Speciality
Spotlight

 




           

Clinical Pharmacology

       

     





  • Leape
    LL, Cullen DJ, Clapp MD, et al [Harvard School of
    Public Health : Massachusetts Gen. Hospital; Brigham
    and Women’s Hosp., Boston]


    Pharmacist
    Participation on Physicians Rounds and Adverse Drug
    Events in the Intensive Care Unit

    JAMA
    282: 267-270, 1999

       

    Although
    studies show that pharmacist review of ICU
    prescription orders prevents mistakes and lowers
    drug costs by reducing drug use, there have been no
    studies on the benefits of having a pharmacist
    present in the ICU at the time drugs are prescribed.
    The efficacy of pharmacist participation in a
    medical ICU in preventing adverse drug events [ADEs]
    was tested in a controlled clinical trial.

       

    Between
    February 1 and July 31, 1993 [Phase 1
    Preintervention] and October 1, 1994 and July 7,
    1995 [Phase 2 postintervention], the effect of
    pharmacist intervention was tested in a 17-bed ICU
    [the study unit] and compared with no pharmacist
    intervention in a 15-bed coronary care unit with
    similar occupancy rate [the control unit].

       

    ADEs
    were compared for 75 randomly selected patients in
    each of the 3 groups from amongst all patients
    admitted to the study unit in Phase 1 and 2, and all
    patients admitted to the control unit in Phase 2. An
    experienced pharmacist made daily morning rounds
    with ICU personnel in the study unit; an experienced
    pharmacist was available for consultation but did
    not make daily rounds in the control unit.
    Outcome measures included measurements of
    ADEs, interventions the pharmacist made, and the
    acceptance of pharmacist interventions by the
    physicians and nurses.

       

    The
    overall rate of preventable ordering and ADEs/1000
    patient days decreased by 66% in the study unit from
    Phase 1 to 2, with significant savings in drugs
    costs. The
    rate of ADEs came down significantly in the study
    group from Phase 1 to 2. In the control group the
    rate of ADEs continued to remain high.

       

    Of
    the 398 pharmacist interventions reported, 366 were
    related to ordering and 362 were accepted by the
    physicians.  Pharmacist
    – initiated clarifications or correction of
    incomplete orders, wrong dose, wrong frequency,
    inappropriate choice, or duplicate therapy accounted
    for 46% of interventions.
    Drug interactions or adverse reactions were
    prevented in 22 cases.

       

    The
    presence of a pharmacist at rounds in ICUs
    significantly reduces incidence of ADEs and result
    in substantial cost savings.

          

  • Presented
    at XII International symposium
    on Atherosclerosis, Stockholm, Sweden.

    Superstatin boosts Astra Zeneca

    Scrip
    no.2554, July 5, 2000, p.18

       


    Rosuvastatin (ZD4522) is the most potent cholesterol
    lowering agent known.
    It lowers LDL cholesterol by 65% as compared to 25% by
    current statins.

      

    It
    does not produce hepatotoxicity or myotoxicity.
    Liver enzymes and CPK remain normal.
    It has a long half-life (once a day dosing).
    Rosuvastatin is not metabolised by the liver.

        

  • Caelyx
    approved in EC for cancer


    SCRIP
    No.2588, November 1st, 2000, pg.22

      

    Pegylated
    liposomal doxorubicin (Caelyx) also known as Doxil has been approved
    in the EC for ovarian cancer.
    It is administered intravenously once every 4 weeks.
    Although there have been concerns that results of clinical
    trials submitted to US NDA (FDA) were not very meaningful, there are
    no alternative advanced treatment options for ovarian cancer and the
    FDA advisory panel decided that the product may be useful.

         

  • R
    Gupta, Shalini Singhal. et al (Department of Medicine, Monilek
    Hospital and Research Centre, Jaipur)


    Antioxidant and
    Hypocholesterolaemic Effects of Terminalia
    arjuna
    Tree-Bark Powder: A Randomised Placebo-Controlled Trials.


    JAPI,
    Vol.49, February 2001, pg.231 – 235.

      

    One hundred and
    five successive patients with coronary heart disease were divided
    into 3 groups and treated with either placebo, vitamin E capsules
    400 units/day or Terminalia
    arjuna
    500mg/day in capsules.

      

    After 30 days
    follow-up, blood biochemistry was repeated.
    No significant changes in total cholesterol HDL, LDL and
    triglyceride were seen in the placebo group and vitamin E group.  In the group, who received terminalia
    arjuna
    there was significant fall in cholesterol and LDL
    cholesterol.

      

    Conclusion
    by the authors was that terminalia
    arjuna
    has significant antioxidant action and also has a
    significant cholesterol lowering effect.

       

  • HS
    Bawaskar, PH Bawaskar,


    Prazosin Therapy and
    Scorpion Envenomation


    JAPI
    2000, VOL.48(12), P.1175.

      


    One of the most
    dangerous scorpions in the world is Mesobuthus tamulus.
    It is very common on the Western coast of India.
    It is known as the Indian red
    scorpion and is a very
    aggressive species of scorpion and scorpion stings are very common
    among agricultural workers. The
    fatality rate is very high. Most
    victims develop severe hypertension. Use of antivenim has given very
    poor results. The only
    effective treatment of proven value is Prazosin which is an alpha
    adrenergic-blocker.

      

    Response
    to Prazosin given initially by injection and later continued with
    oral doses at 3 hourly intervals prevented the development of severe
    acute hypertension and its consequent complications such as
    pulmonary edema. Prasozin should be now accepted as the standard treatment for
    scorpion envenomation.

       

  • S
    Singh, Department of Internal Medicine, PGIMER, Chandigarh


    Blood Glucose Changes
    Following Anticholinesterase Insecticide Poisoning.


    JAPI
    2000,Vol.48(12),pg.1145

      


    Organophosphates
    (OPC’s) and carbamates are extensively used in India, especially
    by the farming community. Both
    these compounds are very toxic. Biochemically
    there is an accumulation of acetylcholine (ACH).
    Symptomatically the nervous system is affected with muscle
    paralysis, central nervous system dysfunction, bradycardia and
    endocrine changes. Approximately half the victims get hyperglycaemia and glycosuria.
    The biochemical based on hyperglycaemia is not known.
    It is still not clear as to the duration of hyperglycaemia. After acute episode, patients need to be followed up to determine
    the long-term implications.

       

  • R
    Locher, PM Suter, W Vetter (Univ Hosp, Zurich, Switzerland)


    Ethanol Suppresses Smooth
    Muscle Cell Proliferation in the Postprandial State: 
    A
    New
    Antiatherosclerotic Mechanism of Ethanol?

    Am
    J Clin Nutr 67 : 338-341, 1998

       


    It
    is known that smooth muscle cell proliferation in the postprandial
    state (after food) may lead to narrowing of arteries. 
    It is well known that ethanol (alcohol) raises HDL
    cholesterol and thereby gives protection against atherosclerosis and
    heart attack.  It now
    appears that ethanol (alcohol) also suppresses the proliferation of
    smooth muscle cells and thereby gives additional protection in
    patients against atherosclerosis.

