the lack of other generally adverse psychopharmacological actions (eg, sedation, analgesia, motor or behavioural changes), distinguish the pyrrolidones from other psychoactive drug classes.

          

    The mechanisms of action of these drugs are still not fully established; indeed, different compounds in this class may have different modes of action. Interest in this drug class has recently been reawakened by the licensing of levetiracetam as a potentially major new antiepileptic drug and of piracetam for its antimyoclonic action and effects after stroke and in mild cognitive impairment.

           

    Other drugs in this class are currently at an advanced stage of development, and the renewal of interest in this therapeutic area is likely to mean not only that more pyrrolidones will enter clinical practice in the next few years but also that the clinical indications of drugs already licensed will widen.

            

    Licensed
    indications of piracetam in Europe and the USA

          

















     


    Myoclonus


    Cognitive
    impairment


    Post


    stroke


    Other


    Austria

    +

    +

    Alcohol
    withdrawal, alcoholism, head injury (sequelae)

    Belgium

    +

    +

    Alcohol
    withdrawal, learning disorder, vertigo, dyslexia

    UK

    +

    None

    France

    +

    +

    Dyslexia,
    vertigo

    Germany

    +

    +

    +

    Head
    injury (sequelae), dyslexia, learning disorder

    Italy

    +

    ++

    Dyslexia,
    learning disorder, alcohol withdrawal

    Netherlands

    Vertigo

    Norway

    +

    None

    Portugal

    +

    +

    +

    Learning
    disorder, dyslexia, head injury (sequelae),
    post-traumatic vertigo and coma, sickle-cell
    anaemia, alcoholism, epilepsy, alcohol
    withdrawal, Raynaud’s disease, Parkinson’s
    disease

    Spain

    +

    +

    +

    None

    Sweden

    +

    None

    Switzerland

    +

    +

    Dyslexia

    USA

    None

           

  • Terumichi Fujikura 

    New Therapeutic Approaches to the Treatment of Nasal Allergy: Antiinflammatory Effects of H1 Receptor Antagonists

    Drugs of Today Vol.37 (7), July 2001, Pg. 455-461

          

    Histamine is recognised as an important mediator of allergic rhinitis. In addition to the role it plays in the immediate phase reaction of nasal allergy it plays an important role in late phase reaction and protracted allergic inflammation. 

         

    Histamine induces the synthesis and secretion of proinflammatory cytokines and the expression of adhesion molecules. Besides their action of H1 receptor antagonism, antihistamines have been reported to possess multiple anti-inflammatory effects.

         

    Continuous use of antihistamines may reduce the level of minimal persistent inflammation of nasal mucosa in allergy and also produce improvement of coexisting allergic inflammation of lower airways.

         

  • Mark J Caulfield (Dept. of Clinical Pharmacology, St. Bartholomew’s and the Royal London School of Medicine, Charterhouse Square, London, UK).

    Genes for common diseases.

    Br J Clin Pharmacol, 51, 1-3

      

    There is increasing interest in genetic factors that may influence development of common diseases such as hypertension and diabetes. The size of studies require to be adequately powered to detect a true positive effect. The tools are the genetic variants or polymorphisms which each of us has about every 500 bases within our genome. These polymorphisms or variations can be used to identify disease-causing variants or explain genetic influence on a trait.

      

    The most abundant form of polymorphisms are single nucleotide, or base, changes in the code. These single nucleotide polymorphisms or SNPS (pronounced snips) are of great interest. These SNPS will become not only increasingly important in mapping disease genes but also in predicting drug response and are of interest to pharmaceutical industry. There are more complex highly polymorphic markers in addition to these simple polymorphisms.

      

    Population based case-control studies are the most widely used study design to identify a gene for a common disease. Technological advances have occurred in the last 10 years to screen polymorphisms needed to detect common disease causing genes. The first of these was polymerase chain reaction inspired by Kary Mullis. This reaction photocopies DNA within a target sequence.

       

    The second development is methods for high throughput genotyping. The first of these was semiautomated fluorescence based genotyping.

      

    Microarrays and DNA Chips:

    There have also been advances in the methods available to detect single nucleotide polymorphisms. These techniques are currently quite expensive.

        

  • Kevin M O’Shaughnessy

    The genetics of essential hypertension

    Br.J. Clin.Pharmacol, 51,pg.5-11, Jan.2001

      

    Hypertension is currently seen as a ‘complex’ genetic trait caused by multiple susceptibility genes the effect of which are modulated by gene-environment and gene-gene interactions. A number of candidate genes have been proposed but demonstrating consistently the linkage with hypertension has been problematic. The data for angiotensinogen is the most extensive and meta-analysis has confirmed a significant association overall, although risk contributed by this gene is modest. In the past 5 years, success has been achieved in solving the molecular genetics of a number of familial hypertension syndromes.

       

    Animal models : Extensive use of inbred animal strains is made to study genetics of hypertension. This enables control over environment and breeding since this would be impossible to achieve in human studies. There are at least 6 major strains and many more
    substrains.

      

    Human studies: Mainly 2 approaches are followed. Linkage studies based on allele sharing in affected relative pairs (usually sib-pairs) or association studies comparing gene frequencies between cohorts of hypertensive and normal subjects. Evidence implicating a number of genes including
    angiotensinogen, µ-adducin, the b2-adrenoceptor, G-protein beta-3, and the b-subunit of the epithelial sodium channel (b-ENaC) have been obtained using these methods. But the published data are conflicting.

      

    Monogenic hypertension: The greatest advance in recent years has been the study of families in which hypertension is inherited as a simple Mendelian character. The molecular bases for several of these disorders have now been established and are given in Table I.

      

    Table 1. Molecular basis for known familial (monogenic) hypertension syndromes.












 Monogenic syndrome

 Mode of
Inheritance

 Gene
Product

 Chromosomal
Location

   

  

   

   



Apparent
mineralocorticoid excess (AME)



Recessive



Non-functional 11-b-hydroxy steroid
dehydrogenase (11b-HSD Type 2) 

enzyme



16q

   

  

   

   



Glucocorticoid remediable
Aldosteronism (GRA)



Dominant



Hybrid aldosterone synthase (CYP11B2) 

  enzyme expressed
under ACTH control.



8P

   

  

   

   



Hypertensive forms of
Congenital adrenal hyperplasia 10q24



Recessive



Non-functional forms of the correspond- ing
hydroxylases.



8q21 &
(11 b and 17-a hydroxylase types) (CYP11B1 and CYP17A)

   

  

   

   



Liddle’s Syndrome
(pseudo-aldosteronism)



Dominant



Constitutively expressed
amiloride- sensitive sodium channel in distal nephron



16p


  • Peter Collins and Gareth Williams

    Drug Treatment of Obesity: From past failures to future successes ?

    Br J Clin Pharmacol, 51, Jan.2001, 13-25

       

    Obesity is one of the last great unfilled niches in pharmacotherapy. Drugs can only be used that are proven effective and safe. Efficacy remains a stumbling block for many hopeful compounds. Some for example the b3-adrenoreceptor thermogenic agents and perhaps leptin have not yet fulfilled the considerable promise which they showed in lower mammals. Success must be defined as the restoration of normal quality and duration of life rather than arbitrary degrees of weight loss. No sufficiently long-term studies have been performed for drugs like orlistat and
    sibutramine.

       

    Safety : This has been the downfall of many effective drugs e.g. fenfluramine -withdrawn by manufacturers following definite evidence of primary pulmonary hypertension and sclerotic valvular heart disease. Phentermine (often used in combination with fenfluramine) was not endorsed because of inadequate long-term safety data. Many centrally acting drugs affect multiple functions served by neurotransmitters which they target. An example is short-term memory loss with cholecystokinin, whose action as a satiety factor is currently being explored.

      

    Ethical considerations: Injections of diuretics are given to patients when they are not sodium over-loaded and thyroxine when they are euthyroid and use of unproven sundry drugs. A Belgian ‘slimming clinic’ used an unlicensed mixture of fenfluramine, diethylpropion and a Chinese herbal product, the latter contained nephrotoxic Aristoloclivia alkaloids. This led to high presence of renal disease (interstitial fibrosis causing renal failure and urothelial cancers).

      

    Currently available anti-obesity drugs: Orlistat (tetrahydrolipstatin) – It is a synthetic drug derived from a naturally occurring lipase inhibitor produced by streptomyces moulds. It binds covalently to active site of pancreatic lipase. Its action is limited to gut lumen because it is not absorbed. At therapeutic doses (120mg, 3 times daily), it blocks digestion and absorption of about 30% of dietary fat. Unwanted side-effects are fatty stools with diarrhoea, urgency and incontinence.

      

    Sibutramine : It is a centrally acting appetite suppressant and has mild thermogenic properties. It increases action of 5 HT and noradrenaline in hypothalamus by blocking the reuptake. Unlike fenfluramine it does not stimulate the release of 5HT. Inhibition of noradrenaline reuptake increases sympathetic tone, and may produce rise in BP and pulse rate. Because of its actions on both monamines, sibutramine is called an SNRI (Serotonin-noradrenaline reuptake inhibitor)

      

    Leptin- in human obesity – its usefulness in human obesity is uncertain.

      

    Potential targets for novel anti-obesity drugs (1) Neuropeptide.Y (2) Melanocortin system (3) Orexins -A and B peptides which stimulate feeding when injected centrally. Orexin antagonists are under development (4) Satiety factors -cholecystokinin (5) Thermogenic drugs.

              

  • Scott Gottlieb

    NSAIDS can lower risk of Alzheimer’s

    BMJ, Vol.323, 1 Dec, 2001, pg1269

     

    Long term use of anti-inflammatory drugs such as ibuprofen and naproxen can lower the risk of Alzhemier’s disease, probably by reducing inflammation in brain. Researchers of Erasmus Medical Centre in Rotterdam found that adults who use NSAIDs for at lest 2 years were 80% less likely to develop Alzheimer’s disease than individuals who used these drugs for shorter periods or who did not take them at all. The risk decreased as the number of years that patients continued to take the drugs grew.

       

    In contrast, use of NSAIDs was not linked to a reduced risk of vascular dementia.

         

  • Roger Dobson

    Anticoagulatns can interact with herbal medicines.

    BMJ, Vol.323, 1 Dec.2001, pg.1270

      

    Warfarin was found to be the most common drug in interactions with 18 cases, and St. John’s Wort was the most common herb.

       

  • Judy
    Siegel-Itzkovich, Jerusalem

    Scientists develop a “vaccine” against diabetes

    BMJ, Vol.323, 1 Dec. 2001, pg. 1272

      

    Scientists have developed the world’s first drug that successfully halts the immune system’s destruction of pancreatic b-cells in humans called DiaPep277, the drug offers the possibility of preventing type I diabetes in healthy people with a genetic risk of the disease and halting its progression in people whose b-cells have already begun to die.

      

    This peptide has undergone Phase II clinical trial on 35 patients. Mechanism of action may be changes in patients’ T cells. In children the destruction of pancreatic cells is very rapid taking place even in a couple of months.

       

  • Kalifa A Bojang, Paul JM Milligan, et al

    Efficacy of RTS,S/ASO2 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in the Gambia: a randomised trial.

    The Lancet, vol.358, 8 Dec.2001, pg. 1927-34.

      

    RTS,S/ASO2 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HbsAg, incorporating a new adjuvant (ASO2). Authors did a randomised trial of the efficacy of RTS,S/ASO2 against natural P.falciparum infection in semi immune adult men in The Gambia.

       

    Three hundred and six men aged 18-45 years were randomly assigned three doses of either RTS,S/ASO2 or rabies vaccine (control). Volunteers were given sulfadoxine/ pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P.falciparum. Analysis was per protocol.

       

    Interpretation: Of the study was that RTS,S/ASO2 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P.falciparum infection.

        

  • William L Isley

    Pitavastatin (NK-104), A New HMG CoA Reductase Inhibitor

    Drugs of Today, Vol.37, Sept.2001, pg.587-594

      

    Pitavastatin (NK-104), is a new synthetic HMG-CoA reductase inhibitor (statin). Animal studies suggest that in addition to reducing LDL cholesterol, the drug may produce marked reductions in triglyceride-rich particles (VLDL) and intermediate density lipoproteins (IDL). It is not metabolized by the common cytochrome P-450 3A4 enzyme, possibly reducing the risk for drug interactions. Early studies suggest that it may be quite useful for treating common dyslipidemias.

        

  • Yan-Qiong Xiong and Thuan P Le

    Telithromycin (HMR 3647): The first ketolide antibiotic.

    Drugs of Today, Sept.2001, Vol.37, pg.617-628,

      

    Telithromycin, the first ketolide antibiotic to undergo clinical development, has been specifically designed to treat community-acquired respiratory tract infections, including those caused by resistant pathogens. Like macrolides, telithromycin inhibits protein synthesis by acting mainly on the 50S ribosomal unit. It has potent activity against a wide spectrum of Gram +ve and Gram -ve organisms, including erythromycin-resistant
    pneumococci.

     

    Overall the preliminary findings provide evidence that short-term treatment with telithromycin (800mg,p.o.) once daily for 5 days for treatment of acute exacerbation of chronic bronchitis, acute sinusitis and pharyngitis/tonsillitis and 7-10 days for the treatment of community acquired pneumonia appears to be comparable to standard antibiotics for select respiratory tract infection. Telithromycin maintains activity while macrolide resistance increases. It will be an addition to currently available antibiotics to combat increasing trends of resistant respiratory pathogens.

        

  • X. Rabasseda

    Oxcarbazepine: Anticonvulsant Profile and Safety

    Drugs of Today, May 2001, 37(5): 333-355

      

    Oxcarbazepine is a molecule chemically related to carbamazepine that shares most of the pharmacological and therapeutic effects of carbamazepine while displaying a more favourable profile regarding tolerability and drug-drug interactions. In contrast to carbamazepine, oxcarbazepine is metabolized through cytochrome P450-independent reductase, and is thus devoid of inductive effects on hepatic oxidative metabolism. Oxcarbazepine has been shown to be useful both as monotherapy and adjunctive therapy in patients with partial seizures with or without secondary generalization. The drug has been documented as safe and effective in adults as well as children aged 4-16 years. Additional data suggests that oxcarbazepine might improve cognition and psychomotor performance and might increase alertness, in contrast to the cognition/psychomotor impairment observed with some other antiepileptic drugs. Both the pharmacokinetic advantages over other anticonvulsant drugs and the lack of pharmacological interactions with oxcarbazepine may point to this drug as a first-line treatment for the management of partial and tonic-clonic epilepsy.

         

  • S.J. de Visser, J. Van der Post et al 

    Biomarkers for the effects of antipsychotic drugs in healthy volunteers

    Br.J.Cl.Pharm, Vol.51, Feb.2001, pg.119

          

    Subjective and objective measures of alertness, and of visual-visuomotor-auditory and motor skills were most sensitive to antipsychotics, although over half of all the studies failed to show statistically significant differences from placebo. The most consistent effects were observed using prolactin response and saccadic eye movements, where 96% and 83% of all studies respectively showed statistically significant effects. The prolactin inducing dose equivalencies relative to haloperidol of 19 different antipsychotic agents correlated with the lowest recommended daily maintenance dose
    (r2 = 0.52). This relationship could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind prolactin release and antipsychotic activity (probably
    D2-receptor antagonism). The number of tests used in human psychopharmacology appears to be excessive. Future studies should look for the most specific and sensitive test within each of the domains that are most specific and sensitive test within each of the domains that are most susceptible to
    neuroleptics.

          

  • Karen Rowland Yeo & Wilfred W Yeo

    Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes.

    Br.J Clin Pharmacol, vol.51, May 2001; 461-470

          

    Simvastatin is generally well-tolerated and causes few subjective side-effects during chronic treatment. Myopathy which may present as rhabdomyolysis, is a rare but serious side-effect of statin treatment and occurs in 0.1% of patients treated with standard doses of simvastatin or other HMG-CoA reductase inhibitors.

          

    The risk of rhabdomyolysis increases considerably on addition of drugs such as itraconazole and mibefradil. These drugs inhibit CYP3A4 mediated metabolism of simvastatin and lead to marked increase in plasma concentrations of the enzyme HMG-CoA reductase inhibitory activity. Mibefradil has been withdrawn from the market 2 years ago but there is debate with respect to concomitant use of other calcium channel blockers.

         

    In the present study, inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes were investigated. The results of the study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.

          

  • Susan Todd, Anne Whitehead et al

    Interim analysis and sequential designs in phase III studies

    Br.J.Clin.Pharm, vol.51, May 2001, pg.394

         

    Recruitment of patients to a clinical trial usually occurs over a period of time, resulting in the steady accumulation of data throughout the trial’s duration. Yet, according to traditional statistical methods, the sample size of the trial should be determined in advance, and data collected on all subjects before analysis proceeds. For ethical and economic reasons, the technique of sequential testing has been developed to enable the examination of data at a series of interim analyses. The aim is to stop recruitment to the study as soon as there is sufficient evidence to reach a firm conclusion. Authors present the advantages and disadvantages of conducting interim analyses in phase III clinical trials, together with the key steps to enable the successful implementation of sequential methods in this setting. Examples are given of completed trials, which have been carried out sequentially, and references to relevant literature and software are provided.

          

  • E.J.Begg,
    R.A. Robson et al

    Quinapril and its metabolite quinaprilat in human milk

    Br.J.Clin.Pharm, vol.51, May 2001; 478-481

          

    Aim of the study was to measure the milk to plasma ratio (M/P) of quinapril and its active metabolite quinaprilat in lactating mothers and to assess likely infant exposure

          

    A single dose of quinapril 20mg was administered to six healthy mothers who had been breastfeeding their infants for at least 2 weeks.

          

    The M/P ratio for quinapril was 0.12 (95% CI 0.09, 0.14). No quinapril was detected in milk after 4h. No quinaprilat was detected in any of the milk samples. The estimated ‘dose’ of quinapril that would be received by the infant was 1.6% (95% CI 1.0, 2.2) of the maternal dose, adjusted for respective weights.

          

    Quinapril appears to be safe during breastfeeding according to conventional criteria, although as always, the risk : benefit ratio should be considered when it is to be given to a nursing mother.

          

  • H.E.Seymour, A Worsley, J.M. Smith and S.H.L.Thomas

    Anti-TNF agents for rheumatoid arthritis

    Br.J.Clin Pharm, vol.51, March 2001, pg.201-208

        

    Rheumatoid arthritis (RA) is a chronic inflammatory, autoimmune disease with a prevalence of approximately 1% and an annual incidence of 0.04%.

        

    Nonsteroidal anti-inflammatory drugs (NSAIDs) have little effect on the underlying course of RA, but they have some anti-inflammatory and analgesic properties. Disease modifying antirheumatic drugs (DMARDs) have been shown to slow progression of RA and are currently recommended early in the course of treatment of RA which is when disease progression is most rapid.

         

    Etanercept and infliximab belong to a new group of parentally administered antitumour necrosis factor (TNF) drugs.

         

    Etanercept is licensed in the UK for the treatment of active rheumatoid arthritis in patients who have not responded to other DMARDs and in children with polyarticular-course juvenile arthritis who have not responded to or are intolerant of methotrexate. In adults it produces significant improvements in all measures of rheumatic disease activity compared to placebo. In patients whose disease remains active despite methotrexate treatment, further improvement in control is obtained with the addition of etanercept without an increase in toxicity. Infliximab is a monoclonal antibody which is currently licensed in the UK for Crohn’s disease and, in combination with methotrexate for the treatment of rheumatoid arthritis in patients with active disease when the response to disease –modifying drugs, including methotrexate, has been inadequate. Infliximab in combination with methotrexate was shown to be superior to methotrexate or infliximab alone.

         

    There are currently no predictors of a good response to anti-TNF drugs and a percentage of patients fail to respond to treatment (25% to 38% of etanercept patients; 21% to 42% of infliximab patients). Infliximab monotherapy induces the production of anti-infliximab antibodies, which may reduce its effectiveness. Adding methotrexate to infliximab therapy may prevent this response.

         

    Anti-TNF drugs may affect host defences against infection and malignancy; whether these agents affect the development and course of malignancies and chronic infections is unknown and safety and efficacy in patients with immunosuppression or chronic infections has not been investigated. Upper respiratory tract infections were more common in patients treated with etanercept than with placebo.

         

  • Michael A Shaw

    New insights into drug metabolism and toxicology.

    Report of a symposium on drug metabolism and toxicity held at the British Pharmacological Society Meeting in Cardiff, UK in July 2000

    Br. J Clin.Pharm, March 2001, vol.51, pg.209-12

          

    Adverse drug reactions present a major clinical problem. In addition to being a major cause of morbidity and mortality, adverse drug reactions can prevent effective drug therapy and, in extreme cases, can lead to the withdrawal of potentially valuable medicines.

         

    For example, terfernadine is a prodrug that undergoes first pass carboxylation to form the active agent; terfernadine itself, however, can prolong the QT interval, leading to potentially fatal dysrhythmias (torsades des pointes) in some patients. This risk is increased in patients with liver disease, and in patients treated with drugs such as ketoconazole or erythromycin, in whom the conversion of terfenadine to its active metabolite is impaired. Most such reactions are now readily predictable since the role of specific cytochrome P450 isoforms in drug metabolism can be determined from in vitro studies, allowing potential drug interactions to be identified. The risk of such interactions in clinical practice can then be assessed in pharmacokinetic and pharmacodynamic studies.

         

    There is considerable genetic variation in drug metabolism. Approximately 10% of individuals show a deficiency in the CYP2C6 isoform (the principal P450 isoform involved in drug metabolism in humans), and polymorphism of CYP2C9 is also attracting attention due to the involvement of this isoform in warfarin metabolism.

         

    A variety of in vitro and in vivo techniques are now available to predict such genetic variations in drug metabolism.

          

    In addition to being responsible for drug elimination, drug metabolizing enzymes such as cytochromes P450 can also produce reactive metabolites (bioactivation). Such reactions are less predictable, and can cause potentially serious adverse effects. For example, paracetamol is primarily metabolized by phase II glucuronidation and sulphation, but approximately 5-10% is converted to a toxic quinoneimine metabolite, which is detoxified by glutathione. When paracetamol is taken in overdose, the phase II pathways become saturated, leading to increased production of the quinoneimine. This in turn leads to glutathione depletion and hepatocellular damage.

         

    Studies with drugs associated with well characterized hypersensitivity reactions, such as carbamazepine, have shown that these drugs are converted to reactive metabolites that provoke the formation of antibodies to the drug or, in some cases, to cytochrome P450. However, the development of such an immune response, depends on the prevailing cytokine profile. Studies with carbamazepine suggest that exposure of antigen-presenting cells to the drug or its reactive metabolites leads to recruitment of cytotoxic CD8 cells and reversal of the normal CD4:CD8 ratio. The CD8 cells then infiltrate the epidermis, resulting in tissue damage.

          

    New insights into paracetamol toxicity

        

    The use of the paracetamol antidote N-acetylcysteine in early (<12h) paracetamol poisoning is well established, but the choice of oral or intravenous administration has remained controversial. However, a recent meta-analysis suggests that both routes are equally effective. There is evidence that activated charcoal is useful in the treatment of early paracetamol poisoning, provided it is given within 1 h. For example, in a recent study the use of activated charcoal within 1-2h significantly reduced the need for
    N-acetylcysteine.