      

  • BA
    Julian, Jr RR Brantley, CV Barker, et al (Univ of 
    Alabama, Birmingham)


    Losartan, an Angiotensin II
    type 1 Receptor Antagonist, Lowers Hematocrit in Posttransplant
    Erythrocytes
    .

    J
    Am Soc Nephrol 9:1104-1108, 1998
    .

      

    Losartan, significantly lowers hematocrit in patients with
    post-transplant Anaemia (PTE). 
    This suggests that angiotensin II has a pathogenic role in
    post-transplant Anaemia.

       

  • WJ
    Catalona, AW Partin, KM Slawin, et al (Washington Univ, St. Louis,
    Mo; Johns Hopkins Hosp, Baltimore Md; Baylor College of Medicine,
    Houston; et al)


    Use
    of the Percentage of Free Prostate-specific Antigen to Enhance
    Differentiation of Prostate Cancer from Benign Prostatic Disease: A
    Prospective Multicenter Clinical Trial
    .

    JAMA
    279: 1542-1547, 1998
    .

       

    Free PSA percentage is a significant predictor of prostate cancer,
    with a sensitivity of 95% below a cutoff of 25%.
    Patients with prostate cancer and free PSA levels about the
    cutoff had less aggressive disease. Precentage
    of free PSA is an independent predictor of prostate cancer.


           

  • Shoseyov D, Bibi H, Shai P, et al (Hadassa Med School, Jerusalem, Israel; Brazilai Hosp, Ashkelon, Israel; SHIRAM Asaf Harofe Med Ctr, Zerifin, Israel; et al)

    Treatment with Hypertonic Saline versus Normal Saline Nasal Wash of Pediatric Chronic Sinusitis.

    J Allergy Clin Immunol 101: 602-605, 1998.

           

    Thirty patients were studied randomly with double-blind study. 

        

    Instilling 1 -mL hypertonic saline (HS) 3 times daily for 1 month improves the clinical and radiological conditions of children with chronic sinusitis. This treatment is tolerable and inexpensive.

         

    This is an interesting study supporting the use of HS. The exact mechanism is not known.

         

  • Personelle J, de Souza Pinto EB, Ruiz RO (Sao Paulo, Brazil)

    Injection of Vitamin A Acid, Vitamin E, and Vitamin C for Treatment of Tissue Necrosis.

    Aesthetic Plast Surg 22: 58-64, 1998.

        

    Experimental animals used were rats. Injection of ACE pool, composed of all-transretinoic acid, vitamin A, and vitamin E is useful for the treatment of necrosis after routine plastic surgery.

          

    The antioxidants and their general health effects were used orally in selected patients to better prepare their tissue for surgery by G.R. Holt and found this regimen to be useful. 

         

    Well controlled clinical trial is needed – G.R. Holt.

          

  • Ament
    PW, Paterson A (Latrobe Area Hosp, Penn)

    Drug Interactions with the Nonsedating Antihistamines

    Am Fam Physician 56: 223-230, 1997.

          

    The nonsedating antihistamines – which include astemizole, fexofenadine, loratadine and terfenadine – are very commonly prescribed drugs.

         

    Terfenadine and astemizole cause serious adverse effects in interaction with macrolide antibiotics or the antifungal agents, quinine Such interaction appears to be less likely with fexofenadine and Loratadine.

         

    To avoid an adverse effect (drug-drug interactions) one must avoid prescribing any medication that may influence cytochrome P450 system.

         

  • Marvez-Vals
    EG, Ernst AA, Gray J, et a (Louisiana State Univ, New Orleans; Vanderbilt Univ Med Ctr, Nashville, Tenn)

    The role of Betamethasone in the Treatment of Acute Exudative Pharyngitis.

    Acad Emerg Med 5: 567-572, 1998.

         

    The double-blind clinical trial was performed over 3 months. Forty-six patients were randomized to placebo and 46 to Betamethasone.

        

    Betamethasone, used as an adjunct to antibiotic therapy reduces the time to pain relief. Most effective in patients with streptococal positive.

           

  • Walter
    N Kernan, Catherine M Viscoli, et al

    Phenylpropanolamine
    and the Risk of Hemorrhagic Stroke

    New
    Eng J Med. Vol.343(25), December 21, 2000.

       

    Phenylpropanolamine
    is commonly found in appetite suprressants and cough or cold
    remedies. case reports
    have linked the use of products containing phenylpropanolamine to
    hemorrhagic stroke, often after the first use of these products.
    To study the association, the authors designed a case-control
    study.

      

    Men and
    women 18-49 years of age were recruited. 
    Eligibility criteria included occurrence of a subarachnoid or
    intracerebral haemorrhage within 30 days before enrollment and
    absence of previously diagnosed brain lesion.

       

    An
    analysis in men showed no increased risk of a hemorrhagic stroke in
    association with the use of cough or cold remedies containing
    phenylpropanolamine. No men
    reported the use of appetite suppressants.

      

    The
    results suggest that phenylpropanolamine in appetite suppressants
    and possibly in cough and cold remedies, is an independent risk
    factor for hemorrhagic stroke in women.

          

  • Christine
    A Haller and Neal L Benowitz

    Adverse
    Cardiovascular and Central Nervous System Events Associated with
    Dietary Supplements Containing Ephedra Alkaloids.

    BMJ,
    343(25), 21 December 2000, p. 1833-8

      

    Dietary
    supplements that contain ephedra alkaloids (sometimes called ma
    huang) are widely promoted and used in USA as a means of losing
    weight and increasing energy. In
    the light of recently reported adverse events related to the use of
    these products, FDA has proposed limits on the dose and duration of
    use of such supplements.

       

    Authors
    reviewed 140 reports of adverse events related to the use of dietary
    supplements containing ephedra alkaloids.
    A standardised rating system for assessing causation was
    applied to each adverse event.

       

    The
    results revealed that hypertension was the most frequent adverse
    effect followed by palpitations, tachycardia or both, stroke and
    seizures. Ten events resulted
    in death, and 13 events produced permanent disability. It is concluded that, use of dietary supplements that contain
    ephedra alkaloids may pose a health risk to some persons.

         

  • Olli
    T Raitakari and David S Celermajer

    Flow-mediated
    dilatation

    Br.J.Clin
    Pharm. Vol.50, November 2000, pg.397-404

        

    This article describes a non-invasive method for
    measuring endothelial function.

        

    Arterial
    endothelial dysfunction is an early event in atherogenesis and
    precedes structural atherosclerotic changes.
    It is also important in the late stages of obstructive
    atherosclerosis, predisposing to constriction and or thrombosis.

       

    Endothelial
    function can be measured in coronary arteries and in the periphery
    by measuring vasomotor function after intra-arterial infusion of
    pharmacologic agents, which release endothelial nitric oxide.
    A widely used method which is noninvasive uses ultrasound.
    Arterial diameter is measured in response to an increase in
    sheer stress, which causes endothelium dependent dilatation.
    Endothelial function assessed by this method correlates with
    invasive testing of coronary endothelial function, as well as with
    the severity and extent of coronary artherosclerosis. This technique
    provides valuable insights into early atherogenesis, as well as into
    potential reversibility of endothelial dysfunction by various
    strategies including drugs e.g. lipid lowering agents, ACE
    inhibitors, L-arginine and antioxidants.