          

    The mechanisms by which N-acetylcysteine acts in patients with advanced paracetamol poisoning are unknown but free radical scavenging, haemodynamic effects, and changes in oxygen kinetics have all been proposed.

        

    The toxicology of tamoxifen

    Tamoxifen continues to provide considerable benefit in terms of reducing mortality from breast cancer, and the available data suggest that the prophylactic use of tamoxifen is unlikely to produce a significant risk of
    genotoxicity.

         

  • H. Chrystyn

    Methods to identify drug deposition in the lungs following inhalation

    Br. J.Clin.Pharm, April, 2001, vol.51, pg.289-299

         

    Inhalation of bronchodilators and anti-inflammatory agents enables direct delivery to the therapeutic sites in the airways for the management of asthma and chronic obstructive pulmonary disease. Upto 20% of the inhaled dose is delivered to the lungs whilst the majority is swallowed. The proportion of the dose delivered to the lungs, following inhalation, will be cleared either by the mucociliary convenor belt or by absorption through the airway wall into the systemic circulation. The latter is the fraction of the dose that will exert the clinical effect within the airway wall.

        

    Drug particles less than 5mm have the greatest probability of deposition in the lung, whereas those less than 2
    mm tend to be concentrated in the alveoli.

        

    Table below lists pharmacokinetic and scintigraphic methods that have been developed to identify the amount of drug delivered to the lungs following an inhalation.

         

    Scintigraphic methods following inhalation using two and three dimensional imaging are direct methods for the determination of lung deposition.

        

    These techniques can highlight the zones of the lungs into which the drug is deposited. However, they do not differentiate between the removal of drug from the lungs by systemic absorption or by mucociliary clearance and also require modification to the original drug formulation.

         

    Table : Summary of the methods used to identify the bioequivalence of inhaled products.

    Pharmacokinetic (using plasma or urine samples) 

    Relative lung deposition (drugs with an extensive first pass,

    Charcoal block, absorption lag times)

    Total systemic delivery

        

    Gamma scintigraphy

    Two dimensional

    SPECT

    PET

       

    Clinical studies

    Spirometry (crossover or parallel design)

    Bronchoprovocation for lung deposition

    Multiple dosing for extra-pulmonary effects

       

    In vitro

    Determination of the in vitro particle size distribution, fine particle (respirable) dose, emitted dose.

          

  • J.G. Reilly, S.A. Ayis et al 

    Sudden death and thioridiazine

    Br.J.Cl.Pharm, April 2001,vol.51, pg.363.

         

    Risks of QT interval prolongation are higher for some antipsychotic drugs, e.g. thioridazine and droperidol. The risk of sudden cardiac death in recipients of different antipsychotic drugs has not previously been quantified.

          

    However they support the hypothesis that thioridazine-induced cardiac repolarisation abnormalities may result in arrhythmia and sudden cardiac death.

         

  • S
    Akhondzadeh, S.A. Ahmadi-Abhari et al

    Double-blind randomized control trial of baclofen vs clonidine in the treatment of opiate withdrawal

    Br.J.Cl.Pharm, April 2001, vol.51; pg.364

        

    Alpha-adrenoceptor agonists have been used in treatment of opiate withdrawal syndrome over the last 2 decades. Accumulating evidence shows the efficacy of the
    GABAB receptor agonist, baclofen in reducing alcohol intake and cocaine self-administration in rats. The present trial was conducted to examine the ability of a
    GABAB agonist in the management of opiate withdrawal.

         

    Baclofen and clonidine were equally effective in treating the physical symptoms of withdrawal syndromes. However, baclofen showed a significant superiority over clonidine in the management of mental symptoms. These results suggest that baclofen might constitute a novel therapeutic agent for opiate withdrawal syndrome.

         

  • A. Mahmud & J.Feely

    Angiotensin II receptor antagonist reduces arterial stiffness in hypertensive patients; may be additive to ACE inhibition

    Br.J.Cl.Pharm, April, 2001, vol.51, pg. 380p-81p

         

    Angiotensin converting enzyme (ACE) inhibitors have been shown to favourably influence elastic properties of the peripheral arteries in hypertensive patients. The recognition of systolic pressure and pulse pressure as independent cardiovascular risk factors has focused on the arterial haemodynamics of antihypertensive drugs since decreasing arterial stiffness and delaying arterial wave reflection would be logical strategy in the management of hypertension. This study examined the effect of an angiotensin II receptor antagonist, valsartan on the elastic properties of the aorta and peripheral muscular arteries.

         

    The present study shows that an ATH antagonist, in addition to reducing blood pressure may exert an additional haemodynamic effect in improving elastic properties of the aorta and dilating peripheral conduit arteries suggesting reduced stiffness in both large and smaller arteries of magnitude similar to that of an ACE inhibitor. That an ACE inhibitor produced a further reduction in pulse wave velocity in patients under angiotensin II blockade suggests that the effects maybe additive.

         

  • A Mahmud & J. Feely

    The effect of acute and chronic smoking on arterial stiffness in healthy young subjects.

    Br.J.Cl.Pharma, April 2001, vol.51, pg.381.

         

    Smoking is a major cardiovascular risk factor and its effect on the mechanical properties of large arteries may play an important role. Smoking influences endothelium-mediated vascular control, induces vasoconstriction and increases the stiffness of both muscular and elastic arteries. Acute exposure to passive smoking adversely affects arterial wave reflection in healthy subjects. As the acute effects of smoking on pulse wave velocity (PWV) and arterial wave reflection in both non-smokers and chronic smokers have not been looked at, authors therefore examined the effects of active smoking, both acute and chronic, on arterial stiffness.

         

    Authors performed an observational study on a group of 157 healthy students (77 females). Chronic smokers (n=41) were matched for age, height, weight and gender with non-smokers. Arterial wave reflection was measured, using radial applanation tonometry using the generalized transfer function (Sphygmocor® PWV Medical), expressed as a percentage of pulse pressure-augmentation index
    AI%.

        

    This study shows that chronic smokers by the age of 22 years have evidence of increased arterial wave reflection, a marker of vascular stiffness. Furthermore in common with non-smokers their arteries also stiffen further when they smoke a cigarette.

          

  • Krishnan Parameswaran and Frederick E Hargreave

    The use of sputum cell counts to evaluate asthma medications

    Br. J. Cl.Pharm, vol. 52, Aug.2001, 121-128.

          

    Total and differential cell counts from hypertonic-induced, dithiothreitol-dispersed sputum provide reproducible measurements of airway inflammatory cell counts, which are responsive to treatment with anti-inflammatory drugs. They have helped to understand the kinetics of inflammatory cell changes in asthma after the reduction of corticosteroids and the subsequent re-introduction of treatment. They have identified that the presence of sputum eosinophilia in asthma, chronic cough and chronic airflow limitation is a predictor of steroid
    – responsiveness and of lack of ‘asthma control’ Sputum cell counts are also useful to study the potential anti-inflammatory effects of drugs like theophylline, long-acting b-adrenoceptor agonists, leukotriene antagonists and newer drugs in development. They may be helpful to select add-on therapy to corticosteroids in ‘difficult-to-control’ asthma.

         

    Authors conclude that induced sputum examination for inflammatory markers holds much promise in the evaluation of the anti-inflammatory properties of asthma medications and identifying the appropriate medication to control symptoms. They may be useful to compare the relative potencies of different anti-inflammatory drugs. Further research is reserved to investigate the anti-inflammatory effect of newer asthma drugs, to identify the relevance of suppression of airway eosinophilia in the long term management of asthma and to establish a minimally important clinically significant change in airway inflammatory markers including sputum eosinophil count.

          

  • M Pirmohamed

    Editorial – Pharmacogenetics and pharmacogenomics

    Br.J.Cl.Pharma, vol.52, Oct.2001, pg.345

          

    Pharmacognetics has been defined as the study of variability in drug response due to heredity. More recently, with the fashion for adding the ‘suffix omics’ to areas of research, the term ‘pharmacogenomics’ has been introduced. While the former term is largely used in relation to genes determining drug metabolism, the latter is a broader based term that encompasses all genes in the genome that may determine drug response. The distinction however, is arbitrary and both terms can be used interchangeably.

         

    Historical overview of pharmacogenetics and pharmacogenomics

    Year Individual(s) Landmark

         


















    Year

    Individual(s)

    Landmark

    510 BC

    Pythagoras

    Recognition of the dangers of ingesting fava beans, later

    characeterized to be due to deficiency of G6PD.

    1866

    Mendel

    Establishment of the rules of heredity

    1906

    Garrod

    Publication of ‘Inborn Errors of Metabolism’

    1932

    Snyder

    Characterization of the ‘phenylthiourea
    nontaster’ as an

    autosomal recessive trait.

    1956

    Carson et al

    Discovery of glucose-6-phosphate dehydrogenase 

    deficiency.

    1957

    Motulsky

    Further refined the concept that inherited defects of 

    metabolism may explain individual differences in drug

    response.

    1957

    Kalow & Genest

    Characeterization of serum cholinesterase deficiency.

    1957

    Vogel

    Coined the term pharmacogenetics

    1960

    Price Evans

    Characterization of acetylator polymorphism

    1962

    Kalow

    Publication of ‘Pharmacogenetics
    – Heredity and the 

    Response to Drugs’

    1977/79

    Mahgoub et al and Eichelbaum et al

    Discovery of the polymorphism in debrisoquine
    hydroxylase, sparteine oxidase.

    1988

    Gonzalez et al

     Characetrization of the genetic defect in
    debriso-

    quine hydroxylase, later termed CYP2D6.

    1988-2000

    Various

    Identification of specific polymorphisms in various phase 

    I and phase II drug metabolizing enzymes, and latterly in 

    drug transporters.

    2000

    Public-private partnership

    Completion of the first draft of the human
    genome.

    2000

    The International SNP Map Working Group

    Completion of map of human genome sequence
    variation containing 1.42 million SNPs.

     

  • Peter R Jackson, Erica J Wallis et al

    Statins for primary prevention : at what coronary risk is safety assured?

    Br.J.Clin.Pharma, vol.52, Oct.2001, pg.439.

         

    Increasingly HMG CoA reductase inhibitors (statins) are being used for primary prevention of vascular disease in patients with a raised cholesterol but at low absolute risk of coronary heart disease (CHD). This study used clinical trial results to explore the limits of absolute safety for statin use in such patients.

         

    The major placebo controlled statin outcome trials were identified by automated and manual literature searches. Principal results including all cause mortality in placebo and intervention groups and baseline values of standard coronary risk factors were abstracted for each trial.

         

    The regression line describing the relationship between mortality benefit and risk suggests that statin use could be associated with an increase in mortality of 1% in 10 years. This would be sufficiently large to negate statin’s beneficial effect on CHD mortality in patients with a CHD event risk less than 13% over 10 years.

          

    Absolute safety of statins has not been demonstrated for patients at low risk of CHD. Patients absolute risk of CHD should be calculated before starting statin treatment for primary prevention. Extensions of such treatment to low risk patients should await further evidence of safety.

         

  • Masaki
    Tagawa, Michiko Kano et al

    Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine.

    Br. J Clin.Pharm, vol.52, Nov.2001, pg.501

          

    Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood-brain-barrier and the consequent occupation of brain histamine H1-receptors. Authors previously studied the mechanism of sedation caused by antihistaines using positron emission tomography (PET). Recently, authors revealed the nonsedative characteristic of ebastine, a second –generation antihistamine, with cognitive performance tests. In the present study, H1-receptor occupation by ebastine was examined in the human brain using PET.

          

    Ebastine 10mg and (+)-chlorpheniramine 2 or 6mg were orally given to healthy male volunteers. PET scans with
    {11C}-doxepin, a potent H1-receptor antagonist, were conducted near t
    max of respective drugs.

          

    Ebastine (10mg orally) causes brain histamine H1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H1-receptors even at a low but sedative dose of 2mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.

             

  • K.Lindhart, S Gizurarson, et al

    Electroencephalographic effects and serum concentrations after intranasal and intravenous administration of diazepam to healthy volunteers

    Br.J.Clin.Pharm, vol.52, Nov.2001,pg.521

          

    The present study was carried out to assess the intranasal administration of diazepam as a potential alternative to intravenous and rectal dosing in the treatment of acute epileptic seizures. A nasal spray is beneficial when a rapid onset of effect (within seconds or minutes) is required. Animal experiments have shown that the intranasal administration of diazepam may induce effects within 5
    mins.

          

    The study had a cross-over design with 8 volunteers. It consisted of 4 legs with 4 different administrations: intranasal (i.n) placebo, 4mg diazepam i.n., 7mg diazepam i.n. and 5mg intravenous (i.v.) diazepam. Polyethylene glycol 300 (PEG 300) was used as a vehicle in the nasal formulations to solubilise a clinically relevant dose of diazepam.

          

    The study indicates that it is possible to deliver a clinically effective nasal dose of diazepam for the acute treatment of epilepsy using PEG 300 as a
    solubiliser.

           

  • Luis A Garcia Rodriguez, Sonia Hernandez-Diaz & Francisco J de Abajo.

    Association between aspirin and upper gastrointestinal complications: Systematic review of epidemiologic studies.

    Br.J.Clin.Pharm. Vol.52, Nov.2001, pg.563

           

    Because of the widespread use of aspirin for prevention of cardiovascular diseases, side-effects associated with thromboprophylactic doses are of interest. This study summarizes the relative risk (RR) for serious upper gastrointestinal complications (UGIC) associated with aspirin exposure in general and with specific aspirin doses and formulations in particular.

            

    Aspirin was associated with UGIC even when used at low doses or in buffered or enteric-coated formulations. The latter findings may be partially explained by channeling of susceptible patients to these formulations.

          

  • Adriane
    Fugh-Berman & E. Ernst

    Herb-drug interactions: Review and assessment of report reliability

    Br.J.Clin.Phar, vol.52, Nov.2001, pg.587

          

    The aim of this systematic review was to assess the published clinical evidence on interactions between herbal and conventional drugs.

          

    Four electronic databases were searched for case reports, case series or clinical trials of such interactions. The data were extracted and validated using a scoring systems for interaction probability.

          

    Clinical studies have documented that St John’s wort lowers serum concentrations of digoxin, phenprocoumon, indinavir, amitriptyline, and nortriptyline. A recent study found no effect of St. John’s wort (300mg standardized to 0.3% hypericin three times daily (14 days) on carbamazepine pharmacokinetics. Piper longum contains piperine, which has been shown in clinical trials to increase
    Cmax and AUC of phenytoin, propranolol, and
    theophylline.

           

    One study found that mixed valepotriates from Valeriana officinalis reduced the adverse effect of alcohol on concentration. Another demonstrated that Panax ginseng enhanced alcohol clearance in humans. A clinical study of an infusion of Piper methysticum found that kava potentiates impairment when combined with alcohol.

          

    The effect of Catha edulis on the pharmacokinetics of single-dose ampicillin and amoxicillin has been studied. The bioavailability of ampicillin was reduced during a Khat-chewing session but no effect was noted with
    amoxicillin.

          

    Licorice is a common herb in Chinese and Japanese herbal mixtures.

           

    St. John’s wort affects the clearance of many drugs, including cyclosporin, antidepressants (predominantly SSRIs), digoxin, indinavir, and phenprocoumon. The underlying mechanism appears to be
    multifactorial.

            

    Cases of serotonin syndrome could arise if St. John’s wort increased serotonin levels. However, enough cases of interactions with SSRIs have been reported that a serotonergic (or serotonin-amplifying) effect of St. John’s wort could occur.

          

    There is reasonable documentation of interactions between coumarin anticoagulants and St. John’s wort, danshen, dong quai, ginseng, and ginkgo. Most of these case reports are probably not true interactions but result from additive anticoagulant effects. Dong quai contains coumarins, and would be expected to augment the effects of a coumarin-derived anticoagulant. Ginkgo and garlic interfere with platelet function, and have been associated with bleeding even in the absence of warfarin or other anticoagulant treatment. Danshen also interferes with platelet function but appears to decrease the elimination of warfarin at least in rats.

          

    Herb-drug interactions occur but are under-researched. Patients taking St.John’s wort or anticoagulants are at the highest risk of an interaction. Patients on coumarin anticoagulants should be specifically advised to avoid taking herbal medicines or to have their INR measured within 2 weeks of starting the product. Patients taking garlic, ginkgo, danshen or other HMPs affecting platelet function should also be monitored.                                  

                                             

  • Ian B Wilkinson & David J Webb                        

    Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications              

    Br. J Clin.Pharm, vol.52, Dec.2001, pg.631                           

                                                                  

    Venous occlusion plethysmography provides a simple, and robust method for assessing blood flow in vivo. It is most frequently 
    applied to the forearm and is a versatile technique that has proved extremely valuable in assessing human vascular physiology 
    and pharmacology, especially when coupled with intra-arterial drug infusion. It has also been employed extensively to assess  
    endothelial function in vivo, for which it remains the gold standard. Unfortunately, the invasive nature of the technique has  
    prevented its use in addressing the important question of whether changes in endothelial function, particularly following drug  
    therapy, are a reliable surrogate of cardiovascular risk.                  

                                                                                                

    However, plethysmographic assessment of forearm blood flow does provide an ideal method for assessing the effects of various drugs and endogenous peptides on the peripheral resistance vessels in vivo, without the need to conduct systemic studies. The technique is at its most powerful when used to compare responses within an individual during a single study, for example construction of dose-response curves before and after administration of an antagonist. Use of receptor antagonists has also extended our understanding of the physiological and pathological processes regulating blood flow in vivo. Clearly, almost 100 years after its first description, the place of venous occlusion plethysmography in physiology and pharmacology remains firmly established due to the robust validation of the technique and its great utility for addressing the important issues of the time.   

                                                                                                                                                       

  • Jacqueline Compton, Therese van Amelsvoort & Declan Murphy                     

    HRT and its effect on normal ageing of the brain and dementia                                  

    Br. J. Clin Pharm. Vol.52 (6), Dec. 2001, pg.647-653.                                            

                                                                                               

    There are significant gender differences in human brain disease. For example, females are significantly more likely to suffer from Alzheimer’s disease (AD) than .men (even after correcting for differences in life expectancy), and females on hormone replacement therapy (HRT) are significantly less likely to suffer from Alzheimer’s disease than women who do not take HRT. Thus the current literature supports the hypothesis that sex steroids can modulate brain ageing, and this provides a neurobiological explanation for the significantly higher prevalence of AD in females who do not take HRT, and may lead to new treatment approaches for age-related brain disease including AD.                                                

                                                                                                                                          

    The loss of brain tissue was greater in females than males in hippocampus and parietal lobes. A study measuring glucose metabolism and using positron emission tomography (PET) and 18F-2-fluoro-2-deoxy-D-glucose (FDG), showed that age-related decline in brain metabolism is asymmetrical in males, but symmetrical in females, and women have significant age-related decreases in hippocampal glucose metabolism, but men do not. Women are more likely to develop AD than men, and this cannot be explained solely by their longer life expectancy as women also have a greater disease severity and a higher age-adjusted prevalence of AD than men.                  

                                                                       

    Risk factors for AD include a positive family history, presence of Down‘s syndrome, head injury, female sex, hypothyroidism, depression and the possession of the apolipoprotein E4 gene. In contrast, education, smoking, and nonsteroidal anti-inflammatory agents may be protective factors.                 

                                    

    It is now becoming clear that oestrogens do more than regulate sexual and reproductive behaviour: in addition to their well  
    known effects on bones and heart, oestrogens have significant effects on brain structure and function.

                                                    

    Intracellular oestrogen receptors (ER) are widespread and are found in the cerebral cortex, midbrain, hippocampus, brain stem,   
    hypothalamus and pituitary gland. Novel actions of oestrogen have been described, for example, inducing neuronal                   
    depolarization and oestrogen’s antioxidant effects. Recently oestrogen has been shown to bind to cell membrane receptors,
    although they have not been well characterized in the brain, and use the same second messenger systems used by growth   factors and neurotransmitters.                                                      

                                                                                         

    Oestrogens regulate synaptogenesis in the CA1 area of the hippocampus in that they increase synaptic and dendritic spine    density in this area of the brain. The CA1 region of the hippocampus is crucial to memory function and spatial and declarative   learning and is adversely affected in AD. It has been shown that oestradiol levels are positively correlated with superior     performance on behavioural memory tasks in rats.                                     

                                                                                                        

    Recently, it has been demonstrated that oestrogen induces an increase in
    N-methyl-D-aspartate (NMDA) receptors in rat   hippocampal neurons, in the same region where an increase in dendritic spines is found.                    

                                                                                                          

    Oestrogens also directly affect neurochemical transmitter systems affected in normal ageing. AD, and other neuropsychiatric   disorders. For example, oestrogens can modulate the
    serotonergic, cholinergic and dopaminergic systems.           

                                                                                                                     

    In addition to direct effects on neurons, oestrogens also work with neurotrophins (such as nerve growth factor) to stimulate    indirectly nerve cell growth.                                                      

                                                                                                            

    Oestrogen also has a neuroprotective action against several toxins that boost production of free radicals; including glutamate 
    and b amyloid by enhancing the cleavage of Alzheimer amyloid precursor protein (Alzheimer APP) into soluble peptides. It has   been proposed that
    17b-oestradiol elevates protein kinase C activity, an effect possibly mediated by growth factors, and this   increases the activity of
    a-secretase, one of the enzymes that cleaves Alzheimer APP thus prevents deposition of the intact   amyloid peptide. It has been shown that oestrogen may also act as an antioxidant.                     

                                                       

    Compared with women, whose serum oestradiol levels drop at the menopause, men have higher brain oestradiol levels compared with age-matched postmenopausal women. This occurs as the testes continue to produce testosterone throughout life and testosterone is aromatized to estradiol in neuronal nuclei. This mechanism may also contribute to explaining the gender difference in neuropsychiatric disease.                

                                                                              

    Sex steroids are crucial to the development and ageing of hippocampus and parietal lobe – brain areas significantly affected in AD.                                   

                                                   

    Thus, there is recent evidence that oestrogen affects not only verbal but also nonverbal aspects of cognitive function in healthy postmenopausal women.                          

                                                                                   

    Epidemiological studies have reported that the prevalence of AD is significantly decreased in females on HRT, and that those women with AD who were taking HRT had a milder disease than those who were not.          

                                                                                  

    There is insufficient evidence that oestrogen benefits patients with established AD and its use as a sole agent for AD cannot be justified because of the risks associated with HRT, for example, breast cancer and thromboembolic disease.            

                                                                 

    Future studies may be able to determine if the route of administration of HRT or treating with combined HRT or androgens result in different therapeutic outcomes.                                         

                                                         

    Women are particularly at risk and the role of sex steroids and its effects on the brain has been a major focus in AD research. There is evidence that sex steroids modulate brain development and ageing and can affect cognitive function. With regard to AD, epidemiological, neuropsychological, and biological studies appear to support the hypothesis that oestrogens may be  
    implicated in its genesis and treatment. Currently, routine therapeutic use of oestrogens in women with AD is not justified but it may have a role in the prophylaxis of AD.                                                

                              

    In the future new oestrogens may be synthesized which have the neuroprotective characteristics of the currently available oestrogens, but which do not carry the same side-effects (e.g. risk of breast cancer and thromboembolic disease). The recent finding that certain subtypes of oestrogens may be more ‘neuroprotective’ than others may help us identify such a compound . In conclusion, besides the need for clinical trials in people with AD there is a continuing search for a more selective oestrogen preparation without the unwanted side-effects of current preparations.                              

                                                        

  • Johan D Lefrandt, Jorg Heitmann, Knut Sevre, et al                           

    Contrasting effects of verapamil and amlodipine on cardiovascular stress responses in hypertension.          

    Br.J.Clin.Pharm, vol.52, Dec.2001, pg.687-692                     

                                                 

    Aim of the study was to compare the effects of two long-acting calcium antagonists of different types on cardiovascular stress responses in hypertension.                      

                                                

    One hundred and forty-five patients with mild to moderate hypertension and a mean (± s.e. mean) age of 51 ± 0.9 years received for 8 weeks the phenylalkylamine verapamil sustained release (240mg) and the dihydropyridine amlodipine (5mg) in a double-blind cross-over design, both after 4 weeks of placebo. Blood pressure, heart rate and plasma noradrenaline were monitored during 3 min of sustained isometric handgrip and 2 min of cold
    pressor.             

                                                                           

    Verapamil is more effective in reducing blood pressure and rate-pressure product responses to stress compared with amlodipine. Although plasma noradrenaline is lower with verapamil at rest and after stress, the increase during stress is not different.      

                                                                           

  • Tejal N Mitchell and Josemir W Sander           

    Levetiracetam: A New Antiepileptic Drug for the Adjunctive Therapy of Chronic Epilepsy.                

    Drugs of Today 2001, 37(10): 665-673.            

                                                                               

    Levetiracetam is a new antiepileptic agent licensed for use as adjunctive therapy for partial seizures with or without secondary 
    generalization. Preclinical studies suggest a novel site of action and efficacy against a broad spectrum of seizures with a wide 
    margin of safety. Data from animal studies have suggested an antiepileptogenic effect of levetiracetam, but clinical trials are  
    required to assess this further. Three large double-blind, randomized trials have proven levetiracetam to be effective as an  
    adjunctive agent in patients with partial seizures, with promising preliminary results as monotherapy and in children. There is also clinical evidence for sustained efficacy with long-term therapy and no apparent development of tolerance. It has a favourable pharmacokinetic profile, with almost 100% oral bioavailability. It is well tolerated and has a low potential for interactions with other drugs. Treatment with levetiracetam can be initiated in a twice daily regimen at a therapeutic dose (500mg twice daily). Further information is required for high-risk groups which were excluded from the major trials and the potential teratogenic effects in  
    humans.                     
       

                    
                                              

                                                                                                                          

  • Seema Kumar and Vishnu Ji Ram (Medicinal Chemistry Divn., Central Drug Research Institute, Lucknow, India)

    Future Trends in the Treatment of Cognitive Disorders

    Drugs of Today, 2001, 37(10): 675-689



    Table 1 : Strategy of stroke treatment

                              


                                  














    Strategy 

    Stroke Treatment

    Unblocking arterial occlusion

    Fibrinolysins
    (tPA), interventional radiology techniques,anti-platelet agents (aspirin).

    Treatment of vasoconstriction 

    Ca2+ channel blockers
    (nimodipine, nicardipine), b-adrenoceptor blockers.

    Altering blood 
    rheological characteristics, reducing viscosity

    Hemodilution, decreasing fibrinogen activity
    (ancrod, fish oils), piracetam, pentoxifylline, sulodexide and heparin-induced extracorporeal
    (LDL)/fibrinogen precipitation (HELP).

    Increasing delivery of oxygen 

    Perfluorocarbons

    Reducing effects
    of excitatory neurotoxins 

    NMDA receptor-blocking agents
    (memantine hydrochloride)

    Reducing brain energy demands 

    Hypotherrnia, barbiturates

    Neurtralizing free radicals

    Vitamin C, Vitamin E, superoxide dismutase (SOD),
    Nicergoline.

    Protecting cell membranes

    GM1
    gangliosides, citicoline

    Reducing ischemic tissue lactate

    Reducing blood sugar production

    Neutralizing effects of brain
    opioid production.

    Blockade of opiate receptors
    (naloxone)

    Preventing
    or reducing brain edema.

    Mannitol,
    glycerol, diuretics 

     Table
    2 : Cholinergic  enhancement therapy for
    Alzheimer’s disease












    Compound

    Phase

    Dose

    Tacrine
    ( Cognex )

    Preregistered/launched

    40-160
    mg/day

    SDZ-ENZ-713
    ( Exelon )

    II/III

    3-9
    mg/day

    Eptastigmine

    II/III

    40-60
    mg/day

    Donepezil
    (E-2020,Aricept )

    III/preregistered/registered

    5-10
    mg/day

    Galanthamine 

    III/preregistered/launched

    20-45 mg/day

    Huperzine A

    III/preclinical

    0.15-0.25 mg
    t.i.d.

    Metrifonate

    II/III

    30-60 mg/day

    Velnacrine
    (HP-029)

    III

     150-225 mg/day

                        

  • Muscarinic agonists and antagonists         

                 


    Investigation on arecoline, bethanecol, pilocarpine, oxotremorine and RS-86 has been abandoned due to peripheral parasympathetic side effects in addition to low potency, a short duration of action and poor oral bioavailability. Xanomeline, an M1 agonist, has greater potential for combatting the cognitive and behavioral problems (psychosis, agitation, suspiciousness, verbal and physical aggression) associated with Alzheimer’s disease, and the newer compounds which are selective muscarinic agonists, are potential candidates for Alzheimer’s disease treatment.          

                            

    Cognitive therapy with M1 receptor agonists has a bright future since this receptor has been mostly localized to the hippocampus and necrotic regions of the brain, regions important in memory and learning. Preclinical evidence also indicates that M1 agonists have neuroprotective activity, with increased nonamyloidogenic processing of APP and tau
    dephosphorylation.                

     

  • Nicotinic agonists                    
      


                                                       

    A significant reduction in nicotinic receptors in the cortex and hippocampus has been implicated in demented illnesses such as Alzheimer’s disease. Stimulation of these receptors has been associated with enhanced memory, learning and attention capabilities in humans. Experimental evidence of protection against
    b-amyloid peptide toxicity in nicotinic receptor-stimulated cultured rat neutrons indicated that targeting of these receptors by nicotinic acetylcholine receptor agonists may lead to efficacy in treating cognitive decline associated with Alzheimer’s disease. Neuroprotective effects are generated upon nicotinic acetylcholine receptor activation mediated by the release of neurotrophic (NGF, BDNF,
    a-fibroblast) growth factors. However, despite these positive effects, the therapeutic use of compounds interacting with nicotinic acetylcholine receptors is associated with the negative attributes of nicotine, although some drugs acting on a3b4 and a4b2 subunits are under development for Alzheimer’s disease, including ABT_418, ABT-089, RJR-1734, RJR-2403 (metanicotine), ARR-17779, RJR-2557 and SIB-1553A, which are currently in phase I clinical trials for Alzheimer’s disease. Recently, a concerted effort has been made to discover highly subtype-selective agonists and antagonists.

                                                     
                         

    An imbalance in the release of various neurotransmitters is a general feature of cognitive disorders which needs to be addressed using different classes of site-specific drugs acting on their corresponding receptors as agonists or antagonists. Cholinergic therapy for the treatment of Alzheimer’s disease and mild cognitive decline is the most common modality, although the benefit seems to be limited in the case of Alzheimer’s disease. Cholinesterase inhibitors are the first generation of antidementia drugs to increase acetylcholine transmission across the synapse, but their efficient use is still not possible due to the inability to reliably detect the disease at an early stage. The use of acetylcholine-releasing agents has so far proved ineffective, only linopirdine reaching clinical trials. Nicotine’s effect on cognition appears to be more positive and attempts are being made to specifically stimulate nicotinic receptors so as to avoid the negative effects associated with nicotine. The dementia resulting from progressive neurodegeneration over the years is multifactorial, and thus the strategy most suitable should include therapeutic intervention along different lines in the form of combination therapy. Treatment designed to modulate factors such as free radical toxicity, restoring calcium homeostasis, decreasing inflammation, preventing cell membrane damage, excitotoxicity and neuronal apoptosis may also be effective.              
            

                                                           
                                                                                                                       

  • Gillian M Shenfield         

    Therapeutic drug monitoring beyond 2000              

    Br.J.Clin.Pharm, vol.52, suppl.1, 2000, pg.3S         

                                                  

    Pioneers of drug monitoring in the 1970s focused on adverse drug reactions and demonstrated quite clearly, that by constructing therapeutic ranges, the incidence of toxicity to drugs such as digoxin, phenytoin, lithium and theophylline could be reduced. It was also recognized that a number from a laboratory could not be interpreted in isolation but needed to be reviewed together with clinical details of the patient from whom the sample had been taken. Thus the indications for drug monitoring widened to include efficacy, compliance, interactions etc. This gave Clinical Pharmacologists a clearly identified role and, certainly in Australia, a number of Clinical Pharmacology departments were established in the late 1970s and early 1980s, with a primary role of performing drug monitoring. Whether part of an academic unit or directly answerable to a teaching hospital, these units not only performed routine services but conduced research in many areas where drug concentrations could easily be incorporated. This engendered a somewhat complacent attitude, when it was claimed that the value of TDM to a practicing physician was ‘an hypothesis in need of testing’. Although TDM is an attractive concept there was very little evidence that it improved overall patient outcome. It was argued that careful dosage adjustments based on clinical response and biochemical findings could be just as effective without closing the circuit by including the plasma drug concentration.

                                                

    In contrast more recent work has provided some evidence for the usefulness of drug assays in certain specific situations and Cridland has provided a number of ways in which drug monitoring services can be assessed as to their usefulness and cost effectiveness. A meta-analysis of studies on TDM, albeit of a limited number of drugs, showed that TDM does appear to be beneficial for patients taking theophylline or digoxin. Furthermore, the service reduced the proportion of inappropriately collected samples. 

                                                            

    Besides the long established areas of anticonvulsants, antiarrhythmics and antibiotics, there have been some interesting and exciting developments in the areas of immunosuppressants, cytotoxic drugs and psychotropic drugs. All too often the pharmacodynamic aspects of interpretation are omitted from discussions on
    TDM.           
           

                                         

  • Annette S Gross

    Best Practice in therapeutic drug monitoring

    Br.J.Clin.Pharm, Suppl.1, 2000, pg.5S.

                                           

    Table 1 : Reasons for requesting drug concentration measurements.  


    Toxicity suspected 
    –  toxic concentration ?

    Lack of response    –  subtherapeutic concentrations ?

    Assessment of compliance with medication regimen

    Assess therapy following a change in dosage regimen

    Change in clinical state of the patient

    Potential drug interaction due to change in comedications

    Manifestations of toxicity and disease state are similar.


    Table 2 :
    The information required to interpret a drug concentration.


    The information required to interpret a drug concentration includes:

          time blood sample taken

          time dose given

          dosage regimen (dose, duration, dosage form)

          patient demographics (sex, age, concomitant disease, ethnicity etc.)

          comedications

          indication for monitoring

          pharmacokinetics and therapeutic range of the drug.


     

  • Evan J Begg, Murray L Barclay & Carl M.J. Kirkpatrick         


    The therapeutic monitoring of antimicrobial agents 
             

    Br.J.Clin.Pharm, vol.52, 2001, pg.35S-43S.         

                       

    The aim of the study was to review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents.

                   

    There is a strong historical case for monitoring aminoglycosides.               

                        

    The approach to monitoring aminoglycosides is being redefined in the light of once daily dosing. It may be that less stringent monitoring is required in some circumstances but toxicity, especially ototoxicity, remains a problem with these drugs. Monitoring to avoid high AUCs (areas under the concentration-time curve) is recommended. The ideal method for monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is sometimes monitored to ensure efficacy while flucytosine may be monitored to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.         

                                                

  • Gwen L Zornberg, Hershel Jick

    Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study.

    The Lancet, vol.356; Oct.7, 2000: 1219-23    

                                       

    Aim of the study was to assess the risk of venous thromboembolism in users of conventional antipsychotic drugs who had been diagnosed with first-time, idiopathic venous
    thromboembolism.        

                                 

    Current exposure to conventional antipsychotic drugs was associated with a significantly increased risk of idiopathic venous thromboembolism compared with non-use. Although, authors found no difference between phenothiazines, thioxanthenes, or other conventional antipsychotic drugs, low potency antipsychotic drugs such as chlorpromazine and thioridazine were more strongly associated with venous thromboembolism than were high potency antipsychotic drugs such as haloperidol. The risk for venous thrombosis was highest during the first few months of conventional antipsychotic drug use.       

                                    

    Interpretation of this study is that current exposure to conventional antipsychotic drugs significantly increases the risk of idiopathic venous thromboembolism in men and women younger than 60 years of age.       

                         

  • Victor E Tapson

    Commentary – Risk of venous thromboembolism with use of antipsychotic agents.

    The Lancet, vol.356, Oct.7, 2000, pg.1206

                             

    The relation between antipsychotic medicines and venous thromboembolism (VTE) was first suggested about four decades ago, only a few years after the introduction of phenothiazines and reserpine. Despite these early descriptions and subsequent reports, the evidence for a true link has not yet been deemed sufficient for inclusion in lists of risk factors in standard textbooks or review articles on venous throboembolism. Many of the early studies lacked controls and convincing evidence of the absence of concomitant thrombogenic risk factors.           

                                          

    The case-control analysis by Gwen Zornberg and Hershel Jick reported in the Lancet suggests that this association should be re-examined.         

                           

    Although this clinical study suffers from the usual limitations of a case-control design, the cohort was large (nearly 30000) and the observation period was long (mean 6.8 years). Also, the diagnosis of VTE was confirmed by objective tests, and patients with certain disease states that have not been clearly identified as risk factors (e.g. diabetes, cystic fibrosis, disorders due to alcohol and substance misuse) were also excluded, but this point would probably have affected both cases and controls equally. The attempt to exclude patients with other risk factors and to identify more clearly use of antipsychotic agents as a risk factor is important. However, it is quite possible that, in the presence of additional risk factors such as previous VTE, obesity, or cancer, antipsychotic agents may further enhance the risk of
    thromboembolism.              

                                                                              

  • Francois Nosten               

    Commentary – Prophylactic effect of Malarone against malaria: all good news?           

    Lancet, vol.356, Dec.2, 2000, pg.1864.          

                           

    Birthe Hogh colleagues report the results of a large, detailed, and well-conducted trial of Malarone (Glaxo-Wellcome) for the prophylaxis of malaria in travellers. This fixed combination of atovaquone and proguanil was a safe and effective prophylactic agent in travellers. To people trying to combat increasing drug resistance in Plasmodium falciparum, this finding seems like good news – or is it?  

                              

    The main component of the combination (atovaquone) belongs to a family of anti-infective compounds, the hydroxynaphthoquinones, which has been known for over 50 years to be active against P.falciparum. The first studies in human beings were disappointing, and the prototypes of this group of drugs were not studied further.      

                                

    Meanwhile, when it became clear that P.facliparum was developing resistance to other classes of drugs at an alarming pace, the antimalarial property of atovaquone was re-explored.                  

                                        

    Mass chemoprophylaxis is not recommended currently (except in pregnancy) for fear of encouraging resistance, and the drug is far too expensive for poor tropical countries.                             

                                      

    For the treatment of P.falciparum infections, Malarone (if affordable) could prove very valuable in areas where the parasite is becoming resistant to all other drugs.               

                                     

    By inhibiting mitochondrial electron transport in the parasite, atovaquone reduces pyrimidine synthesis and causes collapse of the mitochondrial membrane potential. Despite the combination with proguanil, atovaquone is clearly vulnerable to resistance, as shown in clinical studies. New, safe, and the affordable antimalarial drugs are unlikely to be developed in the near future, so malarone needs to be protected. Protection can be achieved by judicious use and by combining Malarone with an artemisinin derivative. Thus, the finding that Malarone is safe and effective in protecting wealthy travellers is good news, but not necessarily for the millions living (and dying) with malaria in the tropics.                                        

                                 

  • Kathryn Senior       

    Neuropeptide may shift rheumatoid arthritis into remission.              

    Lancet, No.357, May 5, 2001, pg.1418        

                                                       

    A preclinical study suggests that vasoactive intestinal peptide (VIP) may reduce some of the disabling joint problems that can develop as a result of rheumatoid arthritis (RA).
    “VIP appears to have therapeutic potential for RA and other chronic inflammatory disease and Th1-dependent autoimmune disorders such as Crohn’s disease, multiple sclerosis, and autoimmune
    diabetes”, says lead author Mario Delgado.          

                                                                                  

    Delgado and colleagues chose to study the effects of VIP on the Th1/Th2 systems in collagen-induced arthritis (CIA), a murine experimental model of human RA. RA-like symptoms were induced by immunization of mice with type II collagen. After two immunisations, but before symptoms appeared, VIP was administered in different doses, either as a single injection or as multiple injections given every day, or every 2 days, for a period of 2 weeks. Mice treated with VIP showed delayed onset, lower incidence, or decreased severity of induced arthritis-effects that were dose dependent. Daily or every-other-day dosage offered the best protection against disease, but one single dose had a significant impact on the development of arthritis. Symptoms in the mice were slow to develop after VIP treatment ceased, indicating that short spells of VIP administration may be enough for long-term disease control.    

                                               

    Further detailed experiments explored the exact nature of the action of VIP on the murine immune system and confirmed that VIP was acting through a specific inhibitory effect of the Th1 response.         

                                           

    The future prospects of VIP hinge on imminent toxicology studies, but Delgado is still optimistic.           

                                    
                                                  

  • Sheila A. Doggrell (Department of Physiology and Pharmacology, The University of Queensland, Brisbane, Queensland, Australia)  

    Targets to Trials in Diabetic Complications    

    Drugs of Today, Vol. 37(11), November 2001, Pg. 739-748  

                  

    Diabetes is now the leading cause of end-stage renal disease, blindness, lower-extremity amputations and impotence. 

                            
       

    Targets with potential for therapeutic intervention in diabetic complications

                               
             


    Genetic studies: Aldose reductase inhibitors   

                              

    A candidate gene near the transcription site of the aldose reductase gene has been identified. Aldose reductase inhibitors have not been shown to be beneficial in diabetic complications. A possible explanation for this is that aldose reductase is only one pathway that leads to stimulation of MAPKs (mitogen-activated protein kinases), which may be common mediators of diabetic complications and thus inhibition of aldose reductase alone is not effective.      

                                   

    MAPKs (Mitogen-activated protein kinases)        

                                           

    Professor David Tomlinson (University of Manchester, U. K.) presented evidence that the MAPKs trigger all of the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy. Professor Tomlinson suggested that the damaging effects of glucose, regardless of pathway (sorbitol, nonenzymatic glycation of proteins, oxidative stress) were finally mediated by the MAPKs (ERK, JNK and p38).         

                                               
       

    To support his hypothesis Professor Tomlinson provided experimental evidence using selective inhibitors of p38 (SB202190 and SB238063) and ERK (U0126) but stated that selective antagonists of JNK were not presently available. Some suggested that the MAPKs are far too widespread and involved in too many functions to be therapeutic without serious side effects and that signaling upstream of MAPKs would make more selective targets.    

                                  
                                 

    Others suggested that in low doses MAPKs may have some therapeutic potential in diabetic complications. 

                           

    PKC (Protein kinase C)

                                       
      

    PKC is upstream in the MAP-kinase pathway. Inhibition of glomerular PKC activity by a specific inhibitor of the
    ß isoform (LY333531) has been shown to prevent diabetes-related vascular dysfunction and increases in albuminuria in an animal model (12).

                                     

    Activation of a specific isoform of PKC may be involved in retinopathy and this isoform is a potential target. The identification of a specific isoform of PKC associated with retinopathy increases the likelihood of having beneficial effects in retinopathy without excessive side effects.     

                    
                                  

    TGF-ß (Transforming growth factor-ß)       

                              
            

    The important role of TGF-ß in mesangial and macro- and microvascular dysfunction was considered by Professor Kumar Sharma (Thomas Jefferson University, Philadelphia, U.S.A.). In an animal model of type II diabetes, the diabetic glomerular hypertrophy could be prevented with
    anti-TGF-ß antibodies. 

                                                      
     

    The reported beneficial effects of the ACE inhibitor captopril and the
    AT1-receptor antagonist losartan in diabetic kidney disease may be partly due to inhibiting angiotensin II stimulation of
    TGF-ß. As TGF-ß has beneficial effects at other sites, it seems an unlikely target for therapeutic intervention in diabetic complications, as these beneficial effects may also be inhibited. 

                                                  

    However, if there is excessive production of TGF-ß in diabetic complications, it may be possible to reduce the excessive effects without modifying the beneficial functions. 

                                                 
     

    Another possible target is the interrupting of various downstream effects of
    TGF-ß. Thus, USF-1 (upstream stimulatory factor-1), GRE (glucose response element), IP3R (the inositol 1,4,5-triphosphate receptor) may be important therapeutic targets to combat diabetic complications.   

             
                       

    Nitric oxide/tetrahydrobiopterin  

                                  
           

    Diabetics have reduced vasodilatation and inadequate angiogenesis. These disturbed vascular responses appear to be the result of impaired synthesis of nitric oxide (NO). The roles of NO and tetrahydrobiopterin, an essential cofactor for NO synthase, in vascular dysfunction in diabetes were discussed by Dr. Cynthia Meininger. 

                                        

    There are several possible ways to improve the endothelial dysfunction in diabetes. Tetrahydrobiopterin supplements could be used. The nitrates and the NO-donor drugs also have the potential to overcome this dysfunction. 

                                  

    Antioxidants/superoxide dismutase

                               

    Oxidative stress with superoxide production also contributes to the vascular dysfunction in diabetes. However, when vitamin E, an antioxidant, was used in the HOPE study it was ineffective.   

             
                                      

    They assessed whether vitamin E supplementation for three months would improve conduit and resistance vessel vasodilator function in 41 subjects with type I diabetes, in a double-blind, placebo-controlled, randomized study. 

                          
                

    Vitamin E improved endothelial function assessed by brachial flow-mediated dilatation and by intraarterial acetylcholine. This improvement was associated with a decrease in LDL cholesterol oxidation.   

                            
         

    Wound healing: VEGF  

                               
     

    Delayed wound healing, or an inability to carry out tissue repair processes, is a major complication of diabetes leading to an increased incidence of chronic wounds such as leg ulcers.   

                          
                    

    There are a number of factors involved in the healing impairment in diabetes. These include the acute effects of hyperglycemia, the long-term effects of advanced glycosylation of extracellular matrix proteins and changes in expression levels and availability of growth factors or cytokines.   

                      
                 

    VEGF is very important in angiogenesis but it is reduced in diabetic wounds. VEGF is detrimental in retinopathy. Thus, the local administration of VEGF to diabetic wounds will need careful testing of whether it is beneficial to the wounds without being detrimental to the eye.   

                    
                               

    Inhibition of advanced glycation endproducts (AGE) formation.  

                                            

    ACE inhibition with ramipril decreased AGE levels in experimental diabetes and this effect may have contributed to the benefit of ramipril in diabetic patients in the HOPE trial.  