       

    Diameter
    of target artery is measured by high resolution external vascular
    ultrasound in response to an increase in blood flow (causing shear
    stress) during reactive hyperaemia (induced by cuff inflation and
    then deflation). This leads
    to endothelium dependent dilatation, the response is contrasted with
    that to sublingual nitrogylcerin, an endothelium – independent
    dilator.

      

  • Manel
    Esteller, Jesus Garcia Foncillas et al

    Inactivation of the DNA repair gene MGMT and the clinical response of gliomas to alkylating agents.

    New Eng J Med. Vol.343, Nov.9, 2000,pg.1350.

       

    Summary : The DNA repair enzyme O6-methyl-guanine-DNA methyltransferase (MGMT) inhibits the killing of tumour cells by alkylating agents. MGMT activity is controlled by a promoter and methylation of the promoter silences the gene in cancer and the cells no longer produce MGMT. Authors examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumour to alkylating agents.



    MGMT promoter in tumour DNA was analysed by a specific PCR assay. Gliomas were obtained from patients treated with carmustine. Molecular data were correlated with the clinical outcome. MGMT promoter was methylated in 40% of gliomas and this was associated with regression of the tumour and prolonged overall and disease free survival. It was an independent and stronger prognostic factor than age, stage, tumour grade or performance status.



    The conclusion was that methylation of the MGMT promoter in gliomas is a useful predictor of responsiveness of the tumours to alkylating agents.

       



    Editorial :
    John N Weinsten, pg.1408

    Pharmacogenomics – Teaching old drugs new tricks.

    Summary: Traditionally, cancer treatments have been selected on the basis of tumour type, pathological features, clinical stage, the patient’s age and performance status and other nonmolecular considerations. The field of pharmacogenomics, through the study of large number of genes that influence drug activity, toxicity and metabolism, provides the opportunity to tailor drug treatments and to eliminate many of the uncertainties of current therapy for cancer.

      


    Strong support for this concept is provided by the study of genetic polymorphisms that influence drug metabolism. CYP2D6 affects metabolism of several drugs (beta-blockers, antidepressants, antipsychotics and opioids). Dihydropyrimidine dehydrogenase influences metabolism and therefore neurotoxicity of fluorouracil.

      


    Esteller and colleagues provide clinical evidence to explain the resistance of some gliomas to nitrosourea alkylating agents. Carmustine and other nitrosoureas kill by alkylating O6 position of guanine and thereby cross-linking adjacent strands of DNA. Formation of these cross-links can be prevented by MGMT, which rapidly reverses alkylation. About 30% of gliomas lack MGMT. A lack of MGMT appears to correlate with sensitivity to carmustine. Methylation of MGMT promoter could be used to predict responses to treatment with carmustine.

       


    Pharmacogenomics studies will produce benefits both for clinical research and standard practice. Potential advantages include discovery of better drugs, elimination of poor candidates early in the development process, and dramatic decrease in size and expense of clinical trials.

      

  • Scott Gottlieb, New York

    Cancer drug may cause heart failure

    BMJ, Vol.321, July 29, 2000, pg.259.

        

    Trastuzumab (Herceptin) is a monoclonal antibody that binds to a protein found on the surface of some cells. The protein, HER2, helps to regulate cell growth. By binding to tumour cells, trastuzumab inhibits growth of cancerous cells. It is currently approved for use in metastatic breast cancer.

      


    Editorial in ‘Circulation’ has reported that heart failure occurs in 7% of women taking trastuzumab alone and this rate increases to 28% in women taking the drug with other chemotherapy drugs.

      


    A team of researchers is calling for long-term studies investigating the risk of heart failure among women taking trastuzumab.

      

  • D R Morgan, M Trimble et al 

    Atrial Fibrillation associated with sumatriptan

    BMJ, Vol.321, July 29, 2000, pg.275

        

    This is a case report of a 34 year old man with a history of migraine, who presented with palpitations after taking sumatriptan by nasal spray for a severe headache. On examination, ventricular rate was 130 beats/min. The patient recalled having had a fast irregular pulse after taking sumatriptan previously. He reverted to sinus rhythm spontaneously within 12 hours of admission.

      


    Sumatriptan (5HT agonist at IB and ID receptors) may cause chest tightness and pain in upto 15% of patients. This is presumed to be due to vasoconstriction of coronary arteries. Myocardial infarction has been reported after sumatriptan treatment and its use is contraindicated in patients with IHD. Atrial fibrillation associated with sumatriptan is uncommon.

       

  • David C G Skegg

    Editorial – Third generation oral contraceptives – Caution is still justified.

    BMJ, Vol.321, July 22, 2000, pg.190-191

         

    I
    n October 1995, the Committee on Safety of medicines in UK warned that oral contraceptives containing desogestrel or gestodene carried a small increase in risk of venous thromboembolism compared with older preparations. Four well-designed studies gave the picture that women using 3rd generation oral contraceptives (OCs) had about twice the risk of venous thromboembolism of women using preparations containing levonorgestrel. These conclusions have been debated extensively.

      


    The absolute risks are small, but are they of no consequence ? Studies in Britain and New Zealand, where 3rd generation pills have been commonly used, estimate that the annual death rate from idiopathic venous thromboembolism in users of OC is about 1 in 100,000. Thus, the risk of dying of a woman using the pill for 2-3 years is of the same order of magnitude as the risk of fatal aplastic anaemia in a patient treated with chloramphenicol. Non-fatal events which can still have serious consequences may be at least 30 times more common.

       

  • Editorial – E Ernst

    Herbal medicines: where is the evidence ? 

    Growing evidence of effectiveness is counter balanced by inadequate regulation.

    BMJ, Vol.321, Aug.12, 2000, pg.395-396.  

        

    Sales of herbal medicines are booming. Fastest growth is for St. John’s wort, a herbal antidepressant. In a meta-analysis of 23 randomized trials with mild to moderate depression, the authors concluded that extracts of hypericum were significantly more effective than placebo and as effective as conventional antidepressants.

      


    Controlled trials of ginkgo biloba for dementia showed that ginkgo was more effective than placebo. A meta-analysis showed palmetto as a symptomatic treatment for benign prostatic hyperplasia. It improved urological symptoms and flow measures significantly more than placebo. Saw palmetto was as effective as finasteride and had fewer adverse effects. A systematic review of horse chestnut seed extracts for chronic venous insufficiency indicated equivalence with other active therapies.

      


    Even though herbal remedies may be effective, do their benefits outweigh the risks ? Most herbal remedies in UK and USA are sold as food supplements. Thus, they evade regulation of their quality and safety. Two British cases of severe nephropathy caused by Chinese herbal tea administered to treat eczema illustrate this. Huge variations exist in the quality of herbal medicinal preparations.

      


    A recent study of herbal creams in UK showed that 8 of 11 preparations contained undeclared dexamethasone.

      


    The possibility of herb-drug interactions is a further important issue. Ginseng, on its own, has few serious adverse effects. When combined with warfarin, its antiplatelet activity might cause over anticoagulation.

      


    There is need for reliable information on herbal medicines, and should be met by undergraduate and postgraduate education. Detailed questions about use of herbal drugs should form a part of taking medical history.

      

  • Wilson S Colucci, Uri Elkayam et al

    Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure.