                            

    Connective tissue growth factor (CTGF)   

                                      

    CTGF is a potent inducer of extracellular matrix and its gene expression is increased in rodent models of diabetes. AGE induces CTGF through a non-PKC-dependent pathway, and AGE and CTGF induce fibronectin through a PKC-dependent mechanism. 

                            

    Thus, CTGF may be a new target for consideration in the treatment of complications of diabetes.   

                                        

    Glucose transformer isoform 1 (GLUT-1) transporter   

                                     

    As the GLUT-1 transporter is overexpressed in mesangial cells subject to mechanical stress, this is a potential site for pharmacological intervention in diabetic complications.   

             
                        

    Nephrin  

                 
                          

    Nephrin is a cytoskeletal protein that localizes to the slit pore of podocytes. In some proteinuric models, deficiencies in nephrin have been associated with increases in albuminuria. Nephrin is a potential target for pharmacological intervention in diabetes associated with hypertension. 

                        
      

    Mineralization inhibitors

                               
              

    Calcification of the media of peripheral arteries is referred to as Monckeberg’s sclerosis and occurs commonly in diabetic individuals, often in association with neuropathy and uremia. Its presence is an independent predictor of cardiovascular events and is associated with trophic foot ulceration and peripheral artery occlusive disease. 

                      
                 

    Vascular calcification is an actively regulated process. This process results in the deposition of hydroxyapatite, the mineral found in bone, the vessel wall and ultimately leads to osteogenic metaplasia and the formation of bone trabeculae. 

                           
              

    Dr. Shanahan suggested that factors that can effect the rate of vascular smooth muscle apoptosis or that can effect the differentiation of the smooth muscle cells into an osteo/chondrocryptic phenotype could potentially regulate the rate of calcification in vessels. 

                            

    Mineralization inhibitors, such as etidronate, which slow the formation and dissolution of hydroxyapatite crystals have not been tested to date on vascular calcification. 

                      
               

    The glitazones

                
                                  

    Mechanisms: Potential for treatment of restenosis

                         

    The thiazolidinedione glitazones are a recently introduced group of drugs for the treatment of diabetes that increase insulin sensitivity and are more powerful in doing this than metformin. 

                             

    The glitazones stimulate peroxisome proliferator-activated receptor
    (PPAR)-ß in the adipocytes and muscle to decrease free fatty acids. The glitazones also act on muscle to increase sensitivity to insulin. As the glitazones have only recently been introduced, intriguing questions remain as to their long-term effects. For instance, will they reduce cardiovascular events or mortality?

                     
                                  

    Glitazones and other PPAR-Y ligands may have therapeutic potential in the treatment of restenosis. Although the atherogenic effect, if any, of insulin is small, hyperinsulinemia is a major culprit in the development of restenosis following coronary artery angioplasty or stenting. 

                
                                 

    Insulin also potentiates proliferative signals or more potent mitogens such as PDGF, bFGF, and EGF. Rosiglitazone, troglitazone (which also acts as an antioxidant) and pioglitazone stimulate
    PPAR-Y to inhibit insulin-mediated ERK (a mitogen activated protein kinase) -dependent smooth muscle proliferation.        

                             
         

    Thus, the glitazones have clinical potential in the treatment of restenosis and atherosclerosis. 

                                 

    Vasopeptidase inhibitors

                                 

    Most advanced diabetics need at least two or more drugs (including renin-angiotensin system inhibitors) to achieve adequate blood pressure control. 

                           
        

    Vasopeptidase inhibitors are simultaneous inhibitors of ACE and the neutral endopeptidase (NEP), which is the major enzymatic pathway for the degradation of atrial natriuretic peptide (ANP). NEP is widely distributed in the body and shows a broad substrate specificity including the degradation of bradykinin, endothelin and substance P as the conversion of angiotensin I into angiotensin III.

                                  
              

    Vasopeptidase inhibitors produced a dose-dependent reduction in blood pressure that was greater than that with equivalent doses of ACE inhibitors. Treatment with vasopeptidase inhibitors also caused a reduction in cardiac hypertrophy, which was over and above that observed due to blood pressure reduction alone. 

                                    

    This suggests that the vasopeptidase inhibitors have a specific antitrophic effect, possibly by reducing angiotensin II and increasing ANP. In diabetic SHR, vasopeptidase inhibitors were effective antihypertensive agents that reduced heart weight and albuminuria, increased natriuresis and did not have adverse effects on renal function.   

                                    

    In the 5/6 nephrectomized rat model of chronic renal failure, which shares some hemodynamic similarities with diabetic nephropathy, treatment for 12 weeks with a vasopeptidase inhibitor reduced blood pressure, proteinuria and improved renal structural changes, including glomerulosclerosis and tubulointerstitial injury. Following these experimental studies, the vasopeptidase inhibitor should be tested in human diabetes and renal failure.            

                                         

    Triple inhibitors:            

                              

    These are drugs that inhibit the conversion of proendothelin to endothelin by endothelin-converting enzyme in addition to inhibiting ACE and NEP. The triple inhibitors are presently being tested in animal models of diabetes.         

                                      

    Clinical trials with ACE inhibitors and vitamin E             

                                         

    The Heart Outcomes Prevention Evaluation (HOPE) study and Microalbuminuria, Cardiovascular and Renal Outcomes (MICRO-HOPE) substudy         

                                 

    In the MICRO-HOPE substudy, the 3577 subjects included in the HOPE study with diabetes were analyzed. In diabetics, ramipril lowered the risk of myocardial infarction, stroke, revascularization and overt nephropathy.        

                  

  • Markus Muller 

    Science, medicine and the future – Microdialysis

    BMJ, VOL.324, March 9, 2002, pg.588

      

    Monitoring tissue chemistry in patients by microdialysis is likely to become routine in clinical paractice.

      

    Many diagnostic and therapeutic decisions in medical practice are based on measuring blood concentration of endogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Assessing tissue chemistry should theoretically provide more accurate data, and this can now be achieved relatively cheaply and minimally invasively with microdialysis.

        

    Principles of microdialysis

    In vivo microdialysis measures the chemical composition of the interstitial tissue fluid- that is, the fluid to which cells and other target structures are directly exposed. In contrast to imaging techniques or biosensors, which serve as detecting tools, microdialysis is a sampling tool and needs to be linked to an analytical device. Depending on the availability of an appropriate analytical assay, virtually every soluble molecule in the interstitial space fluid can be measured by microdialysis. In recent years, the use of microdialysis has moved from preclinical evaluation and validation to clinical application, reflected by a considerable growth in the literature.

       

    The concept of microdialysis goes back to the early 1960s, when push-pull cannulas, dialysis sacs, and dialytrodes were inserted into animal tissues to study tissue biochemistry directly.

      

    Summary points

    Microdialysis enables the in vivo measurement of tissue chemistry in humans and is feasible in virtually every human organ.

       

    It is currently being used to monitor brain ischaemia and metabolic control.

    The technique is set to become a standard tool in drug monitoring and development.

    In the future “bedside” microdialysis will allow monitoring of tissue metabolism in a wide range of diseases.



    Current clinical research applications of microdialysis

    Elucidating the chemical basis for initiation of seizures (such as pre-epileptic increase in glutamate and a consecutive surge in
    γ-aminobutyric acid).

      

    Studying neurochemical patterns in defined brain areas (such as increased dopamine release in human amygdala during performance of cognitive tasks).

       

    Studying local physiology of adipose tissue, muscle, and skin.

      

    Measuring peptides and metabolites at site of action or release and describing paracrine regulations in select organs or tissues such as the ovary and subcutaneous fat.

        

    Administering drug locally by microdialysis without inducing systemic side effects and simultaneously measuring the corresponding tissue response, such as catecholamine induced lipolysis. 

     

  • Lap Ho and Giulio Maria Pasinetti

    The Potential of Selective Cox-2 Inhibitors in Inflammatory and Other Diseases

    Drugs of Today 2001, 37(3), 181-185

        


    There are two known COX isoforms with distinct physiological functions, COX-1 and COX-2. COX-1 is a constitutively expressed protein found in most tissues. In the gastric mucosa, COX-1 is involved in the production of cytoprotective prostacyclin. In platelets, COX-1 is required for the generation of thromboxane A2, which promotes platelet aggregation leading to thrombus formation. In contrast to COX-1, COX-2 is strongly inducible by a variety of mitogens such as cytokines and growth factors, and plays a key role in the production of inflammatory prostaglandins.

        


    Efforts to identify new anti-inflammatory compounds which are less damaging to the stomach led to the marketing of meloxicam, etodolac and nimesulide, all since recognized to be selective COX-2 inhibitors. More recent generations of drug such as rofecoxib and celecoxib, which are specifically designed to be selective COX-2 inhibitors, are available on the market. The availability of selective COX-2 inhibitors is expected to improve therapeutic applications in traditional inflammatory diseases, as well as in cancer and neurodegenerative disorders.

       


    Development of assays to predict selectivity of NSAIDs for COX-1or COX-2 is critical to the development of the next generation NSAIDs. A key consideration is that these assays should be based on human COX systems.



    Caution Regarding COX-2 Inhibitors

    One of the concerns regarding therapeutics of COX-2 inhibition is its potential effect on renal function.



    COX-2 plays a pivotal role in the regulation of extracellular fluid volume and COX-2 inhibition could impede normal renal function. This is of particular concern in the face of salt depletion in man or in diseases characterized by abnormalities of salt and water homeostasis such as congestive heart failure or hepatic cirrhosis and ascites. Another area of concern regarding COX-2 inhibition and renal function is that COX-2 is critical for nephron differentiation and maturation.



    Selective COX-2 inhibition may also have undesirable effects on the cardiovascular system. COX-2 is expressed in both normal and inflamed vasculature. The suppression of prostacyclin and its cardiovascular implications needs to be considered in clinical trials of COX-2 inhibitors.



    Evidence indicates that COX-2 has a role in the healing of gastric ulcer. The mechanisms that NSAIDs may interfere with in ulcer healing might be similar to those that induce apoptosis in malignant cells. Therefore, utility of COX-2 inhibitors among high-risk patients, e.g. colitic patients, requires careful consideration and monitoring.



    Selective COX-2 inhibition in Cancer.

    COX-2 has been found to be upregulated in a variety of cancers, including colon, skin, lung, breast, bladder and prostate cancers. Consistent with the current view that COX-2 promotes tumor growth and development, selective COX-2 inhibitors or disruption of COX-2 gene suppress carcinogenic phenotype of transformed cells in vitro and tumor formation in animal models in vivo.

        


    The apparent efficacy of NSAIDs in treating cancer may involve the induction of apoptotic mechanisms in cancer cells. NSAIDs induce apoptosis in vitro in a wide variety of neoplastic cells in vitro as well as colorectal tumors in vivo. NSAID induced apoptosis in some cell systems may be independent of interaction with COX-1 or COX-2. This is supported by evidence that relatively high concentrations of NSAIDs are required to induce apoptosis, and that NSAIDs can induce apoptosis in cells deficient in both COX isoforms.

       


    Ongoing investigations will clarify whether COX-2 has a prognostic value in malignant diseases and which type of tumors will benefit from therapy with selective COX-2 drugs.

        


    Selective COX-2 Inhibition in Neurodegenerative Disorders

    In the brain, COX-2 is overexpressed in response to ischemia, trauma, seizures and neurodegeneration such as in Alzheimer’s Disease (AD).

       


    It is likely that the neuroprotective mechanisms of action of NSAIDs in AD are mediated in part by inhibition of COX-2 activity in the brain. This potential neuroprotective role has generally been attributed to suppression of deleterious inflammatory activities.

       


    Place of Selective COX-2 Inhibitors in Therapy.

    NSAIDs induce damage to the gastrointestinal tract and impair ulcer healing. Selective COX-2 inhibitors appear to cause no more gastrointestinal problems than placebo. The current consensus is that since standard NSAIDs are nonspecific for both COX isoforms, the side effects of selective COX-2 inhibitors should be no different and no greater in comparison to standard NSAIDs when equivalent doses are used. The advent of selective COX-2 inhibitors that spare gastrointestinal prostaglandin synthesis is a major conceptual and therapeutic advance. Outstanding questions are whether the selective COX-2 inhibitors may inhibit gastrointestinal tract healing or provoke the relapse of gastrointestinal ulceration or associated colitis.

                   

  • Scott
    Gottlieb

    News : b Blockers Improve Bypass Surgery Survival
    Rates


    BMJ, 11 May, 02, Vol.324, pg.1118

      

    Patients who take b blockers before coronary artery
    bypass surgery can increase their odds of surviving, a
    new study says.

     

    The study found that 2.8% of patients who took b
    blockers before surgery died within a month, compared
    with 3.4% of patients who did not take the drugs.

      

  • David
    N. Herndon, David W. Hart, et al

    Reversal of Catabolism by Beta-Blockade After
    Severe Burns


    New Eng J Med. Vol.345, Oct.25, 2001, pg.1223-9

      

    Catecholamine-mediated hypermetabolic response to
    severe burns causes increased energy expenditure and
    muscle-protein catabolism. Authors hypothesized that
    blockade of b-adrenergic stimulation with propranolol
    would increase resting energy expenditure and muscle
    catabolism in patients with severe burns.

      

    Twenty-five children with acute and severe burns (more
    than 40 percent of total body-surface area) were
    studied in a randomized trial. Thirteen received oral
    propranolol for at least two weeks, and 12 served as
    untreated controls. The dose of propranolol was
    adjusted to decrease the resting heart rate by 20
    percent from each patient’s base-line value.

      

    Resting energy expenditure and skeletal-muscle protein
    kinetics were measured before and after two weeks of
    beta-blockade (or no therapy, in controls). Body
    composition was measured serially throughout
    hospitalization.

      

    The net muscle-protein balance increased by 82 percent
    over base-line values in the propranolol group.

     

    In children with burns, treatment with propranolol
    during hospitalization attenuates hypermetabolism and
    reverses muscle-protein catabolism.

      

  • Paul S. Frenette

    Locking a Leukocyte Integrin with Statins

    New Eng J Med. Vol.345, Nov. 8, 2001, pg.1419-21

      

    Because lipid intermediates of cholesterol synthesis (isoprenoids) allow the attachment to the cell membrane of signaling proteins involved in various functions, statins have other biological effects. They can stimulate bone formation, alter the function of endothelial cells, induce apoptosis of smooth-muscle cells, inhibit the growth of tumor cells, and reduce the inflammatory response.

      

    Recently, Weitz-Schmidt and coworkers found that statins also influence the inflammatory response by directly inhibiting the main b2 intergrin, a1b2 integrin. A region in the extracellular domain of a1b2 integrin referred to as the inserted, or I, domain mediates the binding of the protein to its main ligand, intercellular adhesion molecule 1 (ICAM-1).

      

    The function of a1b2 integrin varies depending on the leukocyte subgroup on which it is expressed. For example, a1b2 integrin on T cells participates in the immune response when it and the T-cell receptor are simultaneously engaged, whereas a1b2 integrin on myeloid cells promotes diapedesis of leukocytes across the endothelium.

      

    Kallen et al. found that one of the statins (lovastatin) blocks the interaction between a1b2 integrin and ICAM-1 in vitro. Weitz-Schmidt et al. found that other statins, including simvastatin and mevastatin, but not pravastatin, also inhibit the interaction between a1b2 integrin and ICAM-1.

     

    The inhibition of a1b2 integrin by statins was specific. Guided by the crystal structure of the complex formed by a1b2 integrin and lovastatin, Weitz-Schmidt et al. designed a compound, LFA703, that strongly inhibits a1b2 integrin but does not affect the activity of HMG-CoA reductase. LFA730 profoundly inhibits the proliferation of T cells mediated by a1b2 integrin, and oral administration of LFA703 reduces the recruitment of polymorphonuclear neutrophils into chemically inflamed peritoneum in mice.

      

    These findings have important clinical implications. Since patients receiving statin drugs are at risk for arteriosclerotic lesions characterized by the infiltration of monocytes and T cells, blockade of a1b2 integrin by statins could influence the progression of arteriosclerosis. It is important to remember, however, that although statins block HMG-CoA reductase at very low concentrations (in the nanomolar range), the inhibition of the interaction between a1b2 integrin and ICAM-1 requires much higher concentrations of statins (in the micromolar range), which may not be achieved with the use of the standard doses of approved statin drugs.

      

    Statins that do not block the function of a1b2 integrin can have clinically significant antiinflammatory effects. For example, pravastatin improves survival and lowers the incidence of acute rejection after heart transplantation. Two recent studies have shown that both pravastatin and lovastatin reduce serum concentrations of C-reactive protein, a marker of inflammation, by approximately 15 percent.

      

    The statin-like inhibitor synthesized by Weitz-Schmidt et al. is the first in a new class of synthetic inhibitors that can profoundly alter the function of b2 integrins in vivo. Given the dual function of a1b2 integrin, such agents may prove useful in preventing and treating disorders involving both myeloid and T cells, such as graft-versus-host disease and a number of autoimmune diseases.

      

    A greater understanding of the biologic functions of integrins and a growing knowledge of the relation between the structure and function of these proteins should allow the investigators to identify clinical situations in which synthetic integrin antagonists could have a profound effect.

        

  • Bengt I. Eriksson, Kenneth A. Bauer, et al

    Fondaparinux Compared with Enoxaparin for the Prevention of Venous Thromboembolism After Hip-Fracture Surgery

    New Eng J Med. Vol.345, Nov. 1, 2001, pg.1298-1304

      

    Surgery for hip fracture carries a high risk of venous thromboembolism, despite the use of current thromboprophylactic treatments. Fondaparinux, a synthetic pentasaccharide, is a new antithrombotic agent that may reduce this risk.

      

    Fondaparinux is a new synthetic pentasaccharide that causes selective inhibition of activated factor X (factor Xa). A recent study of patients undergoing major orthopedic procedures suggested that a once-daily subcutaneous injection of fondaparinux reduces the risk of venous thromboembolism more than does low-molecular-weight heparin.

      

    The authors conducted a multicenter, randomized, double-blind trial to compare two types of thromboprophylaxis after hip-fracture surgery: a once-daily subcutaneous injection of fondaparinux, initiated postoperatively, and a once-daily subcutaneous injection of enoxaparin, initiated preoperatively.

      

    In patients undergoing surgery for hip fracture, fondaparinux was more effective than enoxaparin in preventing venous
    thromboembolism.

        

BACK

     



  
 



 

     

Speciality Spotlight

 

           
Clinical Pharmacology
       

     

  • Ian M. Thompson
    Pharmacologic Agents in Complementary Medicine in Prostatic Disease
    Drugs of Today Vol.37 (6), June 2001, Pg. 427-433 
           
    Summary : Use of alternative medicine has increased considerably in the last 10 years. The very high frequency of urologic diseases such as benign prostatic hyperplasia and prostate cancer makes these diseases natural targets of alternative medicine.
          
    As many as 80% of men at risk of prostate cancer are using alternative therapies. In the majority of cases, physicians were unaware of the fact that their patients were using these treatments.
          
    Treatment of Prostate Cancer :
         
    1) Vitamin E – Main function is its intracellular anti-oxidant activity. In preclinical models, vitamin E has been demonstrated to reduce growth rate of human LNCaP prostate cancer model.
            
    Higher vitamin E levels have been suggested in epidemiologic studies to be associated with lower cancer risk. In a clinical trial it was found that prostate cancer rates were 1/3rd lower in men who had been randomized to receive vitamin E. Effect of vitamin E supplementation was seen almost at the inception of the study and persisted for its duration.
            
    2) Selenium – It is a naturally occurring micronutrient. Humans receive it from ingestion of both plants and animals. A dramatic almost 2/3rds reduction in incidence of prostate cancer was observed among men receiving selenium. A large study is planned to determine relationship of this agent and prostate cancer risk.
            
    3) Soy and Isoflavenoids – Soy is a major source of a group of weak estrogens known as isoflavenoids. One of these agents, genistein may be the most abundant and clinically significant. The exact mode of action of these isoflavenoids is not known.
           
    Besides estrogenic effect, inhibition of epidermal growth factor receptor tyrosine kinase and inhibition of angiogenesis may be involved. Several prostate cancer cell lines have been found to have growth inhibition when exposed to genistein.
           
    4) Dietary Fat – It has been associated with prostate cancer consistently. The precise cause is not understood but may be related to total caloric intake. HMG-CoA reductase inhibitors which block synthesis of cholesterol have a small effect. These agents have been reported to induce apoptosis in prostate cancer cells as well as in stromal cells.

    5) PC-SPES – It has unquestionable activity against existing prostate cancer. It is a mixture of 8 herbs-chrysanthemum, isatis licorice, Ganoderma lucidum, Panax pseudo-ginseng, Rabdosia rubescens, saw palmetto and skullcap.

    6) COX Inhibitors – Highest concentrations of COX-1 and COX-2 are found within the prostate. A significant reduction of prostate cancer risk among men taking NSAIDS or aspirin has been demonstrated.
           
    Treatment of Benign Prostatic Hyperplasia – 
            
    (1) Saw palmetto (2) Pygeum africanum (3) Cernilton (4) b-Sitosterol have been discussed.
            
    There is compelling evidence that a variety of the above therapies for both prostate cancer (prevention and treatment) and lower urinary tract symptoms (BPH) may be effective. Ongoing clinical trials will address to a greater degree of precision, the effect and optimal use of these agents.
          

  • Gene-Jack Wang, Nora D. Volkow, et al
    Brain Dopamine and Obesity
    Lancet Vol.357, February 3, 2001, Pg. 354-357
           
    Summary : The cerebral mechanisms underlying the behaviours that lead to pathological overeating and obesity are poorly understood. Dopamine, a neurotransmitter that modulates rewarding properties of food, is likely to be involved. To test the hypothesis that obese individuals have abnormalities in brain dopamine activity, authors measured the availability of dopamine D2 receptors in brain. 
          
    Brain dopamine D2 receptor availability was measured with positron emission tomography [PET] and [C-11]raclopride (a radioligand for the dopamine D2 receptor). Striatal dopamine D2 receptor availability was significantly lower in the 10 obese individuals than in controls. The interpretation was that the availability of dopamine D2 receptor was decreased in obese individuals in proportion to their BMI (body-mass index). 
           
    Dopamine modulates motivation and reward circuits and hence dopamine deficiency in obese individuals may perpetuate pathological eating as a means to compensate for decreased activation of these circuits. Strategies aimed at improving dopamine function may be beneficial in the treatment of obese individuals.
           

  • Haruya Saji, Michiko Yamanaka, et al
    Losartan and Fetal Toxic Effects
    Lancet Vol.357, February 3, 2001, Pg. 363

    Summary : Authors report a case of maternal exposure to the antihypertensive drug losartan during weeks 20-31 of pregnancy. They saw the fetal toxic effects of oligohydramnios (decreased amniotic fluid), fetal pulmonary hypoplasia, fetal hypoplastic skull bones, and subsequent fetal death. 
           
    This pattern of abnormalities is similar to those seen in exposure to angiotensin-converting-enzyme (ACE) inhibitors during pregnancy, and were probably caused by losartan.
       

  • David M Coulter, Andrew Bate, et al (University of Otago, Dunedin, New Zealand)
    Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study.
    BMJ, 19 May 2001, pg.1207
           
    The objective of the study was to examine the relation between antipsychotic drugs and myocarditis and cardiomyopathy.
           
    The international database on adverse drug reactions run by WHO programme for international drug monitoring was used. Reports mentioning antipsychotic drugs, cardiomyopathy or myocarditis were included. 
          
    Results : A strong signal existed for an association between clozapine and cardiomyopathy and myocarditis. An association was also seen with other antipsychotics as a group. The association was based on sufficient cases with adequate documentation and apparent lack of confounding to constitute a signal. Associations between myocarditis or cardiomyopathy and lithium, chlorpromazine, fluphenazine, haloperidol, and risperidone need further investigation.
          
    Conclusion : Some antipsychotic drugs seem to be linked to cardiomyopathy and myocarditis. 
           

  • Andrew J Krentz, Sherine Mikhail, et al 
    Pseudophaeochromocytoma syndrome associated with clozapine.
    BMJ, vol.32, 19 May 2001,pg.1213.
          
    Clozapine has an established role in treatment of refractory schizophrenia. It produces serious adverse effects which include agranulocytosis. Paradoxical hypertension with increased concentrations of catecholamines has been reported rarely and in association with other antipsychotic treatment.
           
    Authors describe 4 patients with pseudophaeochromocytoma syndrome associated with clozapine. Profuse sweating, hypertension and obesity were common to all the patients. Urinary catecholamine concentrations, measured in 24 hour collections during clozapine treatment were increased in all 4 patients. Computed tomography and isotopic imaging were used to exclude phaeochromocytoma. In 2 cases, urinary catecholamine concentrations normalized and clinical features improved or resolved after withdrawal of the drug, and the patients also lost several kilograms in body weight.
             
    Clozapine has affinity for 5HT2 receptors and adrenergic receptors in vitro. It increases plasma noradrenaline concentrations, by inhibiting synaptic uptake mediated by µ2 adrenergic receptors.
           

  • Jean L Rouleau, Marc A Pfeffer et al
    Comparison of vasopeptidase inhibitor, omapatrilat and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomized trial.
    Lancet, vol.356, Aug.19, 2000, pg.615
           
    Background: Authors aimed to assess in patients with congestive heart failure whether dual inhibition of neutral endopeptidase and angiotensin-converting enzyme (ACE) with the vasopeptidase inhibitor, omapatrilat is better than ACE inhibition alone with lisinopril on functional capacity and clinical outcome.
          
    Methods : Authors did a prospective, randomised, double-blind, parallel trial of 573 patients with New York Heart Association (NYHA) class II-IV congestive heart failure, left-ventricular ejection fraction of 40% or less, and receiving an ACE inhibitor. Patients were randomly assigned omapatrilat at a daily target dose of 40mg (n=289) or lisinopril at a daily target dose of 20 mg (n=284) for 24 weeks. The primary endpoint was improvement in maximum exercise treadmill test (ETT) at week 12. Secondary endpoints included death and comorbid events indicative of worsening heart failure.
           
    Omapatrilat improved NYHA class more than lisinopril in patients who had NYHA class III and IV, but not if patients with NYHA class II were included.
           
    Interpretation : Findings suggest that omapartilat could have some advantages over lisinopril in the treatment of patients with congestive heart failure. Thus use of vasopeptidase inhibitors could constitute a potentially important treatment for further improving the prognosis and well being of patients with this disorder.
            

  • Franz H Messerli, Jurg Nussberger
    Commentary – Vasopeptidase inhibition and angio-oedema
    Lancet, vol.356, Aug.19, 2000, pg.608
          
    Omapatrilat affects the cardiovascular system by inhibiting the ACE (and thereby interrupting the renin-angiotensin-aldosterone cascade), and by inhibiting the neutral endopeptidase (NEP) (and thereby increasing the concentration of natriuretic peptides). Both these enzymes also inactivate bradykinin, and ACE inhibitors alone have been shown to increase plasma kinin concentrations. Bradykinin is probably the mediator of the angio-oedema associated with ACE inhibitors. Plasma bradykinin concentrations can rise more than 10 fold during attacks of angio-oedema associated with an ACE inhibitor. The US FDA has raised concern about this adverse effect and the manufacturer withdrew the application temporarily.
             
    Angio-oedema is a well documented, but rare, adverse event in patients taking ACE inhibitors. It can first appear from a few hours to 8 years after an ACE inhibitor is first taken.
           
    Omapatrilat apart from conferring potential cardiovascular benefits, may be of advantage in CHF patients with renal impairment. But as a dual ACE and NEP inhibitor, omapatrilat also carries a higher risk of life-threatening angio-oedema than do ACE inhibitors alone. For omapatrilat, as for any therapy, the risk/benefit ratio must be quantified before it becomes generally available.
            

  • Simon Shorvon
    Pyrrolidone Derivatives
    Lancet, Vol. 358, December 2001, Pg. 1885-1892
           
    This is a review article of pyrrolidone derivatives – the so-called nootropic agents. The pyrrolidone (2-oxopyrrolidine) family of chemicals has been the subject of research for more than three decades. Experimental and clinical work first focused on their so-called nootropic effects; later came the possibilities for neuroprotection after stroke and use as an antiepileptic agents.
          
    Piracetam, first of the class, was developed by pioneering research by C Giurgea in the late 1960s, and it was he who coined the term “nootropic”, to mean enhancement of learning and memory.
          
    The term is sometimes extended to include other actions such as neuroprotection. These properties, together with the lack of other generally adverse psychopharmacological actions (eg, sedation, analgesia, motor or behavioural changes), distinguish the pyrrolidones from other psychoactive drug classes.
          
    The mechanisms of action of these drugs are still not fully established; indeed, different compounds in this class may have different modes of action. Interest in this drug class has recently been reawakened by the licensing of levetiracetam as a potentially major new antiepileptic drug and of piracetam for its antimyoclonic action and effects after stroke and in mild cognitive impairment.
           
    Other drugs in this class are currently at an advanced stage of development, and the renewal of interest in this therapeutic area is likely to mean not only that more pyrrolidones will enter clinical practice in the next few years but also that the clinical indications of drugs already licensed will widen.
            
    Licensed indications of piracetam in Europe and the USA
          

     

    Myoclonus

    Cognitive impairment

    Post

    stroke

    Other

    Austria

    +

    +

    Alcohol withdrawal, alcoholism, head injury (sequelae)

    Belgium

    +

    +

    Alcohol withdrawal, learning disorder, vertigo, dyslexia

    UK

    +

    None

    France

    +

    +

    Dyslexia, vertigo

    Germany

    +

    +

    +

    Head injury (sequelae), dyslexia, learning disorder

    Italy

    +

    ++

    Dyslexia, learning disorder, alcohol withdrawal

    Netherlands

    Vertigo

    Norway

    +

    None

    Portugal

    +

    +

    +

    Learning disorder, dyslexia, head injury (sequelae), post-traumatic vertigo and coma, sickle-cell anaemia, alcoholism, epilepsy, alcohol withdrawal, Raynaud’s disease, Parkinson’s disease

    Spain

    +

    +

    +

    None

    Sweden

    +

    None

    Switzerland

    +

    +

    Dyslexia

    USA

    None

           

  • Terumichi Fujikura 
    New Therapeutic Approaches to the Treatment of Nasal Allergy: Antiinflammatory Effects of H1 Receptor Antagonists
    Drugs of Today Vol.37 (7), July 2001, Pg. 455-461
          
    Histamine is recognised as an important mediator of allergic rhinitis. In addition to the role it plays in the immediate phase reaction of nasal allergy it plays an important role in late phase reaction and protracted allergic inflammation. 
         
    Histamine induces the synthesis and secretion of proinflammatory cytokines and the expression of adhesion molecules. Besides their action of H1 receptor antagonism, antihistamines have been reported to possess multiple anti-inflammatory effects.
         
    Continuous use of antihistamines may reduce the level of minimal persistent inflammation of nasal mucosa in allergy and also produce improvement of coexisting allergic inflammation of lower airways.
         

  • Mark J Caulfield (Dept. of Clinical Pharmacology, St. Bartholomew’s and the Royal London School of Medicine, Charterhouse Square, London, UK).
    Genes for common diseases.
    Br J Clin Pharmacol, 51, 1-3
      
    There is increasing interest in genetic factors that may influence development of common diseases such as hypertension and diabetes. The size of studies require to be adequately powered to detect a true positive effect. The tools are the genetic variants or polymorphisms which each of us has about every 500 bases within our genome. These polymorphisms or variations can be used to identify disease-causing variants or explain genetic influence on a trait.
      
    The most abundant form of polymorphisms are single nucleotide, or base, changes in the code. These single nucleotide polymorphisms or SNPS (pronounced snips) are of great interest. These SNPS will become not only increasingly important in mapping disease genes but also in predicting drug response and are of interest to pharmaceutical industry. There are more complex highly polymorphic markers in addition to these simple polymorphisms.
      
    Population based case-control studies are the most widely used study design to identify a gene for a common disease. Technological advances have occurred in the last 10 years to screen polymorphisms needed to detect common disease causing genes. The first of these was polymerase chain reaction inspired by Kary Mullis. This reaction photocopies DNA within a target sequence.
       
    The second development is methods for high throughput genotyping. The first of these was semiautomated fluorescence based genotyping.
      
    Microarrays and DNA Chips:
    There have also been advances in the methods available to detect single nucleotide polymorphisms. These techniques are currently quite expensive.
        

  • Kevin M O’Shaughnessy
    The genetics of essential hypertension
    Br.J. Clin.Pharmacol, 51,pg.5-11, Jan.2001
      
    Hypertension is currently seen as a ‘complex’ genetic trait caused by multiple susceptibility genes the effect of which are modulated by gene-environment and gene-gene interactions. A number of candidate genes have been proposed but demonstrating consistently the linkage with hypertension has been problematic. The data for angiotensinogen is the most extensive and meta-analysis has confirmed a significant association overall, although risk contributed by this gene is modest. In the past 5 years, success has been achieved in solving the molecular genetics of a number of familial hypertension syndromes.
       
    Animal models : Extensive use of inbred animal strains is made to study genetics of hypertension. This enables control over environment and breeding since this would be impossible to achieve in human studies. There are at least 6 major strains and many more substrains.
      
    Human studies: Mainly 2 approaches are followed. Linkage studies based on allele sharing in affected relative pairs (usually sib-pairs) or association studies comparing gene frequencies between cohorts of hypertensive and normal subjects. Evidence implicating a number of genes including angiotensinogen, µ-adducin, the b2-adrenoceptor, G-protein beta-3, and the b-subunit of the epithelial sodium channel (b-ENaC) have been obtained using these methods. But the published data are conflicting.
      
    Monogenic hypertension: The greatest advance in recent years has been the study of families in which hypertension is inherited as a simple Mendelian character. The molecular bases for several of these disorders have now been established and are given in Table I.
      
    Table 1. Molecular basis for known familial (monogenic) hypertension syndromes.

 Monogenic syndrome

 Mode of Inheritance

 Gene Product

 Chromosomal Location

   

  

   

   

Apparent mineralocorticoid excess (AME)

Recessive

Non-functional 11-b-hydroxy steroid dehydrogenase (11b-HSD Type 2) 
enzyme

16q

   

  

   

   

Glucocorticoid remediable Aldosteronism (GRA)

Dominant

Hybrid aldosterone synthase (CYP11B2) 
  enzyme expressed under ACTH control.

8P

   

  

   

   

Hypertensive forms of Congenital adrenal hyperplasia 10q24

Recessive

Non-functional forms of the correspond- ing hydroxylases.

8q21 & (11 b and 17-a hydroxylase types) (CYP11B1 and CYP17A)

   

  

   

   

Liddle’s Syndrome (pseudo-aldosteronism)

Dominant

Constitutively expressed amiloride- sensitive sodium channel in distal nephron

16p

  • Peter Collins and Gareth Williams
    Drug Treatment of Obesity: From past failures to future successes ?
    Br J Clin Pharmacol, 51, Jan.2001, 13-25
       
    Obesity is one of the last great unfilled niches in pharmacotherapy. Drugs can only be used that are proven effective and safe. Efficacy remains a stumbling block for many hopeful compounds. Some for example the b3-adrenoreceptor thermogenic agents and perhaps leptin have not yet fulfilled the considerable promise which they showed in lower mammals. Success must be defined as the restoration of normal quality and duration of life rather than arbitrary degrees of weight loss. No sufficiently long-term studies have been performed for drugs like orlistat and sibutramine.
       
    Safety : This has been the downfall of many effective drugs e.g. fenfluramine -withdrawn by manufacturers following definite evidence of primary pulmonary hypertension and sclerotic valvular heart disease. Phentermine (often used in combination with fenfluramine) was not endorsed because of inadequate long-term safety data. Many centrally acting drugs affect multiple functions served by neurotransmitters which they target. An example is short-term memory loss with cholecystokinin, whose action as a satiety factor is currently being explored.
      
    Ethical considerations: Injections of diuretics are given to patients when they are not sodium over-loaded and thyroxine when they are euthyroid and use of unproven sundry drugs. A Belgian ‘slimming clinic’ used an unlicensed mixture of fenfluramine, diethylpropion and a Chinese herbal product, the latter contained nephrotoxic Aristoloclivia alkaloids. This led to high presence of renal disease (interstitial fibrosis causing renal failure and urothelial cancers).
      
    Currently available anti-obesity drugs: Orlistat (tetrahydrolipstatin) – It is a synthetic drug derived from a naturally occurring lipase inhibitor produced by streptomyces moulds. It binds covalently to active site of pancreatic lipase. Its action is limited to gut lumen because it is not absorbed. At therapeutic doses (120mg, 3 times daily), it blocks digestion and absorption of about 30% of dietary fat. Unwanted side-effects are fatty stools with diarrhoea, urgency and incontinence.
      
    Sibutramine : It is a centrally acting appetite suppressant and has mild thermogenic properties. It increases action of 5 HT and noradrenaline in hypothalamus by blocking the reuptake. Unlike fenfluramine it does not stimulate the release of 5HT. Inhibition of noradrenaline reuptake increases sympathetic tone, and may produce rise in BP and pulse rate. Because of its actions on both monamines, sibutramine is called an SNRI (Serotonin-noradrenaline reuptake inhibitor)
      
    Leptin- in human obesity – its usefulness in human obesity is uncertain.
      
    Potential targets for novel anti-obesity drugs (1) Neuropeptide.Y (2) Melanocortin system (3) Orexins -A and B peptides which stimulate feeding when injected centrally. Orexin antagonists are under development (4) Satiety factors -cholecystokinin (5) Thermogenic drugs.
              

  • Scott Gottlieb
    NSAIDS can lower risk of Alzheimer’s
    BMJ, Vol.323, 1 Dec, 2001, pg1269
     
    Long term use of anti-inflammatory drugs such as ibuprofen and naproxen can lower the risk of Alzhemier’s disease, probably by reducing inflammation in brain. Researchers of Erasmus Medical Centre in Rotterdam found that adults who use NSAIDs for at lest 2 years were 80% less likely to develop Alzheimer’s disease than individuals who used these drugs for shorter periods or who did not take them at all. The risk decreased as the number of years that patients continued to take the drugs grew.
       
    In contrast, use of NSAIDs was not linked to a reduced risk of vascular dementia.
         

  • Roger Dobson
    Anticoagulatns can interact with herbal medicines.
    BMJ, Vol.323, 1 Dec.2001, pg.1270
      
    Warfarin was found to be the most common drug in interactions with 18 cases, and St. John’s Wort was the most common herb.
       

  • Judy Siegel-Itzkovich, Jerusalem
    Scientists develop a “vaccine” against diabetes
    BMJ, Vol.323, 1 Dec. 2001, pg. 1272
      
    Scientists have developed the world’s first drug that successfully halts the immune system’s destruction of pancreatic b-cells in humans called DiaPep277, the drug offers the possibility of preventing type I diabetes in healthy people with a genetic risk of the disease and halting its progression in people whose b-cells have already begun to die.
      
    This peptide has undergone Phase II clinical trial on 35 patients. Mechanism of action may be changes in patients’ T cells. In children the destruction of pancreatic cells is very rapid taking place even in a couple of months.
       

  • Kalifa A Bojang, Paul JM Milligan, et al
    Efficacy of RTS,S/ASO2 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in the Gambia: a randomised trial.
    The Lancet, vol.358, 8 Dec.2001, pg. 1927-34.
      
    RTS,S/ASO2 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HbsAg, incorporating a new adjuvant (ASO2). Authors did a randomised trial of the efficacy of RTS,S/ASO2 against natural P.falciparum infection in semi immune adult men in The Gambia.
       
    Three hundred and six men aged 18-45 years were randomly assigned three doses of either RTS,S/ASO2 or rabies vaccine (control). Volunteers were given sulfadoxine/ pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P.falciparum. Analysis was per protocol.
       
    Interpretation: Of the study was that RTS,S/ASO2 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P.falciparum infection.
        

  • William L Isley
    Pitavastatin (NK-104), A New HMG CoA Reductase Inhibitor
    Drugs of Today, Vol.37, Sept.2001, pg.587-594
      
    Pitavastatin (NK-104), is a new synthetic HMG-CoA reductase inhibitor (statin). Animal studies suggest that in addition to reducing LDL cholesterol, the drug may produce marked reductions in triglyceride-rich particles (VLDL) and intermediate density lipoproteins (IDL). It is not metabolized by the common cytochrome P-450 3A4 enzyme, possibly reducing the risk for drug interactions. Early studies suggest that it may be quite useful for treating common dyslipidemias.
        

  • Yan-Qiong Xiong and Thuan P Le
    Telithromycin (HMR 3647): The first ketolide antibiotic.
    Drugs of Today, Sept.2001, Vol.37, pg.617-628,
      
    Telithromycin, the first ketolide antibiotic to undergo clinical development, has been specifically designed to treat community-acquired respiratory tract infections, including those caused by resistant pathogens. Like macrolides, telithromycin inhibits protein synthesis by acting mainly on the 50S ribosomal unit. It has potent activity against a wide spectrum of Gram +ve and Gram -ve organisms, including erythromycin-resistant pneumococci.
     
    Overall the preliminary findings provide evidence that short-term treatment with telithromycin (800mg,p.o.) once daily for 5 days for treatment of acute exacerbation of chronic bronchitis, acute sinusitis and pharyngitis/tonsillitis and 7-10 days for the treatment of community acquired pneumonia appears to be comparable to standard antibiotics for select respiratory tract infection. Telithromycin maintains activity while macrolide resistance increases. It will be an addition to currently available antibiotics to combat increasing trends of resistant respiratory pathogens.
        

  • X. Rabasseda
    Oxcarbazepine: Anticonvulsant Profile and Safety
    Drugs of Today, May 2001, 37(5): 333-355
      
    Oxcarbazepine is a molecule chemically related to carbamazepine that shares most of the pharmacological and therapeutic effects of carbamazepine while displaying a more favourable profile regarding tolerability and drug-drug interactions. In contrast to carbamazepine, oxcarbazepine is metabolized through cytochrome P450-independent reductase, and is thus devoid of inductive effects on hepatic oxidative metabolism. Oxcarbazepine has been shown to be useful both as monotherapy and adjunctive therapy in patients with partial seizures with or without secondary generalization. The drug has been documented as safe and effective in adults as well as children aged 4-16 years. Additional data suggests that oxcarbazepine might improve cognition and psychomotor performance and might increase alertness, in contrast to the cognition/psychomotor impairment observed with some other antiepileptic drugs. Both the pharmacokinetic advantages over other anticonvulsant drugs and the lack of pharmacological interactions with oxcarbazepine may point to this drug as a first-line treatment for the management of partial and tonic-clonic epilepsy.
         

  • S.J. de Visser, J. Van der Post et al 
    Biomarkers for the effects of antipsychotic drugs in healthy volunteers
    Br.J.Cl.Pharm, Vol.51, Feb.2001, pg.119
          
    Subjective and objective measures of alertness, and of visual-visuomotor-auditory and motor skills were most sensitive to antipsychotics, although over half of all the studies failed to show statistically significant differences from placebo. The most consistent effects were observed using prolactin response and saccadic eye movements, where 96% and 83% of all studies respectively showed statistically significant effects. The prolactin inducing dose equivalencies relative to haloperidol of 19 different antipsychotic agents correlated with the lowest recommended daily maintenance dose (r2 = 0.52). This relationship could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind prolactin release and antipsychotic activity (probably D2-receptor antagonism). The number of tests used in human psychopharmacology appears to be excessive. Future studies should look for the most specific and sensitive test within each of the domains that are most specific and sensitive test within each of the domains that are most susceptible to neuroleptics.
          

  • Karen Rowland Yeo & Wilfred W Yeo
    Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes.
    Br.J Clin Pharmacol, vol.51, May 2001; 461-470
          
    Simvastatin is generally well-tolerated and causes few subjective side-effects during chronic treatment. Myopathy which may present as rhabdomyolysis, is a rare but serious side-effect of statin treatment and occurs in 0.1% of patients treated with standard doses of simvastatin or other HMG-CoA reductase inhibitors.
          
    The risk of rhabdomyolysis increases considerably on addition of drugs such as itraconazole and mibefradil. These drugs inhibit CYP3A4 mediated metabolism of simvastatin and lead to marked increase in plasma concentrations of the enzyme HMG-CoA reductase inhibitory activity. Mibefradil has been withdrawn from the market 2 years ago but there is debate with respect to concomitant use of other calcium channel blockers.
         
    In the present study, inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes were investigated. The results of the study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.
          

  • Susan Todd, Anne Whitehead et al
    Interim analysis and sequential designs in phase III studies
    Br.J.Clin.Pharm, vol.51, May 2001, pg.394
         
    Recruitment of patients to a clinical trial usually occurs over a period of time, resulting in the steady accumulation of data throughout the trial’s duration. Yet, according to traditional statistical methods, the sample size of the trial should be determined in advance, and data collected on all subjects before analysis proceeds. For ethical and economic reasons, the technique of sequential testing has been developed to enable the examination of data at a series of interim analyses. The aim is to stop recruitment to the study as soon as there is sufficient evidence to reach a firm conclusion. Authors present the advantages and disadvantages of conducting interim analyses in phase III clinical trials, together with the key steps to enable the successful implementation of sequential methods in this setting. Examples are given of completed trials, which have been carried out sequentially, and references to relevant literature and software are provided.
          

  • E.J.Begg, R.A. Robson et al
    Quinapril and its metabolite quinaprilat in human milk
    Br.J.Clin.Pharm, vol.51, May 2001; 478-481
          
    Aim of the study was to measure the milk to plasma ratio (M/P) of quinapril and its active metabolite quinaprilat in lactating mothers and to assess likely infant exposure
          
    A single dose of quinapril 20mg was administered to six healthy mothers who had been breastfeeding their infants for at least 2 weeks.
          
    The M/P ratio for quinapril was 0.12 (95% CI 0.09, 0.14). No quinapril was detected in milk after 4h. No quinaprilat was detected in any of the milk samples. The estimated ‘dose’ of quinapril that would be received by the infant was 1.6% (95% CI 1.0, 2.2) of the maternal dose, adjusted for respective weights.
          