    New Eng J Med, vol.343, July 27, 2000, pg.246.

        

    Intravenous infusion of nesiritide, a brain (B-type) natriuretic peptide, has beneficial hemodynamic effects in patients with decompensated congestive heart failure. Authros investigated the clinical use of nesiritide in such patients. Nesiritide was infused at rates of 0.015 and 0.03 ug per kg per minute. It decreased pulmonary capillary wedge pressure, reduced dyspnoea and fatigue.

      


    It was concluded that in patients hospitalized with decompensated congestive heart failure, nesiritide improves hemodynamic function and clinical status. Intravenous nesiritide is useful for short-term treatment of decompensated congestive heart failure.

            

  • Angela C Shore (Dept. of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, Univ. of Exeter)

    Capillaroscopy and the measurment of capillary pressure

    Br J Clin. Pharmacol, 50, 501-513

        

    Capillaries play a vital role in cardiovascular function as the point of exchange of nutrients and waste products, between tissues and circulation. Skin capillaries can be studied by the technique of capillaroscopy, which enables the investigator to assess morphology, density and blood flow velocity. It is also possible to estimate capillary pressure by direct cannulation using glass micropipettes.

      

    This is a review article, which describes the techniques used to make assessments and outlines some of the changes that are seen in health and disease.

          

  • Paul A Vasey (CRC Dept of Medical Oncology, Univ. of Glasgow)

    Immunotherapy for renal carcinoma: theoretical basis and current standard of care

    Br.J.Clin. Pharmacol 50, 521-529.

       

    There is no internationally recognised standard therapy for metastatic renal cancer and patients are treated with IFA or rIL-2 monotherapy or combinations. New approaches are needed.

       

    There are a number of preclinical studies which suggest that simultaneous exposure to both interferons and retinoids can result in enhanced antiproliferative and differentiation effects, compared with either agent alone. The EORTC are conducting a randomised trial of IFA in combination with 13-cis retinoic acid, a natural metabolite of vitamin A which has anticancer activity through a number of mechanisms including antiangiogenesis, differentiation induction and inhibition of IL-6.

        

    Immunostimulation by exogenously administered cytokines serves to enhance the function of the existing host immune system, rather than act as a cytotoxic agent that will eradicate or cure a disease process such as cancer. Continued development and exploration of novel therapies such as antiangiogenic compounds (e.g. thalidomide), differentiating agents, and newer immuno-stimulating agents will hopefully improve the outlook for patients in the future.

        

  • Kelly
    Morriss

    Macrodoctor, come meet the manodoctors

    Lancet, vol. 357, march 10, 2000, p.778

         

    In the 1996 film Fantastic Voyage, a mini-submarine of medics
    travels from vein to brain to laser a clot. The scenario remains
    science fiction, but emerging field of nanomedicine may make it a
    science fact.

      

    Billions of minute, self-assembling, computerised
    bioelectromechanical systems ‘nanobots’ swarming to the injury site,
    sensing, diagnosing and activating therapeutic systems and cellular
    repair is envisaged. Nanobots may be one day made with molecular
    nanotechnology.

       

    The team at Cornell University used tiny nickel nanopropellors to
    link with ATPase and is investigating ways to turn light energy into
    ATP, generating recyclable fuel that would render such devices
    autonomous.

       

    Tree-like polymers called dendrimers could deliver gene therapy or
    intracranial implants without eliciting immune response.

       

    Tejal Desai (Univ. of Chicago) has developed silicone based
    microcapsules with nanopores to deliver cells, drugs, proteins,
    peptides and nucleic acids. Similar type capsules may travel through
    bloodstream and release their contents at desired locations based on
    binding to cell-specific receptors.

       

    PEBBLES are probes encapsulated by biological, localised embedding-nanospheres
    20-200 nm wide, delivered into cells with 99% viability, via
    liposomes, a gene gun, or even macrophage ingestion. An individual
    PEBBLE can measure pH, oxygen, electrolytes, nitric oxide or early
    changes of apoptosis.

       

    Lethal ‘nanobots’ do not sound comfortable, but safety requirements
    will be built into systems.

        

    The problem is whether we want to make nanorobotics a reality. An
    injection of nanorobots could completely clear a stroke clot in a
    time that is in the order of one blood circulation time. Such
    treatment needs to prove itself superior to thrombolysis.



    Eric Drexler (Chairman of
    ‘Foresight’) predicts that nanomedicine will dominate medocal
    technology research for at least half this century.

          

  • J
    M Trivier, J Caron, M Mahieu et al

    Fatal aplastic anaemia associated with clopidogrel.

    Lancet, vol.357, Feb.10, 2001, pg.446.

        

    Clopidogrel, an inhibitor of platelet aggregation was thought to be
    free of the side effects of ticlopidine. Authors describe a man who
    developed aplastic anaemia after 5 months of treatment with
    clopidogrel. There were no other plausible causes, and fatal
    aplastic anaemia might have been induced by clopidogrel.

         

  • Bruno Garcia, Fidy Ramahulimihaso et al

    Ischaemic colitis in a patient taking meloxicam

    Lancet, vol.357, March 3, 2001, pg.690

          

    The safety of cyclo-oxygenase 2 (Cox-2) preferential inhibitors such as meloxicam is debated. Authors describe a patient who presented with bloody diarrhoea after 15mg meloxicam daily for 10 days forosteoarthritis. The endoscopic and histological features were consistent with the diagnosis of ischaemic colitis. Symptoms and endoscopic lesions quickly regressed within 1 week of meloxicam withdrawl. Authors suggest that meloxicam might have intestinal toxic effects when taken in high doses, because of reduced Cox-2 selectivity.

       

  • Editorial –

    Animal research in the post-genome area.

    Lancet, vol.357, March 17, 2001, pg.817

      


    The intimidation in recent months of staff of and investors in Huntingdon Life Sciences, an animal-testing contractor, has brought the debate on animal research to the forefront in the UK.

      


    Regulations introduced 2 years ago require that an ethical review in terms of animal welfare be conducted before and during the project. The project also undergoes a cost benefit assessment to ensure that it will produce maximum benefit.

       


    The 3Rs approach to the problem is reducing number of animals used through better experimental design, refining procedures to minimise suffering to the animals, and replacing animal work with alternative methods.

       


    The unravelling of human genome could change trends drastically e.g. scientists can target specific genetic defects underlying disease instead of creating animal models. Genetic models of human disease are not easy to create and interaction between gene or genes and environment is likely to be more important than single gene defects in pathogenesis of disease.

       


    Animal work was also a requrement by licensing authorities. The authorities have begun to accept some replacement tests and in November last year, the requirement for LD50 for acute effects was dropped from OECD guidelines for testing of chemicals.

         

  • Abigail Pound

    E.coli engineered to mass-procedure erythromycin

    Lancet, vol.357, March 3, 2001, pg;692

        


    A team of researchers in USA, have genetically engineered Escherichia coli to produce polyketides – a group of complex natural products to which erythromycin belongs. At present, they can be produced only by fermentation. Blain Pfeifer and colleagues have reported in Science how E.coli is used to produce polyketides cheaply, quickly and in large quantities.

       

  • Scott Gottlieb

    Risk of ulcer soars with combination of arthritis drugs.

    BMJ, Feb.3, 2001, pg.258

      


    Alendronate and naproxen are commonly used in patients with osteoporosis. Although both drugs cause gastric ulcers when used individually, the authors found that when they are taken together, the incidence of stomach ulcers is far greater than would be expected. Stomach ulcers developed in 8% of the study participants receiving alendronate alone, in 12% of those receiving naproxen alone, and in 38% of the participants taking both alendronate and naproxen. Even in volunteers who did not develop ulcers, the damage to the lining of the stomach was significantly worse in those who received the combination of drugs than in those who took either drug alone.

      

  • Scott Gottlieb

    Methylphenidate works by increasing dopamine levels. 

    BMJ, Feb.3, 2001, pg.259

      

    Methylphenidate works in the treatment of attention deficit hyperactivity disorder by increasing dopamine in children’s brains according to a study reported in the Journal of Neuroscience.



    It raises the level of dopamine by blocking the activity of dopamine transporters which remove dopamine once it has been released. Dopamine decreases background firing rates and increases the signal to noise ratio in target neurones. As a result, methylphenidate may improve attention and decrease distractability in activities that normally do not hold the attention of children with attention deficit hyperactivity disorder.

      

    The drug increases dopamine levels like many addictive drugs (cocaine, alcohol, amphetamine) but the key difference may be the length of time that the drugs take to reach the brain. A drug must reach brain very quickly to become addictive. Oral methylphenidate takes about an hour to have effect on the brain, which prevents the drug from causing the ‘high’ produced by most drugs that stimulate dopamine. It could become addictive when tablets are crushed and then either snorted or injected which allows the drug to reach the brain more rapidly.

      

  • Jason M Kendall, Barnaby C Reeves, et al

    Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures.

    BMJ, Feb.3, 2001, pg.261

      

    Objective of the study was to compare the effectiveness of nasal diamorphine spray with intramuscular morphine for analgesia in children and teenagers with acute pain due to clinical fractures.



    Study was conducted in 404 patients. Onset of relief was faster in the spray group than in the intramuscular group, with lower pain scores at 5, 10, and 20 mins. after the treatment but no difference between the groups after 30 mins. 80% of patients given the spray showed no obvious discomfort compared with 9% given IM morphine.

       

  • Monica Escher, Jules Desmeules et al.

    Hepatitis associated with Kava, a herbal remedy for anxiety.

    BMJ, Jan.20, 2001, pg.139

      

    Kava, the rhizome of the pepper plant Piper methysticum, has been widely used in the South Pacific as a narcotic drink. Lactones, the major constituents of Kava, are considered to be active ingredients and sold in Europe and USA as standardised extracts for anxiety and tension.



    This is a case report of a 50-yr old man who presented with jaundice. He was taking 3-4 capsules of Kava extract daily for 2 months for anxiety (maximum recommended dose 3 capsules) corresponding to a dose of 210-280mg lactones. He took no other drugs and did not consume alcohol. Liver function tests were abnormal and he developed encephalopathy. He received a liver transplant 2 days later and recovered uneventfully. Histology of liver showed extensive and severe hepatocellular necrosis and extensive lobular and portal infiltration of lymphocytes and eosinophils. Assessment of causality according to the definitions of WHO is ‘probable’.

      

  • Ranjit Roy Chaudhury

    Commentary – Challenges in using traditional systems of medicine.

    BMJ. Jan.20, 2001, pg.167



    Integration of modern and traditional systems of medicine may result in loss of some of the basic concepts of the traditional systems of medicine. Purists in the traditional systems of medicine such as Ayurveda and Unani in India oppose this trend to ‘modernise’ their systems, particularly when such integration is carried out by experts in allopathy. They have no objection to the use of modern concepts of the methodology of clinical trials in evaluating the efficacy and side-effects of herbal preparations. Such clinical evaluation is essential to use these remedies in allopathic hospitals.

      

    However, carrying out randomised, double-blind, multicentred trials with standardised extracts is a slow and laborious process. Not all herbal medicines need to undergo vigorous trial because these preparations are already in use. The situation is complicated further because randomised trial may not be very appropriate for evaluation of medicines from traditional systems. Where Prakriti (Ayurveda) or Mijaj (Unani) of individual, determines specific therapy to be used.



    In the past 12 years, the Indian Council of Medical Research (ICMR) has set up a network for carrying out clinical trials of herbal medicines. Using this network, the council has shown the efficacy of several traditional medicines, including Picrorhiza kurroa in hepatitis and Pterocarpus marsupium in diabetes. As a result of these trials, these traditional medicines can be used in allopathic hospitals.



    The regulation of traditional systems of medicine, the products used in these systems, and the practitioners of these systems are weak in most countries. This leads to misuse of the medicines by unqualified practitioners and loss in the credibility of the system. WHO has initiated an effort in this direction and may be the appropriate body to help countries to develop a regulatory system and take steps to meet the obligations under Trade Related Intellectual Property Rights Agreement when these become applicable in the developing countries around 2005.

      

  • G.B.
    Bolli, David R Owens (Department of Internal Medicine, University of
    Perugia, Italy; Diabetic Research Unit, University of Wales College
    of Medicine, UK)


    Commentary
    – Insulin Glargine

    Lancet,
    vol.356, August 5, 2000, p.443-444

      

    Insulin glargine
    is a new long-acting insulin analogue, approved for use  in patients with type
    I and Type II diabetes mellitus. It
    is approved by US-FDA and also in Europe.

      

  • Tim
    Higenbottam, Tom Siddons et al 
    (Divison of Clincial Sciences sheffield
    University, UK)


    Commentary
    – A therapeutic role for chronic inhaled nitric oxide.

    Lancet,
    Vol.356, August 5, 2000, pg. 446-447.

      

    Inhaled nitric
    oxide (NO) is a unique selective pulmonary vasodilator, which
    rapidly combines with oxy-haemoglobin to form methaemoglobin and
    nitrate in the alveolar capillaries.
    This combination ensures that the predominant effects are on
    the pulmonary vessels.

      

    Inhaled NO is a potential treatment for the many forms of
    pulmonary hypertension. Acutely
    inhaled NO at maximum doses is about half as effective a pulmonary
    vasodilator as IV prostacyclin. In
    hypoxic lung disease such as COPD, pulmonary hypertension increases
    risk of death. Inhaled NO is
    about twice as effective a pulmonary vasodilator as oxygen.

       

    Preliminary
    results from a randomized controlled study in Vienna, Austria, have
    shown that administration of spiked inhaled NO to patients with COPD
    on long-term oxygen therapy causes a sustained decrease in pulmonary
    artery pressure at 3 months without causing hypoxia.
    Results of long-term studies of inhaled NO in COPD are
    awaited.

        

  • T.Abe,
    S Hayasaka, Y Nagaki, et al (Toyama Med and Pharmaceutical Univ,
    Japan)

    Pseudophakic Cystoid Macular Edema Treated With High-Dose
    Intravenous Methylprednisolone.


    J Cataract Refract Surg. 25: 1286-1288, 1999

       

    High-dose I.V. methylprednisolone was found to be effective in
    treating pseudophakic cystoid macular oedema (CME) in a study of 4
    patients. Visual acuity improved in 3 of the 4 eyes.