    Quinapril appears to be safe during breastfeeding according to conventional criteria, although as always, the risk : benefit ratio should be considered when it is to be given to a nursing mother.
          

  • H.E.Seymour, A Worsley, J.M. Smith and S.H.L.Thomas
    Anti-TNF agents for rheumatoid arthritis
    Br.J.Clin Pharm, vol.51, March 2001, pg.201-208
        
    Rheumatoid arthritis (RA) is a chronic inflammatory, autoimmune disease with a prevalence of approximately 1% and an annual incidence of 0.04%.
        
    Nonsteroidal anti-inflammatory drugs (NSAIDs) have little effect on the underlying course of RA, but they have some anti-inflammatory and analgesic properties. Disease modifying antirheumatic drugs (DMARDs) have been shown to slow progression of RA and are currently recommended early in the course of treatment of RA which is when disease progression is most rapid.
         
    Etanercept and infliximab belong to a new group of parentally administered antitumour necrosis factor (TNF) drugs.
         
    Etanercept is licensed in the UK for the treatment of active rheumatoid arthritis in patients who have not responded to other DMARDs and in children with polyarticular-course juvenile arthritis who have not responded to or are intolerant of methotrexate. In adults it produces significant improvements in all measures of rheumatic disease activity compared to placebo. In patients whose disease remains active despite methotrexate treatment, further improvement in control is obtained with the addition of etanercept without an increase in toxicity. Infliximab is a monoclonal antibody which is currently licensed in the UK for Crohn’s disease and, in combination with methotrexate for the treatment of rheumatoid arthritis in patients with active disease when the response to disease –modifying drugs, including methotrexate, has been inadequate. Infliximab in combination with methotrexate was shown to be superior to methotrexate or infliximab alone.
         
    There are currently no predictors of a good response to anti-TNF drugs and a percentage of patients fail to respond to treatment (25% to 38% of etanercept patients; 21% to 42% of infliximab patients). Infliximab monotherapy induces the production of anti-infliximab antibodies, which may reduce its effectiveness. Adding methotrexate to infliximab therapy may prevent this response.
         
    Anti-TNF drugs may affect host defences against infection and malignancy; whether these agents affect the development and course of malignancies and chronic infections is unknown and safety and efficacy in patients with immunosuppression or chronic infections has not been investigated. Upper respiratory tract infections were more common in patients treated with etanercept than with placebo.
         

  • Michael A Shaw
    New insights into drug metabolism and toxicology.
    Report of a symposium on drug metabolism and toxicity held at the British Pharmacological Society Meeting in Cardiff, UK in July 2000
    Br. J Clin.Pharm, March 2001, vol.51, pg.209-12
          
    Adverse drug reactions present a major clinical problem. In addition to being a major cause of morbidity and mortality, adverse drug reactions can prevent effective drug therapy and, in extreme cases, can lead to the withdrawal of potentially valuable medicines.
         
    For example, terfernadine is a prodrug that undergoes first pass carboxylation to form the active agent; terfernadine itself, however, can prolong the QT interval, leading to potentially fatal dysrhythmias (torsades des pointes) in some patients. This risk is increased in patients with liver disease, and in patients treated with drugs such as ketoconazole or erythromycin, in whom the conversion of terfenadine to its active metabolite is impaired. Most such reactions are now readily predictable since the role of specific cytochrome P450 isoforms in drug metabolism can be determined from in vitro studies, allowing potential drug interactions to be identified. The risk of such interactions in clinical practice can then be assessed in pharmacokinetic and pharmacodynamic studies.
         
    There is considerable genetic variation in drug metabolism. Approximately 10% of individuals show a deficiency in the CYP2C6 isoform (the principal P450 isoform involved in drug metabolism in humans), and polymorphism of CYP2C9 is also attracting attention due to the involvement of this isoform in warfarin metabolism.
         
    A variety of in vitro and in vivo techniques are now available to predict such genetic variations in drug metabolism.
          
    In addition to being responsible for drug elimination, drug metabolizing enzymes such as cytochromes P450 can also produce reactive metabolites (bioactivation). Such reactions are less predictable, and can cause potentially serious adverse effects. For example, paracetamol is primarily metabolized by phase II glucuronidation and sulphation, but approximately 5-10% is converted to a toxic quinoneimine metabolite, which is detoxified by glutathione. When paracetamol is taken in overdose, the phase II pathways become saturated, leading to increased production of the quinoneimine. This in turn leads to glutathione depletion and hepatocellular damage.
         
    Studies with drugs associated with well characterized hypersensitivity reactions, such as carbamazepine, have shown that these drugs are converted to reactive metabolites that provoke the formation of antibodies to the drug or, in some cases, to cytochrome P450. However, the development of such an immune response, depends on the prevailing cytokine profile. Studies with carbamazepine suggest that exposure of antigen-presenting cells to the drug or its reactive metabolites leads to recruitment of cytotoxic CD8 cells and reversal of the normal CD4:CD8 ratio. The CD8 cells then infiltrate the epidermis, resulting in tissue damage.
          
    New insights into paracetamol toxicity
        
    The use of the paracetamol antidote N-acetylcysteine in early (<12h) paracetamol poisoning is well established, but the choice of oral or intravenous administration has remained controversial. However, a recent meta-analysis suggests that both routes are equally effective. There is evidence that activated charcoal is useful in the treatment of early paracetamol poisoning, provided it is given within 1 h. For example, in a recent study the use of activated charcoal within 1-2h significantly reduced the need for N-acetylcysteine.
          
    The mechanisms by which N-acetylcysteine acts in patients with advanced paracetamol poisoning are unknown but free radical scavenging, haemodynamic effects, and changes in oxygen kinetics have all been proposed.
        
    The toxicology of tamoxifen
    Tamoxifen continues to provide considerable benefit in terms of reducing mortality from breast cancer, and the available data suggest that the prophylactic use of tamoxifen is unlikely to produce a significant risk of genotoxicity.
         

  • H. Chrystyn
    Methods to identify drug deposition in the lungs following inhalation
    Br. J.Clin.Pharm, April, 2001, vol.51, pg.289-299
         
    Inhalation of bronchodilators and anti-inflammatory agents enables direct delivery to the therapeutic sites in the airways for the management of asthma and chronic obstructive pulmonary disease. Upto 20% of the inhaled dose is delivered to the lungs whilst the majority is swallowed. The proportion of the dose delivered to the lungs, following inhalation, will be cleared either by the mucociliary convenor belt or by absorption through the airway wall into the systemic circulation. The latter is the fraction of the dose that will exert the clinical effect within the airway wall.
        
    Drug particles less than 5mm have the greatest probability of deposition in the lung, whereas those less than 2 mm tend to be concentrated in the alveoli.
        
    Table below lists pharmacokinetic and scintigraphic methods that have been developed to identify the amount of drug delivered to the lungs following an inhalation.
         
    Scintigraphic methods following inhalation using two and three dimensional imaging are direct methods for the determination of lung deposition.
        
    These techniques can highlight the zones of the lungs into which the drug is deposited. However, they do not differentiate between the removal of drug from the lungs by systemic absorption or by mucociliary clearance and also require modification to the original drug formulation.
         
    Table : Summary of the methods used to identify the bioequivalence of inhaled products.
    Pharmacokinetic (using plasma or urine samples) 
    Relative lung deposition (drugs with an extensive first pass,
    Charcoal block, absorption lag times)
    Total systemic delivery
        
    Gamma scintigraphy
    Two dimensional
    SPECT
    PET
       
    Clinical studies
    Spirometry (crossover or parallel design)
    Bronchoprovocation for lung deposition
    Multiple dosing for extra-pulmonary effects
       
    In vitro
    Determination of the in vitro particle size distribution, fine particle (respirable) dose, emitted dose.
          

  • J.G. Reilly, S.A. Ayis et al 
    Sudden death and thioridiazine
    Br.J.Cl.Pharm, April 2001,vol.51, pg.363.
         
    Risks of QT interval prolongation are higher for some antipsychotic drugs, e.g. thioridazine and droperidol. The risk of sudden cardiac death in recipients of different antipsychotic drugs has not previously been quantified.
          
    However they support the hypothesis that thioridazine-induced cardiac repolarisation abnormalities may result in arrhythmia and sudden cardiac death.
         

  • S Akhondzadeh, S.A. Ahmadi-Abhari et al
    Double-blind randomized control trial of baclofen vs clonidine in the treatment of opiate withdrawal
    Br.J.Cl.Pharm, April 2001, vol.51; pg.364
        
    Alpha-adrenoceptor agonists have been used in treatment of opiate withdrawal syndrome over the last 2 decades. Accumulating evidence shows the efficacy of the GABAB receptor agonist, baclofen in reducing alcohol intake and cocaine self-administration in rats. The present trial was conducted to examine the ability of a GABAB agonist in the management of opiate withdrawal.
         
    Baclofen and clonidine were equally effective in treating the physical symptoms of withdrawal syndromes. However, baclofen showed a significant superiority over clonidine in the management of mental symptoms. These results suggest that baclofen might constitute a novel therapeutic agent for opiate withdrawal syndrome.
         

  • A. Mahmud & J.Feely
    Angiotensin II receptor antagonist reduces arterial stiffness in hypertensive patients; may be additive to ACE inhibition
    Br.J.Cl.Pharm, April, 2001, vol.51, pg. 380p-81p
         
    Angiotensin converting enzyme (ACE) inhibitors have been shown to favourably influence elastic properties of the peripheral arteries in hypertensive patients. The recognition of systolic pressure and pulse pressure as independent cardiovascular risk factors has focused on the arterial haemodynamics of antihypertensive drugs since decreasing arterial stiffness and delaying arterial wave reflection would be logical strategy in the management of hypertension. This study examined the effect of an angiotensin II receptor antagonist, valsartan on the elastic properties of the aorta and peripheral muscular arteries.
         
    The present study shows that an ATH antagonist, in addition to reducing blood pressure may exert an additional haemodynamic effect in improving elastic properties of the aorta and dilating peripheral conduit arteries suggesting reduced stiffness in both large and smaller arteries of magnitude similar to that of an ACE inhibitor. That an ACE inhibitor produced a further reduction in pulse wave velocity in patients under angiotensin II blockade suggests that the effects maybe additive.
         

  • A Mahmud & J. Feely
    The effect of acute and chronic smoking on arterial stiffness in healthy young subjects.
    Br.J.Cl.Pharma, April 2001, vol.51, pg.381.
         
    Smoking is a major cardiovascular risk factor and its effect on the mechanical properties of large arteries may play an important role. Smoking influences endothelium-mediated vascular control, induces vasoconstriction and increases the stiffness of both muscular and elastic arteries. Acute exposure to passive smoking adversely affects arterial wave reflection in healthy subjects. As the acute effects of smoking on pulse wave velocity (PWV) and arterial wave reflection in both non-smokers and chronic smokers have not been looked at, authors therefore examined the effects of active smoking, both acute and chronic, on arterial stiffness.
         
    Authors performed an observational study on a group of 157 healthy students (77 females). Chronic smokers (n=41) were matched for age, height, weight and gender with non-smokers. Arterial wave reflection was measured, using radial applanation tonometry using the generalized transfer function (Sphygmocor® PWV Medical), expressed as a percentage of pulse pressure-augmentation index AI%.
        
    This study shows that chronic smokers by the age of 22 years have evidence of increased arterial wave reflection, a marker of vascular stiffness. Furthermore in common with non-smokers their arteries also stiffen further when they smoke a cigarette.
          

  • Krishnan Parameswaran and Frederick E Hargreave
    The use of sputum cell counts to evaluate asthma medications
    Br. J. Cl.Pharm, vol. 52, Aug.2001, 121-128.
          
    Total and differential cell counts from hypertonic-induced, dithiothreitol-dispersed sputum provide reproducible measurements of airway inflammatory cell counts, which are responsive to treatment with anti-inflammatory drugs. They have helped to understand the kinetics of inflammatory cell changes in asthma after the reduction of corticosteroids and the subsequent re-introduction of treatment. They have identified that the presence of sputum eosinophilia in asthma, chronic cough and chronic airflow limitation is a predictor of steroid – responsiveness and of lack of ‘asthma control’ Sputum cell counts are also useful to study the potential anti-inflammatory effects of drugs like theophylline, long-acting b-adrenoceptor agonists, leukotriene antagonists and newer drugs in development. They may be helpful to select add-on therapy to corticosteroids in ‘difficult-to-control’ asthma.
         
    Authors conclude that induced sputum examination for inflammatory markers holds much promise in the evaluation of the anti-inflammatory properties of asthma medications and identifying the appropriate medication to control symptoms. They may be useful to compare the relative potencies of different anti-inflammatory drugs. Further research is reserved to investigate the anti-inflammatory effect of newer asthma drugs, to identify the relevance of suppression of airway eosinophilia in the long term management of asthma and to establish a minimally important clinically significant change in airway inflammatory markers including sputum eosinophil count.
          

  • M Pirmohamed
    Editorial – Pharmacogenetics and pharmacogenomics
    Br.J.Cl.Pharma, vol.52, Oct.2001, pg.345
          
    Pharmacognetics has been defined as the study of variability in drug response due to heredity. More recently, with the fashion for adding the ‘suffix omics’ to areas of research, the term ‘pharmacogenomics’ has been introduced. While the former term is largely used in relation to genes determining drug metabolism, the latter is a broader based term that encompasses all genes in the genome that may determine drug response. The distinction however, is arbitrary and both terms can be used interchangeably.
         
    Historical overview of pharmacogenetics and pharmacogenomics
    Year Individual(s) Landmark
         

    Year

    Individual(s)

    Landmark

    510 BC

    Pythagoras

    Recognition of the dangers of ingesting fava beans, later
    characeterized to be due to deficiency of G6PD.

    1866

    Mendel

    Establishment of the rules of heredity

    1906

    Garrod

    Publication of ‘Inborn Errors of Metabolism’

    1932

    Snyder

    Characterization of the ‘phenylthiourea nontaster’ as an
    autosomal recessive trait.

    1956

    Carson et al

    Discovery of glucose-6-phosphate dehydrogenase 
    deficiency.

    1957

    Motulsky

    Further refined the concept that inherited defects of 
    metabolism may explain individual differences in drug
    response.

    1957

    Kalow & Genest

    Characeterization of serum cholinesterase deficiency.

    1957

    Vogel

    Coined the term pharmacogenetics

    1960

    Price Evans

    Characterization of acetylator polymorphism

    1962

    Kalow

    Publication of ‘Pharmacogenetics – Heredity and the 
    Response to Drugs’

    1977/79

    Mahgoub et al and Eichelbaum et al

    Discovery of the polymorphism in debrisoquine hydroxylase, sparteine oxidase.

    1988

    Gonzalez et al

     Characetrization of the genetic defect in debriso-
    quine hydroxylase, later termed CYP2D6.

    1988-2000

    Various

    Identification of specific polymorphisms in various phase 
    I and phase II drug metabolizing enzymes, and latterly in 
    drug transporters.

    2000

    Public-private partnership

    Completion of the first draft of the human genome.

    2000

    The International SNP Map Working Group

    Completion of map of human genome sequence variation containing 1.42 million SNPs.

     

  • Peter R Jackson, Erica J Wallis et al
    Statins for primary prevention : at what coronary risk is safety assured?
    Br.J.Clin.Pharma, vol.52, Oct.2001, pg.439.
         
    Increasingly HMG CoA reductase inhibitors (statins) are being used for primary prevention of vascular disease in patients with a raised cholesterol but at low absolute risk of coronary heart disease (CHD). This study used clinical trial results to explore the limits of absolute safety for statin use in such patients.
         
    The major placebo controlled statin outcome trials were identified by automated and manual literature searches. Principal results including all cause mortality in placebo and intervention groups and baseline values of standard coronary risk factors were abstracted for each trial.
         
    The regression line describing the relationship between mortality benefit and risk suggests that statin use could be associated with an increase in mortality of 1% in 10 years. This would be sufficiently large to negate statin’s beneficial effect on CHD mortality in patients with a CHD event risk less than 13% over 10 years.
          
    Absolute safety of statins has not been demonstrated for patients at low risk of CHD. Patients absolute risk of CHD should be calculated before starting statin treatment for primary prevention. Extensions of such treatment to low risk patients should await further evidence of safety.
         

  • Masaki Tagawa, Michiko Kano et al
    Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine.
    Br. J Clin.Pharm, vol.52, Nov.2001, pg.501
          
    Sedation induced by antihistamines is widely recognized to be caused by their penetration through the blood-brain-barrier and the consequent occupation of brain histamine H1-receptors. Authors previously studied the mechanism of sedation caused by antihistaines using positron emission tomography (PET). Recently, authors revealed the nonsedative characteristic of ebastine, a second –generation antihistamine, with cognitive performance tests. In the present study, H1-receptor occupation by ebastine was examined in the human brain using PET.
          
    Ebastine 10mg and (+)-chlorpheniramine 2 or 6mg were orally given to healthy male volunteers. PET scans with {11C}-doxepin, a potent H1-receptor antagonist, were conducted near t max of respective drugs.
          
    Ebastine (10mg orally) causes brain histamine H1-receptor occupation of approximately 10%, consistent with its lower incidence of sedative effect, whereas (+)-chlorpheniramine occupied about 50% of brain H1-receptors even at a low but sedative dose of 2mg; occupancy of (+)-chlorpheniramine was correlated with plasma (+)-chlorpheniramine concentration.
             

  • K.Lindhart, S Gizurarson, et al
    Electroencephalographic effects and serum concentrations after intranasal and intravenous administration of diazepam to healthy volunteers
    Br.J.Clin.Pharm, vol.52, Nov.2001,pg.521
          
    The present study was carried out to assess the intranasal administration of diazepam as a potential alternative to intravenous and rectal dosing in the treatment of acute epileptic seizures. A nasal spray is beneficial when a rapid onset of effect (within seconds or minutes) is required. Animal experiments have shown that the intranasal administration of diazepam may induce effects within 5 mins.
          
    The study had a cross-over design with 8 volunteers. It consisted of 4 legs with 4 different administrations: intranasal (i.n) placebo, 4mg diazepam i.n., 7mg diazepam i.n. and 5mg intravenous (i.v.) diazepam. Polyethylene glycol 300 (PEG 300) was used as a vehicle in the nasal formulations to solubilise a clinically relevant dose of diazepam.
          
    The study indicates that it is possible to deliver a clinically effective nasal dose of diazepam for the acute treatment of epilepsy using PEG 300 as a solubiliser.
           

  • Luis A Garcia Rodriguez, Sonia Hernandez-Diaz & Francisco J de Abajo.
    Association between aspirin and upper gastrointestinal complications: Systematic review of epidemiologic studies.
    Br.J.Clin.Pharm. Vol.52, Nov.2001, pg.563
           
    Because of the widespread use of aspirin for prevention of cardiovascular diseases, side-effects associated with thromboprophylactic doses are of interest. This study summarizes the relative risk (RR) for serious upper gastrointestinal complications (UGIC) associated with aspirin exposure in general and with specific aspirin doses and formulations in particular.
            
    Aspirin was associated with UGIC even when used at low doses or in buffered or enteric-coated formulations. The latter findings may be partially explained by channeling of susceptible patients to these formulations.
          

  • Adriane Fugh-Berman & E. Ernst
    Herb-drug interactions: Review and assessment of report reliability
    Br.J.Clin.Phar, vol.52, Nov.2001, pg.587
          
    The aim of this systematic review was to assess the published clinical evidence on interactions between herbal and conventional drugs.
          
    Four electronic databases were searched for case reports, case series or clinical trials of such interactions. The data were extracted and validated using a scoring systems for interaction probability.
          
    Clinical studies have documented that St John’s wort lowers serum concentrations of digoxin, phenprocoumon, indinavir, amitriptyline, and nortriptyline. A recent study found no effect of St. John’s wort (300mg standardized to 0.3% hypericin three times daily (14 days) on carbamazepine pharmacokinetics. Piper longum contains piperine, which has been shown in clinical trials to increase Cmax and AUC of phenytoin, propranolol, and theophylline.
           
    One study found that mixed valepotriates from Valeriana officinalis reduced the adverse effect of alcohol on concentration. Another demonstrated that Panax ginseng enhanced alcohol clearance in humans. A clinical study of an infusion of Piper methysticum found that kava potentiates impairment when combined with alcohol.
          
    The effect of Catha edulis on the pharmacokinetics of single-dose ampicillin and amoxicillin has been studied. The bioavailability of ampicillin was reduced during a Khat-chewing session but no effect was noted with amoxicillin.
          
    Licorice is a common herb in Chinese and Japanese herbal mixtures.
           
    St. John’s wort affects the clearance of many drugs, including cyclosporin, antidepressants (predominantly SSRIs), digoxin, indinavir, and phenprocoumon. The underlying mechanism appears to be multifactorial.
            
    Cases of serotonin syndrome could arise if St. John’s wort increased serotonin levels. However, enough cases of interactions with SSRIs have been reported that a serotonergic (or serotonin-amplifying) effect of St. John’s wort could occur.
          
    There is reasonable documentation of interactions between coumarin anticoagulants and St. John’s wort, danshen, dong quai, ginseng, and ginkgo. Most of these case reports are probably not true interactions but result from additive anticoagulant effects. Dong quai contains coumarins, and would be expected to augment the effects of a coumarin-derived anticoagulant. Ginkgo and garlic interfere with platelet function, and have been associated with bleeding even in the absence of warfarin or other anticoagulant treatment. Danshen also interferes with platelet function but appears to decrease the elimination of warfarin at least in rats.
          