        

    Each of the 4 patients had a ruptured posterior capsule for which
    anterior vitrectomy was done. The latter may also have played a role
    in improving visual acuity.

       

  • Rainer G, Menapace R, Schmetterer K, et al (Univ of Vienna)

    Effect of Dorzolamide and Latanoprost on Intraocular Pressure After Small Incision Cataract Surgery.

    J Cataract Refract Surg 25: 1624-1629, 1999.

       

    If there is elevated intraocular pressure (IOP) within 24 hrs. of cataract surgery, there may be a risk of developing corneal epithelial oedema, pain, retinal artery occlusion or anterior ischaemic optic neuropathy.

      

    In a study of 102 patients, it was found that both dorzolamide and latanoprost effectively reduced IOP rises after 6 hours. However only
    dorzolamide was of help after 20 to 24 hours.

      

    If untreated IOP rose about 5mmHg in 6 hrs and 1.5mm Hg within 24 hours. Using dorzolamide reduced the increase of IOP significantly. Latanoprost worked well only in the shorter term. Neither dorzolamide nor latanoprost could prevent IOP spikes of 30mm Hg or above.

       

  • Rasheed ES (El Maghraby Eye
    Ctr, Madina)


    Initial Trabeculectomy with Intraoperative Mitomycin-C Application in Primary Glaucomas


    Ophthalmic Surg Lasers 30: 360-366, 1999.

      


    Mitomycin C is an alkylating agent acting at all stages of the cell cycle. It reportedly inhibits fibroblast proliferation by preventing DNA synthesis, thereby decreasing the amount of scar tissue formation after
    trabeculectomy.

      


    The authors conducted a randomized study which compared the overall efficacy of the intraoperative application of Mitomycin C. They found that the use of intraoperative Mitomycin C may increase the success rate of glaucoma surgery. They felt that close follow-up and meticulous patient management are required, especially in the early post-operative period.

      


    Complications described are those that occur immediately postoperatively, related primarily to excessive filtration. Eyes with an overfiltering or leaking bleb are often uncomfortable to the patient. Vision is blurred due to low pressure and the excessive moisture on the corneal surface and the patient may suffer from photophobia.

      


    The late complications can be endophthalmitis, blebitis and
    hyptomy.

       

  • CD
    Hall, and the AIDS Clinical Trials Group 243 Team (Univ of North
    Carolina, Chapel Hill; Harvard School of Public Health, Boston;
    Mount Sinai School of Medicine, New York, et al )


    Failure of Cytarabine in
    Progressive Multifocal Leukoencephalopathy Associated with Human
    Immunodeficiency Virus Infection.

    N Engl J Med 338: 1345-1351, 1998.

      

    About 4% of patients with AIDS syndrome have progressive
    multifocal leukoencephalopathy (PML). 
    No therapy has been proven effective 
    for PML – survival after its diagnosis averages 3 months.

     

    In a study of 57 patients it was found that neither intrathecal nor
    intravenous cytarabine halted progression of PML better than
    antiretroviral therapy alone. Antiretroviral
    therapy itself offers no improvement in PML to these patients.

        

  • DM
    Treiman, for the Veterans Affairs Status Epilepticus Cooperative
    Study Group (Veterans Affairs Med Ctr, West Los Angeles; Veterans
    Affairs med Ctr,
    Bronx, NY; Veterans Affairs Med Ctr, Birmingham, Ala; 
    et al)


    A
    Comparison of Four Treatments for Generalized Convulsive Status
    Epilepticus.

    N
    Engl J Med 339 : 792-798, 1998.

         

    Three hundred
    eight-four patients with a verified diagnosis of status epilepticus
    and 134 patients with subtle generalized convulsive status
    epilepticus were enrolled in a 5-year randomized, double-blind,
    multicentre study.

        

    The four intravenous drugs used were (i) diazepam, 0.15mg/kg body
    weight followed by phenytoin, 18mg/kg (ii) Lorazepam, 0.1mg/kg  
    (iii) Phenobarbital 15mg/kg and (iv) Phenytoin, 18mg/kg.

         

    The author concludes that Lorazepam is more effective than phenytoin
    for the initial iv
    treatment of overt generalized convulsive status epilepticus.
    Lorazepam is easier to use than the other agents tested.

       

  • FE
    Dreifuss, NP Rosman, JC Cloyd, et al (Univ of Virginia,
    Chartlottesville; New England Med Ctr, Boston; Univ of Minnesota,
    Minneapolis, et al)

    A Comparison of Rectal Diazepam Gel and Placebo for Acute
    Repetitive Seizures.

    N Engl J Med 338: 1869-1875, 1998.

       

    Epilepsy affects about 2 million people in the United States. When
    the patient is actively convulsing, oral and sublingual
    administration is difficult and hazardous. Rectal diazepam is used
    to treat acute repetitive, prolonged and febrile seizures. It is
    effective, well tolerated and can be administered at home by trained
    caregivers.

       

  • D
    Gaist, I Tsiropoulos, SH Sindrup et al [Odense Univ, Denmark]

    Inappropriate Use of
    Sumatriptan : Polulation Based Register and Interview Study

    BMJ
    316-1352-1353, 1998

      

    Sumatriptan succinate is a commonly prescribed headache
    drug in Denmark. The appropriateness of the use of this drug was
    assessed in a polulation-based interview study.

      

    The standard antimigraine drugs when taken in excessive amounts, are
    now known to either cause or sustain headache. Quite a few patients
    overuse sumatriptan and may in future, overuse the newer triptans as
    well.

       

    The study point out that, many overusers were using the medication
    for inappropriate types of headaches, namely tension-type and
    drug-induced headaches.

       

    Physicians must understand both the precise indications for the use
    of triptans and the danger of prescribing immoderate amounts. The
    quantity and frequency of use of these medications must be plainly
    specified to.

      

  • Miyake
    K, Ota I, Maekubo, et al (Miyake Eye Hosp, Nagoya, Japan)

    Latanoprost Accelerates Disruption of the Blood-Aqueous Barrier
    and the Incidence of Angiographic Cystoid Macular Edema in Early
    Postoperative Pseudophakias.


    Arch Ophthalmol 117: 34-40, 1999

       

    Latanoprost (prostaglandin F2) lowers intraocular pressure (IOP) by
    increasing uveoscleral outflow. In human models, latanoprost did not
    disrupt the blood-aqueous barrier and did not affect cystoid macular
    oedema (CME) formation in eyes with longstanding pseudophakias.

        

    However, endogenous prostaglandins synthesized in the anterior uvea
    DO have a role in disrupting the blood-aqueous barrier and in
    inducing CME after cataract extraction.

       

    In a randomized, double-blind trial for latanoprost, as well as an
    open-label controlled trial for studying the effects of NSA drops on
    latanoprost and its place, the authors found that latanoprost
    disrupts the blood aqueous barrier and increases the incidence of
    angiographic CME in early postoperative pseduophakia.

       

    Concurrent instillation of NSA drops (e.g. diclofenac) can prevent
    the adverse effects of latanoprost and thus maintain the decrease in
    IOP.

        

  • AAQ
    Aranjo, AP Wells, AD Dick, JV Forrester (Dept. of Ophthalmology, Aberdeen Royal Infirmary, Aberdeen)

    Early treatment with cyclosporin in serpiginous choroidopathy maintains remission and good visual outcome

    Br J Ophthalmol 2000; 84: 979-982.