    Herb-drug interactions occur but are under-researched. Patients taking St.John’s wort or anticoagulants are at the highest risk of an interaction. Patients on coumarin anticoagulants should be specifically advised to avoid taking herbal medicines or to have their INR measured within 2 weeks of starting the product. Patients taking garlic, ginkgo, danshen or other HMPs affecting platelet function should also be monitored.                                  
                                             

  • Ian B Wilkinson & David J Webb                        
    Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications              
    Br. J Clin.Pharm, vol.52, Dec.2001, pg.631                           
                                                                  
    Venous occlusion plethysmography provides a simple, and robust method for assessing blood flow in vivo. It is most frequently  applied to the forearm and is a versatile technique that has proved extremely valuable in assessing human vascular physiology  and pharmacology, especially when coupled with intra-arterial drug infusion. It has also been employed extensively to assess   endothelial function in vivo, for which it remains the gold standard. Unfortunately, the invasive nature of the technique has   prevented its use in addressing the important question of whether changes in endothelial function, particularly following drug   therapy, are a reliable surrogate of cardiovascular risk.                  
                                                                                                
    However, plethysmographic assessment of forearm blood flow does provide an ideal method for assessing the effects of various drugs and endogenous peptides on the peripheral resistance vessels in vivo, without the need to conduct systemic studies. The technique is at its most powerful when used to compare responses within an individual during a single study, for example construction of dose-response curves before and after administration of an antagonist. Use of receptor antagonists has also extended our understanding of the physiological and pathological processes regulating blood flow in vivo. Clearly, almost 100 years after its first description, the place of venous occlusion plethysmography in physiology and pharmacology remains firmly established due to the robust validation of the technique and its great utility for addressing the important issues of the time.   
                                                                                                                                                       

  • Jacqueline Compton, Therese van Amelsvoort & Declan Murphy                     
    HRT and its effect on normal ageing of the brain and dementia                                  
    Br. J. Clin Pharm. Vol.52 (6), Dec. 2001, pg.647-653.                                            
                                                                                               
    There are significant gender differences in human brain disease. For example, females are significantly more likely to suffer from Alzheimer’s disease (AD) than .men (even after correcting for differences in life expectancy), and females on hormone replacement therapy (HRT) are significantly less likely to suffer from Alzheimer’s disease than women who do not take HRT. Thus the current literature supports the hypothesis that sex steroids can modulate brain ageing, and this provides a neurobiological explanation for the significantly higher prevalence of AD in females who do not take HRT, and may lead to new treatment approaches for age-related brain disease including AD.                                                
                                                                                                                                          
    The loss of brain tissue was greater in females than males in hippocampus and parietal lobes. A study measuring glucose metabolism and using positron emission tomography (PET) and 18F-2-fluoro-2-deoxy-D-glucose (FDG), showed that age-related decline in brain metabolism is asymmetrical in males, but symmetrical in females, and women have significant age-related decreases in hippocampal glucose metabolism, but men do not. Women are more likely to develop AD than men, and this cannot be explained solely by their longer life expectancy as women also have a greater disease severity and a higher age-adjusted prevalence of AD than men.                  
                                                                       
    Risk factors for AD include a positive family history, presence of Down‘s syndrome, head injury, female sex, hypothyroidism, depression and the possession of the apolipoprotein E4 gene. In contrast, education, smoking, and nonsteroidal anti-inflammatory agents may be protective factors.                 
                                    
    It is now becoming clear that oestrogens do more than regulate sexual and reproductive behaviour: in addition to their well   known effects on bones and heart, oestrogens have significant effects on brain structure and function.
                                                    
    Intracellular oestrogen receptors (ER) are widespread and are found in the cerebral cortex, midbrain, hippocampus, brain stem,    hypothalamus and pituitary gland. Novel actions of oestrogen have been described, for example, inducing neuronal                    depolarization and oestrogen’s antioxidant effects. Recently oestrogen has been shown to bind to cell membrane receptors, although they have not been well characterized in the brain, and use the same second messenger systems used by growth   factors and neurotransmitters.                                                      
                                                                                         
    Oestrogens regulate synaptogenesis in the CA1 area of the hippocampus in that they increase synaptic and dendritic spine    density in this area of the brain. The CA1 region of the hippocampus is crucial to memory function and spatial and declarative   learning and is adversely affected in AD. It has been shown that oestradiol levels are positively correlated with superior     performance on behavioural memory tasks in rats.                                     
                                                                                                        
    Recently, it has been demonstrated that oestrogen induces an increase in N-methyl-D-aspartate (NMDA) receptors in rat   hippocampal neurons, in the same region where an increase in dendritic spines is found.                    
                                                                                                          
    Oestrogens also directly affect neurochemical transmitter systems affected in normal ageing. AD, and other neuropsychiatric   disorders. For example, oestrogens can modulate the serotonergic, cholinergic and dopaminergic systems.           
                                                                                                                     
    In addition to direct effects on neurons, oestrogens also work with neurotrophins (such as nerve growth factor) to stimulate    indirectly nerve cell growth.                                                      
                                                                                                            
    Oestrogen also has a neuroprotective action against several toxins that boost production of free radicals; including glutamate  and b amyloid by enhancing the cleavage of Alzheimer amyloid precursor protein (Alzheimer APP) into soluble peptides. It has   been proposed that 17b-oestradiol elevates protein kinase C activity, an effect possibly mediated by growth factors, and this   increases the activity of a-secretase, one of the enzymes that cleaves Alzheimer APP thus prevents deposition of the intact   amyloid peptide. It has been shown that oestrogen may also act as an antioxidant.                     
                                                       
    Compared with women, whose serum oestradiol levels drop at the menopause, men have higher brain oestradiol levels compared with age-matched postmenopausal women. This occurs as the testes continue to produce testosterone throughout life and testosterone is aromatized to estradiol in neuronal nuclei. This mechanism may also contribute to explaining the gender difference in neuropsychiatric disease.                
                                                                              
    Sex steroids are crucial to the development and ageing of hippocampus and parietal lobe – brain areas significantly affected in AD.                                   
                                                   
    Thus, there is recent evidence that oestrogen affects not only verbal but also nonverbal aspects of cognitive function in healthy postmenopausal women.                          
                                                                                   
    Epidemiological studies have reported that the prevalence of AD is significantly decreased in females on HRT, and that those women with AD who were taking HRT had a milder disease than those who were not.          
                                                                                  
    There is insufficient evidence that oestrogen benefits patients with established AD and its use as a sole agent for AD cannot be justified because of the risks associated with HRT, for example, breast cancer and thromboembolic disease.            
                                                                 
    Future studies may be able to determine if the route of administration of HRT or treating with combined HRT or androgens result in different therapeutic outcomes.                                         
                                                         
    Women are particularly at risk and the role of sex steroids and its effects on the brain has been a major focus in AD research. There is evidence that sex steroids modulate brain development and ageing and can affect cognitive function. With regard to AD, epidemiological, neuropsychological, and biological studies appear to support the hypothesis that oestrogens may be   implicated in its genesis and treatment. Currently, routine therapeutic use of oestrogens in women with AD is not justified but it may have a role in the prophylaxis of AD.                                                
                              
    In the future new oestrogens may be synthesized which have the neuroprotective characteristics of the currently available oestrogens, but which do not carry the same side-effects (e.g. risk of breast cancer and thromboembolic disease). The recent finding that certain subtypes of oestrogens may be more ‘neuroprotective’ than others may help us identify such a compound . In conclusion, besides the need for clinical trials in people with AD there is a continuing search for a more selective oestrogen preparation without the unwanted side-effects of current preparations.                              
                                                        

  • Johan D Lefrandt, Jorg Heitmann, Knut Sevre, et al                           
    Contrasting effects of verapamil and amlodipine on cardiovascular stress responses in hypertension.          
    Br.J.Clin.Pharm, vol.52, Dec.2001, pg.687-692                     
                                                 
    Aim of the study was to compare the effects of two long-acting calcium antagonists of different types on cardiovascular stress responses in hypertension.                      
                                                
    One hundred and forty-five patients with mild to moderate hypertension and a mean (± s.e. mean) age of 51 ± 0.9 years received for 8 weeks the phenylalkylamine verapamil sustained release (240mg) and the dihydropyridine amlodipine (5mg) in a double-blind cross-over design, both after 4 weeks of placebo. Blood pressure, heart rate and plasma noradrenaline were monitored during 3 min of sustained isometric handgrip and 2 min of cold pressor.             
                                                                           
    Verapamil is more effective in reducing blood pressure and rate-pressure product responses to stress compared with amlodipine. Although plasma noradrenaline is lower with verapamil at rest and after stress, the increase during stress is not different.      
                                                                           

  • Tejal N Mitchell and Josemir W Sander           
    Levetiracetam: A New Antiepileptic Drug for the Adjunctive Therapy of Chronic Epilepsy.                
    Drugs of Today 2001, 37(10): 665-673.            
                                                                               
    Levetiracetam is a new antiepileptic agent licensed for use as adjunctive therapy for partial seizures with or without secondary  generalization. Preclinical studies suggest a novel site of action and efficacy against a broad spectrum of seizures with a wide  margin of safety. Data from animal studies have suggested an antiepileptogenic effect of levetiracetam, but clinical trials are   required to assess this further. Three large double-blind, randomized trials have proven levetiracetam to be effective as an   adjunctive agent in patients with partial seizures, with promising preliminary results as monotherapy and in children. There is also clinical evidence for sustained efficacy with long-term therapy and no apparent development of tolerance. It has a favourable pharmacokinetic profile, with almost 100% oral bioavailability. It is well tolerated and has a low potential for interactions with other drugs. Treatment with levetiracetam can be initiated in a twice daily regimen at a therapeutic dose (500mg twice daily). Further information is required for high-risk groups which were excluded from the major trials and the potential teratogenic effects in   humans.                         
                                                               
                                                                                                                          

  • Seema Kumar and Vishnu Ji Ram (Medicinal Chemistry Divn., Central Drug Research Institute, Lucknow, India)
    Future Trends in the Treatment of Cognitive Disorders
    Drugs of Today, 2001, 37(10): 675-689

    Table 1 : Strategy of stroke treatment
                              
                                  

    Strategy 

    Stroke Treatment

    Unblocking arterial occlusion

    Fibrinolysins (tPA), interventional radiology techniques,anti-platelet agents (aspirin).

    Treatment of vasoconstriction 

    Ca2+ channel blockers (nimodipine, nicardipine), b-adrenoceptor blockers.

    Altering blood  rheological characteristics, reducing viscosity

    Hemodilution, decreasing fibrinogen activity (ancrod, fish oils), piracetam, pentoxifylline, sulodexide and heparin-induced extracorporeal (LDL)/fibrinogen precipitation (HELP).

    Increasing delivery of oxygen 

    Perfluorocarbons

    Reducing effects of excitatory neurotoxins 

    NMDA receptor-blocking agents (memantine hydrochloride)

    Reducing brain energy demands 

    Hypotherrnia, barbiturates

    Neurtralizing free radicals

    Vitamin C, Vitamin E, superoxide dismutase (SOD), Nicergoline.

    Protecting cell membranes

    GM1 gangliosides, citicoline

    Reducing ischemic tissue lactate

    Reducing blood sugar production

    Neutralizing effects of brain opioid production.

    Blockade of opiate receptors (naloxone)

    Preventing or reducing brain edema.

    Mannitol, glycerol, diuretics 

     Table 2 : Cholinergic  enhancement therapy for Alzheimer’s disease

    Compound

    Phase

    Dose

    Tacrine ( Cognex )

    Preregistered/launched

    40-160 mg/day

    SDZ-ENZ-713 ( Exelon )

    II/III

    3-9 mg/day

    Eptastigmine

    II/III

    40-60 mg/day

    Donepezil (E-2020,Aricept )

    III/preregistered/registered

    5-10 mg/day

    Galanthamine 

    III/preregistered/launched

    20-45 mg/day

    Huperzine A

    III/preclinical

    0.15-0.25 mg t.i.d.

    Metrifonate

    II/III

    30-60 mg/day

    Velnacrine (HP-029)

    III

     150-225 mg/day

                        

  • Muscarinic agonists and antagonists         
                 

    Investigation on arecoline, bethanecol, pilocarpine, oxotremorine and RS-86 has been abandoned due to peripheral parasympathetic side effects in addition to low potency, a short duration of action and poor oral bioavailability. Xanomeline, an M1 agonist, has greater potential for combatting the cognitive and behavioral problems (psychosis, agitation, suspiciousness, verbal and physical aggression) associated with Alzheimer’s disease, and the newer compounds which are selective muscarinic agonists, are potential candidates for Alzheimer’s disease treatment.          
                            
    Cognitive therapy with M1 receptor agonists has a bright future since this receptor has been mostly localized to the hippocampus and necrotic regions of the brain, regions important in memory and learning. Preclinical evidence also indicates that M1 agonists have neuroprotective activity, with increased nonamyloidogenic processing of APP and tau dephosphorylation.                
     

  • Nicotinic agonists                       
                                                       
    A significant reduction in nicotinic receptors in the cortex and hippocampus has been implicated in demented illnesses such as Alzheimer’s disease. Stimulation of these receptors has been associated with enhanced memory, learning and attention capabilities in humans. Experimental evidence of protection against b-amyloid peptide toxicity in nicotinic receptor-stimulated cultured rat neutrons indicated that targeting of these receptors by nicotinic acetylcholine receptor agonists may lead to efficacy in treating cognitive decline associated with Alzheimer’s disease. Neuroprotective effects are generated upon nicotinic acetylcholine receptor activation mediated by the release of neurotrophic (NGF, BDNF, a-fibroblast) growth factors. However, despite these positive effects, the therapeutic use of compounds interacting with nicotinic acetylcholine receptors is associated with the negative attributes of nicotine, although some drugs acting on a3b4 and a4b2 subunits are under development for Alzheimer’s disease, including ABT_418, ABT-089, RJR-1734, RJR-2403 (metanicotine), ARR-17779, RJR-2557 and SIB-1553A, which are currently in phase I clinical trials for Alzheimer’s disease. Recently, a concerted effort has been made to discover highly subtype-selective agonists and antagonists.
                                                                           
    An imbalance in the release of various neurotransmitters is a general feature of cognitive disorders which needs to be addressed using different classes of site-specific drugs acting on their corresponding receptors as agonists or antagonists. Cholinergic therapy for the treatment of Alzheimer’s disease and mild cognitive decline is the most common modality, although the benefit seems to be limited in the case of Alzheimer’s disease. Cholinesterase inhibitors are the first generation of antidementia drugs to increase acetylcholine transmission across the synapse, but their efficient use is still not possible due to the inability to reliably detect the disease at an early stage. The use of acetylcholine-releasing agents has so far proved ineffective, only linopirdine reaching clinical trials. Nicotine’s effect on cognition appears to be more positive and attempts are being made to specifically stimulate nicotinic receptors so as to avoid the negative effects associated with nicotine. The dementia resulting from progressive neurodegeneration over the years is multifactorial, and thus the strategy most suitable should include therapeutic intervention along different lines in the form of combination therapy. Treatment designed to modulate factors such as free radical toxicity, restoring calcium homeostasis, decreasing inflammation, preventing cell membrane damage, excitotoxicity and neuronal apoptosis may also be effective.                       
                                                                                                                                                                               

  • Gillian M Shenfield         
    Therapeutic drug monitoring beyond 2000              
    Br.J.Clin.Pharm, vol.52, suppl.1, 2000, pg.3S         
                                                  
    Pioneers of drug monitoring in the 1970s focused on adverse drug reactions and demonstrated quite clearly, that by constructing therapeutic ranges, the incidence of toxicity to drugs such as digoxin, phenytoin, lithium and theophylline could be reduced. It was also recognized that a number from a laboratory could not be interpreted in isolation but needed to be reviewed together with clinical details of the patient from whom the sample had been taken. Thus the indications for drug monitoring widened to include efficacy, compliance, interactions etc. This gave Clinical Pharmacologists a clearly identified role and, certainly in Australia, a number of Clinical Pharmacology departments were established in the late 1970s and early 1980s, with a primary role of performing drug monitoring. Whether part of an academic unit or directly answerable to a teaching hospital, these units not only performed routine services but conduced research in many areas where drug concentrations could easily be incorporated. This engendered a somewhat complacent attitude, when it was claimed that the value of TDM to a practicing physician was ‘an hypothesis in need of testing’. Although TDM is an attractive concept there was very little evidence that it improved overall patient outcome. It was argued that careful dosage adjustments based on clinical response and biochemical findings could be just as effective without closing the circuit by including the plasma drug concentration.
                                                
    In contrast more recent work has provided some evidence for the usefulness of drug assays in certain specific situations and Cridland has provided a number of ways in which drug monitoring services can be assessed as to their usefulness and cost effectiveness. A meta-analysis of studies on TDM, albeit of a limited number of drugs, showed that TDM does appear to be beneficial for patients taking theophylline or digoxin. Furthermore, the service reduced the proportion of inappropriately collected samples. 
                                                            
    Besides the long established areas of anticonvulsants, antiarrhythmics and antibiotics, there have been some interesting and exciting developments in the areas of immunosuppressants, cytotoxic drugs and psychotropic drugs. All too often the pharmacodynamic aspects of interpretation are omitted from discussions on TDM.                   
                                         

  • Annette S Gross
    Best Practice in therapeutic drug monitoring
    Br.J.Clin.Pharm, Suppl.1, 2000, pg.5S.
                                           
    Table 1 : Reasons for requesting drug concentration measurements.  


    Toxicity suspected  –  toxic concentration ?
    Lack of response    –  subtherapeutic concentrations ?
    Assessment of compliance with medication regimen
    Assess therapy following a change in dosage regimen
    Change in clinical state of the patient
    Potential drug interaction due to change in comedications
    Manifestations of toxicity and disease state are similar.


    Table 2 : The information required to interpret a drug concentration.


    The information required to interpret a drug concentration includes:
          time blood sample taken
          time dose given
          dosage regimen (dose, duration, dosage form)
          patient demographics (sex, age, concomitant disease, ethnicity etc.)
          comedications
          indication for monitoring
          pharmacokinetics and therapeutic range of the drug.


     

  • Evan J Begg, Murray L Barclay & Carl M.J. Kirkpatrick         
    The therapeutic monitoring of antimicrobial agents          
    Br.J.Clin.Pharm, vol.52, 2001, pg.35S-43S.         
                       
    The aim of the study was to review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents.
                   
    There is a strong historical case for monitoring aminoglycosides.               
                        
    The approach to monitoring aminoglycosides is being redefined in the light of once daily dosing. It may be that less stringent monitoring is required in some circumstances but toxicity, especially ototoxicity, remains a problem with these drugs. Monitoring to avoid high AUCs (areas under the concentration-time curve) is recommended. The ideal method for monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is sometimes monitored to ensure efficacy while flucytosine may be monitored to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.         
                                                

  • Gwen L Zornberg, Hershel Jick
    Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study.
    The Lancet, vol.356; Oct.7, 2000: 1219-23    
                                       
    Aim of the study was to assess the risk of venous thromboembolism in users of conventional antipsychotic drugs who had been diagnosed with first-time, idiopathic venous thromboembolism.        
                                 
    Current exposure to conventional antipsychotic drugs was associated with a significantly increased risk of idiopathic venous thromboembolism compared with non-use. Although, authors found no difference between phenothiazines, thioxanthenes, or other conventional antipsychotic drugs, low potency antipsychotic drugs such as chlorpromazine and thioridazine were more strongly associated with venous thromboembolism than were high potency antipsychotic drugs such as haloperidol. The risk for venous thrombosis was highest during the first few months of conventional antipsychotic drug use.       
                                    
    Interpretation of this study is that current exposure to conventional antipsychotic drugs significantly increases the risk of idiopathic venous thromboembolism in men and women younger than 60 years of age.       
                         

  • Victor E Tapson
    Commentary – Risk of venous thromboembolism with use of antipsychotic agents.
    The Lancet, vol.356, Oct.7, 2000, pg.1206
                             
    The relation between antipsychotic medicines and venous thromboembolism (VTE) was first suggested about four decades ago, only a few years after the introduction of phenothiazines and reserpine. Despite these early descriptions and subsequent reports, the evidence for a true link has not yet been deemed sufficient for inclusion in lists of risk factors in standard textbooks or review articles on venous throboembolism. Many of the early studies lacked controls and convincing evidence of the absence of concomitant thrombogenic risk factors.           
                                          
    The case-control analysis by Gwen Zornberg and Hershel Jick reported in the Lancet suggests that this association should be re-examined.         
                           
    Although this clinical study suffers from the usual limitations of a case-control design, the cohort was large (nearly 30000) and the observation period was long (mean 6.8 years). Also, the diagnosis of VTE was confirmed by objective tests, and patients with certain disease states that have not been clearly identified as risk factors (e.g. diabetes, cystic fibrosis, disorders due to alcohol and substance misuse) were also excluded, but this point would probably have affected both cases and controls equally. The attempt to exclude patients with other risk factors and to identify more clearly use of antipsychotic agents as a risk factor is important. However, it is quite possible that, in the presence of additional risk factors such as previous VTE, obesity, or cancer, antipsychotic agents may further enhance the risk of thromboembolism.              
                                                                              

  • Francois Nosten               
    Commentary – Prophylactic effect of Malarone against malaria: all good news?           
    Lancet, vol.356, Dec.2, 2000, pg.1864.          
                           
    Birthe Hogh colleagues report the results of a large, detailed, and well-conducted trial of Malarone (Glaxo-Wellcome) for the prophylaxis of malaria in travellers. This fixed combination of atovaquone and proguanil was a safe and effective prophylactic agent in travellers. To people trying to combat increasing drug resistance in Plasmodium falciparum, this finding seems like good news – or is it?  
                              
    The main component of the combination (atovaquone) belongs to a family of anti-infective compounds, the hydroxynaphthoquinones, which has been known for over 50 years to be active against P.falciparum. The first studies in human beings were disappointing, and the prototypes of this group of drugs were not studied further.      
                                
    Meanwhile, when it became clear that P.facliparum was developing resistance to other classes of drugs at an alarming pace, the antimalarial property of atovaquone was re-explored.                  
                                        
    Mass chemoprophylaxis is not recommended currently (except in pregnancy) for fear of encouraging resistance, and the drug is far too expensive for poor tropical countries.                             
                                      
    For the treatment of P.falciparum infections, Malarone (if affordable) could prove very valuable in areas where the parasite is becoming resistant to all other drugs.               
                                     
    By inhibiting mitochondrial electron transport in the parasite, atovaquone reduces pyrimidine synthesis and causes collapse of the mitochondrial membrane potential. Despite the combination with proguanil, atovaquone is clearly vulnerable to resistance, as shown in clinical studies. New, safe, and the affordable antimalarial drugs are unlikely to be developed in the near future, so malarone needs to be protected. Protection can be achieved by judicious use and by combining Malarone with an artemisinin derivative. Thus, the finding that Malarone is safe and effective in protecting wealthy travellers is good news, but not necessarily for the millions living (and dying) with malaria in the tropics.                                        
                                 

  • Kathryn Senior       
    Neuropeptide may shift rheumatoid arthritis into remission.              
    Lancet, No.357, May 5, 2001, pg.1418        
                                                       
    A preclinical study suggests that vasoactive intestinal peptide (VIP) may reduce some of the disabling joint problems that can develop as a result of rheumatoid arthritis (RA). “VIP appears to have therapeutic potential for RA and other chronic inflammatory disease and Th1-dependent autoimmune disorders such as Crohn’s disease, multiple sclerosis, and autoimmune diabetes”, says lead author Mario Delgado.          
                                                                                  
    Delgado and colleagues chose to study the effects of VIP on the Th1/Th2 systems in collagen-induced arthritis (CIA), a murine experimental model of human RA. RA-like symptoms were induced by immunization of mice with type II collagen. After two immunisations, but before symptoms appeared, VIP was administered in different doses, either as a single injection or as multiple injections given every day, or every 2 days, for a period of 2 weeks. Mice treated with VIP showed delayed onset, lower incidence, or decreased severity of induced arthritis-effects that were dose dependent. Daily or every-other-day dosage offered the best protection against disease, but one single dose had a significant impact on the development of arthritis. Symptoms in the mice were slow to develop after VIP treatment ceased, indicating that short spells of VIP administration may be enough for long-term disease control.    
                                               
    Further detailed experiments explored the exact nature of the action of VIP on the murine immune system and confirmed that VIP was acting through a specific inhibitory effect of the Th1 response.         
                                           
    The future prospects of VIP hinge on imminent toxicology studies, but Delgado is still optimistic.           
                                                                                   

  • Sheila A. Doggrell (Department of Physiology and Pharmacology, The University of Queensland, Brisbane, Queensland, Australia)  
    Targets to Trials in Diabetic Complications    
    Drugs of Today, Vol. 37(11), November 2001, Pg. 739-748  
                  
    Diabetes is now the leading cause of end-stage renal disease, blindness, lower-extremity amputations and impotence. 
                                