       

    Serpiginous choroidopathy is characterised by geographic areas of choroidal atrophy (in both eyes), which occur around the optic disc and spread in a helicoid pattern along the major vascular arcades towards the macula. Recurrences are common.

       

    Visual disability may result from retinal lesions affecting the central macula, or from secondary choroidal neovascularization due to disruption of the Bruch’s membrane-retinal pigment epithelium.

      

    The authors present a case series of 14 eyes of seven patients with serpiginous choroidopathy with follow up ranging from 1.3 to 13 years.

      

    No patients suffered significant loss of acuity after starting systemic immunosuppression with cyclosporin as the primary agent. There were no serious complications from immunosuppression.

      

    Adequate immunosuppression can result in clinical remission and cessation of therapy in some patients.

       

  • L.M.
    Van Beck, M Mulder, N J van Haeringen, Aize Kijlstra. ( Dept of
    Ophthalmology, Leiden University, Netherlands; Dept of Allergy, CLB
    and Laboratory for Experimental and Clinical Immunology, Univ of
    Amsterdam, Netherlands).

    Topical ophthalmic b blockers may cause release of histamine
    through cytotoxic effects on inflammatory cells.

    Br. J Ophthalmol 2000; 84:1004-1007.

      

    A mixed leucyocyte and basophil preparation was obtained from venous
    blood of healthy non-atopic volunteers. Cell preparations were then
    incubated with betaxolol, metipranolol, timolol, or carteolol.

      

    One hour after incubation, the histamine content of the supernatant
    was analysed by automated fluorometric analysis. Cell viability was
    tested by measuring lactate dehydrogenase (LDH) concentrations.

      

    Betaxolol and metipranolol in concentrations between 10-2M and 10-3M
    liberated histamine from human blood cells in a dose dependent
    manner. Carteolol and timolol had NO effect on histamine at these
    concentrations.

      

    The authors conclude that betaxolol and metipranolol induce
    substantial histamine release from human leucocytes, probably as a
    result of their cytotoxic effect.

       

    This concurs with the observation that patients find timolol eye
    drops more comfortable than metripranolol or betaxolol eye drops.

       

  • C S Naylor, L Steele, et al 

    Cefotetan-induced hemolysis associated with antibiotic prophylaxis for cesarean delivery.

    Am J Obstet Gynecol 2000; 182: 1427-8

      

    The authors described 3 cases of antibiotic-induced hemolysis associated with cefotetan prophylaxis during cesarean delivery. Each of the 3 patients showed development of significant anemia with documented cefotetan-induced hemolysis. When postpartum anemia is associated with antibiotic use, immune hemolytic anemia should be considered and included in the differential diagnosis.

       

  • Lewis B Holmes, Elizabeth A Harvey, et al

    The Teratogenicity of Anticonvulsant Drugs

    NEJM, Vol.344, April 12, 2001, pg.1132-8.

       


    Major malformations, growth retardation, hypoplasia of the mid-face and fingers, known as anticonvulsant embryopathy is increased in infants exposed to anticonvulsant drugs in utero. Whether these abnormalities are caused by maternal epilepsy itself or by exposure to anticonvulsant drugs is not known.

       


    Authors screened 128,049 pregnant women at delivery to identify 3 groups of infants: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures and a control group. Infants were examined for presence of malformations.

       


    The conclusion of the study was that a distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself.

  • BL
    Charous, EF Halpern, GC Steven (Milwaukee Med Clinic, Wis)

    Hydroxychloroquine Improves Airflow and Lowers Circulating IgE Levels in Subjects With Moderate Symptomatic Asthma.

    J Allergy Clin Immunol 102: 198-203, 1998.



    Hydroxychloroquine, which is a disease-modifying agent, has an established efficacy in rheumatologic diseases. Its mechanism of action is thought to involve its ability to interfere with lysozome function and, thereby, inhibit of antigen processing and presentation, and subsequent T-cell activation.



    It has been used in asthma as a steroid sparing agent. Its uncommonly benign toxicity profile allows consideration of its use in these patients. The authors have conducted a double-blind, placebo-controlled trial of hydrochloroquine in patients with moderate symptomatic asthma.



    The authors have demonstrated the ability of hydrochloroquine to statistically significantly improve FEV1, morning and evening peak flows, and requirement for B2-agonists. Immune parameters that improved included the mean total IgE concentration. One final important comment is that as with hydrocholoroquine’s known mode of action in rheumatologic disease, the onset of efficacy in asthma was slow, and these changes did not occur until 30 weeks into the trial. A larger study group is required to further prove its efficacy.

  • E
    Pizzichini, MMM Pizzichini, P Gibson, et al (McMaster Univ, Hamilton, Ont; John Hunter Hosp, Newcastle, Australia; Mayo Clinic and Found, Rochester, Minn)

    Sputum Eosinophilia Predicts Benefit from Prednisone in Smokers With Chronic Obstructive Bronchitis.

    Am J Respir Crit Care Med 158: 1511-1517, 1998.



    Corticosteroid treatment has improved the on-doubt of its usefulness in patients with asthma and decreasing airway eosinophilia. However, its role in the treatment of chronic obstructive bronchitis is controversial. The authors present a placebo-controlled, crossover trial to determine whether the presence of sputum eosinophils predicts benefit from prednisone in 18 smokers with severe chronic obstructive bronchitis.



    Their findings that the presence of significantly elevated eosinophilia in the sputum identified a subset of patients who had objective improvements in effort, dyspnea, quality of life, and in their FEV1 interests us. It not only reduced sputum eosinophilia in these patients, but also reduced sputum fibrinogen concentrations. Thus supporting the concept that the use of prednisone may reduce airway fibrosis and remodeling, thereby slowing the progression of the disorder.



    In fact the findings of sputum eosinophilia may be further implemented in seeing if these patients do benefit with long term inhaled corticosteroids rather subject them to an exposure to systemic
    corticosteroids.

  • SD Aaron, RE Dales, B Pham (Univ of Ottawa, Ont)

    Management of Steroid-dependent Asthma with Methotrexate: A Meta-analysis of Randomized Clinial Trials.

    Respir Med 92: 1059-1065, 1998.

         

    Various alternatives to long-term steroid therapy are needed for the control of severe asthma. The efficacy of methotrexate as a steroid sparing agent was examined in a meta-analysis of randomized clinical trials.

        


    It was concluded from the study that methotrexate use enables modest decreases in oral corticosteroids in patients with severe asthma. However, the benefit is relatively small and the possibility of adverse effects should be always outweighed.

        


    There has been controversy concerning methotrexate’s usefulness as a steroid-sparing modality. Different blinded studies have had diametrically opposed results. This meta-analysis, combining experiences with 250 patients, showed a 6.0% improvement in forced expiratory volume over placebo, and an 18.2% decrease in prednisone dose. 

         


    This is relatively small advantage over the effort which has been applied in the entire study and it remains to be seen whether it is really helpful as the patients were subjected to methotrexate therapy were not without risk as two of them developed pneumonias and 1 had hepatic dysfunction as side effects which was an incidence at 1.2% . For a benefit of 6.0% improvement if there is going to be a risk of 1.2% then probably is not worth the effort.