    Targets with potential for therapeutic intervention in diabetic complications
                                         

    Genetic studies: Aldose reductase inhibitors   
                              
    A candidate gene near the transcription site of the aldose reductase gene has been identified. Aldose reductase inhibitors have not been shown to be beneficial in diabetic complications. A possible explanation for this is that aldose reductase is only one pathway that leads to stimulation of MAPKs (mitogen-activated protein kinases), which may be common mediators of diabetic complications and thus inhibition of aldose reductase alone is not effective.      
                                   
    MAPKs (Mitogen-activated protein kinases)        
                                           
    Professor David Tomlinson (University of Manchester, U. K.) presented evidence that the MAPKs trigger all of the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy. Professor Tomlinson suggested that the damaging effects of glucose, regardless of pathway (sorbitol, nonenzymatic glycation of proteins, oxidative stress) were finally mediated by the MAPKs (ERK, JNK and p38).         
                                                   
    To support his hypothesis Professor Tomlinson provided experimental evidence using selective inhibitors of p38 (SB202190 and SB238063) and ERK (U0126) but stated that selective antagonists of JNK were not presently available. Some suggested that the MAPKs are far too widespread and involved in too many functions to be therapeutic without serious side effects and that signaling upstream of MAPKs would make more selective targets.    
                                                                
    Others suggested that in low doses MAPKs may have some therapeutic potential in diabetic complications. 
                           
    PKC (Protein kinase C)
                                          
    PKC is upstream in the MAP-kinase pathway. Inhibition of glomerular PKC activity by a specific inhibitor of the ß isoform (LY333531) has been shown to prevent diabetes-related vascular dysfunction and increases in albuminuria in an animal model (12).
                                     
    Activation of a specific isoform of PKC may be involved in retinopathy and this isoform is a potential target. The identification of a specific isoform of PKC associated with retinopathy increases the likelihood of having beneficial effects in retinopathy without excessive side effects.     
                                                   
    TGF-ß (Transforming growth factor-ß)       
                                       
    The important role of TGF-ß in mesangial and macro- and microvascular dysfunction was considered by Professor Kumar Sharma (Thomas Jefferson University, Philadelphia, U.S.A.). In an animal model of type II diabetes, the diabetic glomerular hypertrophy could be prevented with anti-TGF-ß antibodies. 
                                                        
    The reported beneficial effects of the ACE inhibitor captopril and the AT1-receptor antagonist losartan in diabetic kidney disease may be partly due to inhibiting angiotensin II stimulation of TGF-ß. As TGF-ß has beneficial effects at other sites, it seems an unlikely target for therapeutic intervention in diabetic complications, as these beneficial effects may also be inhibited. 
                                                  
    However, if there is excessive production of TGF-ß in diabetic complications, it may be possible to reduce the excessive effects without modifying the beneficial functions. 
                                                   
    Another possible target is the interrupting of various downstream effects of TGF-ß. Thus, USF-1 (upstream stimulatory factor-1), GRE (glucose response element), IP3R (the inositol 1,4,5-triphosphate receptor) may be important therapeutic targets to combat diabetic complications.   
                                 
    Nitric oxide/tetrahydrobiopterin  
                                          
    Diabetics have reduced vasodilatation and inadequate angiogenesis. These disturbed vascular responses appear to be the result of impaired synthesis of nitric oxide (NO). The roles of NO and tetrahydrobiopterin, an essential cofactor for NO synthase, in vascular dysfunction in diabetes were discussed by Dr. Cynthia Meininger. 
                                        
    There are several possible ways to improve the endothelial dysfunction in diabetes. Tetrahydrobiopterin supplements could be used. The nitrates and the NO-donor drugs also have the potential to overcome this dysfunction. 
                                  
    Antioxidants/superoxide dismutase
                               
    Oxidative stress with superoxide production also contributes to the vascular dysfunction in diabetes. However, when vitamin E, an antioxidant, was used in the HOPE study it was ineffective.   
                                                
    They assessed whether vitamin E supplementation for three months would improve conduit and resistance vessel vasodilator function in 41 subjects with type I diabetes, in a double-blind, placebo-controlled, randomized study. 
                                       
    Vitamin E improved endothelial function assessed by brachial flow-mediated dilatation and by intraarterial acetylcholine. This improvement was associated with a decrease in LDL cholesterol oxidation.   
                                  
    Wound healing: VEGF  
                                 
    Delayed wound healing, or an inability to carry out tissue repair processes, is a major complication of diabetes leading to an increased incidence of chronic wounds such as leg ulcers.   
                                           
    There are a number of factors involved in the healing impairment in diabetes. These include the acute effects of hyperglycemia, the long-term effects of advanced glycosylation of extracellular matrix proteins and changes in expression levels and availability of growth factors or cytokines.   
                                    
    VEGF is very important in angiogenesis but it is reduced in diabetic wounds. VEGF is detrimental in retinopathy. Thus, the local administration of VEGF to diabetic wounds will need careful testing of whether it is beneficial to the wounds without being detrimental to the eye.   
                                                
    Inhibition of advanced glycation endproducts (AGE) formation.  
                                            
    ACE inhibition with ramipril decreased AGE levels in experimental diabetes and this effect may have contributed to the benefit of ramipril in diabetic patients in the HOPE trial.  
                            
    Connective tissue growth factor (CTGF)   
                                      
    CTGF is a potent inducer of extracellular matrix and its gene expression is increased in rodent models of diabetes. AGE induces CTGF through a non-PKC-dependent pathway, and AGE and CTGF induce fibronectin through a PKC-dependent mechanism. 
                            
    Thus, CTGF may be a new target for consideration in the treatment of complications of diabetes.   
                                        
    Glucose transformer isoform 1 (GLUT-1) transporter   
                                     
    As the GLUT-1 transporter is overexpressed in mesangial cells subject to mechanical stress, this is a potential site for pharmacological intervention in diabetic complications.   
                                  
    Nephrin  
                                        
    Nephrin is a cytoskeletal protein that localizes to the slit pore of podocytes. In some proteinuric models, deficiencies in nephrin have been associated with increases in albuminuria. Nephrin is a potential target for pharmacological intervention in diabetes associated with hypertension. 
                           
    Mineralization inhibitors
                                          
    Calcification of the media of peripheral arteries is referred to as Monckeberg’s sclerosis and occurs commonly in diabetic individuals, often in association with neuropathy and uremia. Its presence is an independent predictor of cardiovascular events and is associated with trophic foot ulceration and peripheral artery occlusive disease. 
                                    
    Vascular calcification is an actively regulated process. This process results in the deposition of hydroxyapatite, the mineral found in bone, the vessel wall and ultimately leads to osteogenic metaplasia and the formation of bone trabeculae. 
                                      
    Dr. Shanahan suggested that factors that can effect the rate of vascular smooth muscle apoptosis or that can effect the differentiation of the smooth muscle cells into an osteo/chondrocryptic phenotype could potentially regulate the rate of calcification in vessels. 
                            
    Mineralization inhibitors, such as etidronate, which slow the formation and dissolution of hydroxyapatite crystals have not been tested to date on vascular calcification. 
                                  
    The glitazones
                                               
    Mechanisms: Potential for treatment of restenosis
                         
    The thiazolidinedione glitazones are a recently introduced group of drugs for the treatment of diabetes that increase insulin sensitivity and are more powerful in doing this than metformin. 
                             
    The glitazones stimulate peroxisome proliferator-activated receptor (PPAR)-ß in the adipocytes and muscle to decrease free fatty acids. The glitazones also act on muscle to increase sensitivity to insulin. As the glitazones have only recently been introduced, intriguing questions remain as to their long-term effects. For instance, will they reduce cardiovascular events or mortality?
                                                    
    Glitazones and other PPAR-Y ligands may have therapeutic potential in the treatment of restenosis. Although the atherogenic effect, if any, of insulin is small, hyperinsulinemia is a major culprit in the development of restenosis following coronary artery angioplasty or stenting. 
                                              
    Insulin also potentiates proliferative signals or more potent mitogens such as PDGF, bFGF, and EGF. Rosiglitazone, troglitazone (which also acts as an antioxidant) and pioglitazone stimulate PPAR-Y to inhibit insulin-mediated ERK (a mitogen activated protein kinase) -dependent smooth muscle proliferation.        
                                   
    Thus, the glitazones have clinical potential in the treatment of restenosis and atherosclerosis. 
                                 
    Vasopeptidase inhibitors
                                 
    Most advanced diabetics need at least two or more drugs (including renin-angiotensin system inhibitors) to achieve adequate blood pressure control. 
                                
    Vasopeptidase inhibitors are simultaneous inhibitors of ACE and the neutral endopeptidase (NEP), which is the major enzymatic pathway for the degradation of atrial natriuretic peptide (ANP). NEP is widely distributed in the body and shows a broad substrate specificity including the degradation of bradykinin, endothelin and substance P as the conversion of angiotensin I into angiotensin III.
                                             
    Vasopeptidase inhibitors produced a dose-dependent reduction in blood pressure that was greater than that with equivalent doses of ACE inhibitors. Treatment with vasopeptidase inhibitors also caused a reduction in cardiac hypertrophy, which was over and above that observed due to blood pressure reduction alone. 
                                    
    This suggests that the vasopeptidase inhibitors have a specific antitrophic effect, possibly by reducing angiotensin II and increasing ANP. In diabetic SHR, vasopeptidase inhibitors were effective antihypertensive agents that reduced heart weight and albuminuria, increased natriuresis and did not have adverse effects on renal function.   
                                    
    In the 5/6 nephrectomized rat model of chronic renal failure, which shares some hemodynamic similarities with diabetic nephropathy, treatment for 12 weeks with a vasopeptidase inhibitor reduced blood pressure, proteinuria and improved renal structural changes, including glomerulosclerosis and tubulointerstitial injury. Following these experimental studies, the vasopeptidase inhibitor should be tested in human diabetes and renal failure.            
                                         
    Triple inhibitors:            
                              
    These are drugs that inhibit the conversion of proendothelin to endothelin by endothelin-converting enzyme in addition to inhibiting ACE and NEP. The triple inhibitors are presently being tested in animal models of diabetes.         
                                      
    Clinical trials with ACE inhibitors and vitamin E             
                                         
    The Heart Outcomes Prevention Evaluation (HOPE) study and Microalbuminuria, Cardiovascular and Renal Outcomes (MICRO-HOPE) substudy         
                                 
    In the MICRO-HOPE substudy, the 3577 subjects included in the HOPE study with diabetes were analyzed. In diabetics, ramipril lowered the risk of myocardial infarction, stroke, revascularization and overt nephropathy.        
                  

  • Markus Muller 
    Science, medicine and the future – Microdialysis
    BMJ, VOL.324, March 9, 2002, pg.588
      
    Monitoring tissue chemistry in patients by microdialysis is likely to become routine in clinical paractice.
      
    Many diagnostic and therapeutic decisions in medical practice are based on measuring blood concentration of endogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Assessing tissue chemistry should theoretically provide more accurate data, and this can now be achieved relatively cheaply and minimally invasively with microdialysis.
        
    Principles of microdialysis
    In vivo microdialysis measures the chemical composition of the interstitial tissue fluid- that is, the fluid to which cells and other target structures are directly exposed. In contrast to imaging techniques or biosensors, which serve as detecting tools, microdialysis is a sampling tool and needs to be linked to an analytical device. Depending on the availability of an appropriate analytical assay, virtually every soluble molecule in the interstitial space fluid can be measured by microdialysis. In recent years, the use of microdialysis has moved from preclinical evaluation and validation to clinical application, reflected by a considerable growth in the literature.
       
    The concept of microdialysis goes back to the early 1960s, when push-pull cannulas, dialysis sacs, and dialytrodes were inserted into animal tissues to study tissue biochemistry directly.
      
    Summary points
    Microdialysis enables the in vivo measurement of tissue chemistry in humans and is feasible in virtually every human organ.
       
    It is currently being used to monitor brain ischaemia and metabolic control.
    The technique is set to become a standard tool in drug monitoring and development.
    In the future “bedside” microdialysis will allow monitoring of tissue metabolism in a wide range of diseases.

    Current clinical research applications of microdialysis
    Elucidating the chemical basis for initiation of seizures (such as pre-epileptic increase in glutamate and a consecutive surge in γ-aminobutyric acid).
      
    Studying neurochemical patterns in defined brain areas (such as increased dopamine release in human amygdala during performance of cognitive tasks).
       
    Studying local physiology of adipose tissue, muscle, and skin.
      
    Measuring peptides and metabolites at site of action or release and describing paracrine regulations in select organs or tissues such as the ovary and subcutaneous fat.
        
    Administering drug locally by microdialysis without inducing systemic side effects and simultaneously measuring the corresponding tissue response, such as catecholamine induced lipolysis. 
     

  • Lap Ho and Giulio Maria Pasinetti
    The Potential of Selective Cox-2 Inhibitors in Inflammatory and Other Diseases
    Drugs of Today 2001, 37(3), 181-185
        
    There are two known COX isoforms with distinct physiological functions, COX-1 and COX-2. COX-1 is a constitutively expressed protein found in most tissues. In the gastric mucosa, COX-1 is involved in the production of cytoprotective prostacyclin. In platelets, COX-1 is required for the generation of thromboxane A2, which promotes platelet aggregation leading to thrombus formation. In contrast to COX-1, COX-2 is strongly inducible by a variety of mitogens such as cytokines and growth factors, and plays a key role in the production of inflammatory prostaglandins.
        
    Efforts to identify new anti-inflammatory compounds which are less damaging to the stomach led to the marketing of meloxicam, etodolac and nimesulide, all since recognized to be selective COX-2 inhibitors. More recent generations of drug such as rofecoxib and celecoxib, which are specifically designed to be selective COX-2 inhibitors, are available on the market. The availability of selective COX-2 inhibitors is expected to improve therapeutic applications in traditional inflammatory diseases, as well as in cancer and neurodegenerative disorders.
       
    Development of assays to predict selectivity of NSAIDs for COX-1or COX-2 is critical to the development of the next generation NSAIDs. A key consideration is that these assays should be based on human COX systems.

    Caution Regarding COX-2 Inhibitors
    One of the concerns regarding therapeutics of COX-2 inhibition is its potential effect on renal function.

    COX-2 plays a pivotal role in the regulation of extracellular fluid volume and COX-2 inhibition could impede normal renal function. This is of particular concern in the face of salt depletion in man or in diseases characterized by abnormalities of salt and water homeostasis such as congestive heart failure or hepatic cirrhosis and ascites. Another area of concern regarding COX-2 inhibition and renal function is that COX-2 is critical for nephron differentiation and maturation.

    Selective COX-2 inhibition may also have undesirable effects on the cardiovascular system. COX-2 is expressed in both normal and inflamed vasculature. The suppression of prostacyclin and its cardiovascular implications needs to be considered in clinical trials of COX-2 inhibitors.

    Evidence indicates that COX-2 has a role in the healing of gastric ulcer. The mechanisms that NSAIDs may interfere with in ulcer healing might be similar to those that induce apoptosis in malignant cells. Therefore, utility of COX-2 inhibitors among high-risk patients, e.g. colitic patients, requires careful consideration and monitoring.

    Selective COX-2 inhibition in Cancer.
    COX-2 has been found to be upregulated in a variety of cancers, including colon, skin, lung, breast, bladder and prostate cancers. Consistent with the current view that COX-2 promotes tumor growth and development, selective COX-2 inhibitors or disruption of COX-2 gene suppress carcinogenic phenotype of transformed cells in vitro and tumor formation in animal models in vivo.
        
    The apparent efficacy of NSAIDs in treating cancer may involve the induction of apoptotic mechanisms in cancer cells. NSAIDs induce apoptosis in vitro in a wide variety of neoplastic cells in vitro as well as colorectal tumors in vivo. NSAID induced apoptosis in some cell systems may be independent of interaction with COX-1 or COX-2. This is supported by evidence that relatively high concentrations of NSAIDs are required to induce apoptosis, and that NSAIDs can induce apoptosis in cells deficient in both COX isoforms.
       
    Ongoing investigations will clarify whether COX-2 has a prognostic value in malignant diseases and which type of tumors will benefit from therapy with selective COX-2 drugs.
        
    Selective COX-2 Inhibition in Neurodegenerative Disorders
    In the brain, COX-2 is overexpressed in response to ischemia, trauma, seizures and neurodegeneration such as in Alzheimer’s Disease (AD).
       
    It is likely that the neuroprotective mechanisms of action of NSAIDs in AD are mediated in part by inhibition of COX-2 activity in the brain. This potential neuroprotective role has generally been attributed to suppression of deleterious inflammatory activities.
       
    Place of Selective COX-2 Inhibitors in Therapy.
    NSAIDs induce damage to the gastrointestinal tract and impair ulcer healing. Selective COX-2 inhibitors appear to cause no more gastrointestinal problems than placebo. The current consensus is that since standard NSAIDs are nonspecific for both COX isoforms, the side effects of selective COX-2 inhibitors should be no different and no greater in comparison to standard NSAIDs when equivalent doses are used. The advent of selective COX-2 inhibitors that spare gastrointestinal prostaglandin synthesis is a major conceptual and therapeutic advance. Outstanding questions are whether the selective COX-2 inhibitors may inhibit gastrointestinal tract healing or provoke the relapse of gastrointestinal ulceration or associated colitis.
                   

  • Scott Gottlieb
    News : b Blockers Improve Bypass Surgery Survival Rates
    BMJ, 11 May, 02, Vol.324, pg.1118
      
    Patients who take b blockers before coronary artery bypass surgery can increase their odds of surviving, a new study says.
     
    The study found that 2.8% of patients who took b blockers before surgery died within a month, compared with 3.4% of patients who did not take the drugs.
      

  • David N. Herndon, David W. Hart, et al
    Reversal of Catabolism by Beta-Blockade After Severe Burns
    New Eng J Med. Vol.345, Oct.25, 2001, pg.1223-9
      
    Catecholamine-mediated hypermetabolic response to severe burns causes increased energy expenditure and muscle-protein catabolism. Authors hypothesized that blockade of b-adrenergic stimulation with propranolol would increase resting energy expenditure and muscle catabolism in patients with severe burns.
      
    Twenty-five children with acute and severe burns (more than 40 percent of total body-surface area) were studied in a randomized trial. Thirteen received oral propranolol for at least two weeks, and 12 served as untreated controls. The dose of propranolol was adjusted to decrease the resting heart rate by 20 percent from each patient’s base-line value.
      
    Resting energy expenditure and skeletal-muscle protein kinetics were measured before and after two weeks of beta-blockade (or no therapy, in controls). Body composition was measured serially throughout hospitalization.
      
    The net muscle-protein balance increased by 82 percent over base-line values in the propranolol group.
     
    In children with burns, treatment with propranolol during hospitalization attenuates hypermetabolism and reverses muscle-protein catabolism.
      

  • Paul S. Frenette
    Locking a Leukocyte Integrin with Statins
    New Eng J Med. Vol.345, Nov. 8, 2001, pg.1419-21
      
    Because lipid intermediates of cholesterol synthesis (isoprenoids) allow the attachment to the cell membrane of signaling proteins involved in various functions, statins have other biological effects. They can stimulate bone formation, alter the function of endothelial cells, induce apoptosis of smooth-muscle cells, inhibit the growth of tumor cells, and reduce the inflammatory response.
      
    Recently, Weitz-Schmidt and coworkers found that statins also influence the inflammatory response by directly inhibiting the main b2 intergrin, a1b2 integrin. A region in the extracellular domain of a1b2 integrin referred to as the inserted, or I, domain mediates the binding of the protein to its main ligand, intercellular adhesion molecule 1 (ICAM-1).
      
    The function of a1b2 integrin varies depending on the leukocyte subgroup on which it is expressed. For example, a1b2 integrin on T cells participates in the immune response when it and the T-cell receptor are simultaneously engaged, whereas a1b2 integrin on myeloid cells promotes diapedesis of leukocytes across the endothelium.
      
    Kallen et al. found that one of the statins (lovastatin) blocks the interaction between a1b2 integrin and ICAM-1 in vitro. Weitz-Schmidt et al. found that other statins, including simvastatin and mevastatin, but not pravastatin, also inhibit the interaction between a1b2 integrin and ICAM-1.
     
    The inhibition of a1b2 integrin by statins was specific. Guided by the crystal structure of the complex formed by a1b2 integrin and lovastatin, Weitz-Schmidt et al. designed a compound, LFA703, that strongly inhibits a1b2 integrin but does not affect the activity of HMG-CoA reductase. LFA730 profoundly inhibits the proliferation of T cells mediated by a1b2 integrin, and oral administration of LFA703 reduces the recruitment of polymorphonuclear neutrophils into chemically inflamed peritoneum in mice.
      
    These findings have important clinical implications. Since patients receiving statin drugs are at risk for arteriosclerotic lesions characterized by the infiltration of monocytes and T cells, blockade of a1b2 integrin by statins could influence the progression of arteriosclerosis. It is important to remember, however, that although statins block HMG-CoA reductase at very low concentrations (in the nanomolar range), the inhibition of the interaction between a1b2 integrin and ICAM-1 requires much higher concentrations of statins (in the micromolar range), which may not be achieved with the use of the standard doses of approved statin drugs.
      
    Statins that do not block the function of a1b2 integrin can have clinically significant antiinflammatory effects. For example, pravastatin improves survival and lowers the incidence of acute rejection after heart transplantation. Two recent studies have shown that both pravastatin and lovastatin reduce serum concentrations of C-reactive protein, a marker of inflammation, by approximately 15 percent.
      
    The statin-like inhibitor synthesized by Weitz-Schmidt et al. is the first in a new class of synthetic inhibitors that can profoundly alter the function of b2 integrins in vivo. Given the dual function of a1b2 integrin, such agents may prove useful in preventing and treating disorders involving both myeloid and T cells, such as graft-versus-host disease and a number of autoimmune diseases.
      
    A greater understanding of the biologic functions of integrins and a growing knowledge of the relation between the structure and function of these proteins should allow the investigators to identify clinical situations in which synthetic integrin antagonists could have a profound effect.
        

  • Bengt I. Eriksson, Kenneth A. Bauer, et al
    Fondaparinux Compared with Enoxaparin for the Prevention of Venous Thromboembolism After Hip-Fracture Surgery
    New Eng J Med. Vol.345, Nov. 1, 2001, pg.1298-1304
      
    Surgery for hip fracture carries a high risk of venous thromboembolism, despite the use of current thromboprophylactic treatments. Fondaparinux, a synthetic pentasaccharide, is a new antithrombotic agent that may reduce this risk.
      
    Fondaparinux is a new synthetic pentasaccharide that causes selective inhibition of activated factor X (factor Xa). A recent study of patients undergoing major orthopedic procedures suggested that a once-daily subcutaneous injection of fondaparinux reduces the risk of venous thromboembolism more than does low-molecular-weight heparin.
      
    The authors conducted a multicenter, randomized, double-blind trial to compare two types of thromboprophylaxis after hip-fracture surgery: a once-daily subcutaneous injection of fondaparinux, initiated postoperatively, and a once-daily subcutaneous injection of enoxaparin, initiated preoperatively.
      
    In patients undergoing surgery for hip fracture, fondaparinux was more effective than enoxaparin in preventing venous thromboembolism.
        

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