           

  • S
    Elwany, M Bassiouny, (Alexandria Univ, Egypt)

    Topical Levocabastine for the Treatment of Perennial Allergic Rhinitis

    J Laryngol Otol 111: 935-940, 1997.

      


    Oral H1-receptor antagonists which have found the primary treatment for chronic allergic rhinitis are associated with severe systemic side effects. Topical therapy should theoretically avoid these events, while producing a higher concentration at the site. A study reported shows the use of a nasal spray containing levocabastine which is a potent and highly selective H1-receptor antagonist, on the nasal mucosa in patients with chronic allergic rhinitis.

       


    The study has some remarkable findings in that there has been a reappearance of normal cilia and microvilli and more acinar cells in the post-treatment specimens collected in the biopsy. The number and activity of goblet cells and serous glands decreased as was the evidence of vascular congestion. These changes reduced the formation of edema fluid, and the reduction in the number of pinocytotic vesicles reduced the transmission of fluid across epithelial cells. Degranulated mast cells and eosinophils however, were still present at the end of the short study. 

       


    Although perhaps not as impressive as topical corticosteroids induced changes, the reported findings certainly suggest moderate anti-inflammatory properties of this topical antihistamine. Hence one should look beyond just the antihistaminic actions of these agents by probably combining with leukotriene and lipoxygenase inhibition studies.

       

  • Sheena McCormack, Richard Hayes et al 

    Microbicides in HIV prevention

    BMJ, Vol.322, Feb. 17, 2001, p.410-413

        

    Although the use of condoms has slowly increased in countries most severely affected by the HIV epidemic, many vulnerable women are unable to ensure they are used. An effective and affordable vaginal microbicide, whose use could be controlled by women, would represent an important addition to the armamentarium against HIV infection. This article examines current progress in microbicide development and discusses their future role in HIV control.

       

    Potential microbicides currently in human trials:

       

      Activity

     
    Product
    groups and active agents    
         Anti-STI     Spermicidal            
    Human trials

    Broad
    spectrum activity

































    Non-ionic
    surfactants:

    Nonoxinol  9*                  
                  
        
                    
       
    ++                    
    +                               
       
    Efficacy

    Chlorhexidine                                    
      
                 
         
    ++                    
    +                      
    Efficacy (vertical transmission)

    Octoxinol  9*                                     
     
                  
         
    ++                    
    +                                  
      
    Safety

    Anionic
    surfactants

    Docusate sodium *                           
      
                   
       
    ++                    
    NA                                  
    Safety

    Cationic
    surfactants:

    Glyminox (C31G)*                                                   
    ++                    
    +                                 
        
    Safety

    Benzalkonium chloride*                          
             
         
    ++                    
    NA                                  
    Safety

    Geda plus *   

    Acid
    buffers:

    Buffer gel                                                   
            
       
    ++                   
    +/ –                                 
    Safety

    Plant
    extracts:

    Praneem polyherbal                                     
         
     
       
    ++                   
    +                                     
    Safety

    Gossypol                                                        
         
      
    NA 
                    
    +                                   
     
    Safety

    Bacteria:

    Lactobacilli                                                      
       
        
                          
                                      
      
    Safety

    Peptides:

    IB367
    (protegrin)                                                      
    +                     
    NA                           
         
    Safety

    Inhibitors
    of viral entry

    Sulphated
    polysaccharides:

    Dextrin sulphate                                                       
    +                       
                                      
    Safety

    Carrageenan                                                       
       
    ++                   
    NA                                 
    Safety

    Cellulose sulphate                                             
         
    ++                   
       
                                
        
    Safety

    Sulphonated
    polymers:

    PRO 2000                                         
                      
      
    ++             
            
                               
          
    Safety

    Inhibitors
    of viral replication

    Reverse
    transcriptase inhibitors:

    Tenofovir
    (PMPA)                                                    
     
                         
                        
     
    Safety (oral administration)



        

       

    STI = sexually transmitted infection.  
    NA = not assessed. 
    * known to be cytotoxic to HIV



  • Patrick M.M.Bossuyt

    Better standards for reporting of RCTs.

    A revised CONSORT statement should further improve standards of reporting

    BMJ, June 2, 2001, pg.1317-1318



    Randomised clinical trial (RCT) are regarded as the best tools for gathering evidence on the effectiveness of health care interventions. To remedy deficiencies in trial reporting, several scientists and editors of bio-medical journals developed the CONSORT statement (the consolidated standards of reporting trials). CONSORT comprises a short checklist of essential items and a flow diagram to be used in reporting trials.



    A revised version of the 1996 statement has been published simultaneously in JAMA, Lancet and Annals of Internal Medicine and is also found on the internet
    (www.consort.statement.org) 

         

  • Yoshiki Sawa

    Therapeutic angiogenesis with gene transfection for ischaemic heart disease.

    Drugs of Today, 2001, 37(1), pg.67-71

       

    Genetic engineering studies conducted in the field of cardiovascular medicine have lead to the use of gene therapy as a means of treating ischaemic disease. Folkman et al have shown that tumour growth is facilitated by revascularisation and revascularization factors are involved in tumour growth. The first revascularisation factor used for therapeutic angiogenesis was basic fibroblast growth factor (bFGF). In a rabbit model of acute leg ischaemia, 14 day IM treatment with bFGF at a dose of 1 or 3 mg promoted the formation of collaterals in the legs. Possibility of treating myocardial infarction has also been reported. Intramyocardial injection of vascular endothelial growth factor (VEGF) on induction of myocardial revascularisation has been shown in dogs and pigs.

        

    Clinical trials of gene therapy using VEGF have started at Tufts University in U.S. This therapy is designed to treat severe ischemic disease with revascularisation. VEGF genes were injected locally into myocardium after small thoracotomy. More than 70 patients have undergone this therapy and revascularisation and improved regional blood flow as assessed by angiography and myocardial scintigraphy has been reported. Crystal and coworkers at Cornell University have administered VEGF cDNA on an adenovirus vector into the myocardia of about 30 patients, with or without coronary artery bypass grafting, and reported revascularising effect and safety of this therapy. 

        

    Revascularising effects of HGF:- Hepatocyte growth factor has been shown to be specific to vascular endothelium and does not affect proliferation of vascular smooth muscle.

       

    Studies in rats have shown that HGF increases the number of newly formed blood vessels. HGF is more potent than VEGF and clinically useful. Introduction of HGF gene, which is a revascularisation factor produced endogenously, may be a new means of treating severe ischaemic heart disease.

        

  • S.L. Udupa

    Indigenous drugs and atherosclerosis

    Drugs of Today 2001, 37(1), 37-47

         


    An encouraging field for the application of indigenous drugs is regression of atherosclerosis. Vitamins C and E, carotenoids, flavonoids, terpenoids present in indigenous drugs have been shown to slow down progression of experimental atherosclerosis. Potassium and magnesium found in herbals are also beneficial.

         

    This is a review of some of the Indian indigenous drugs, found to be antiatherogenic. 

         

    The drugs included are: 

    (1) Achyranthus aspera – contains triterpenoids. Hypocholesterolemic effect in rats. 

         

    (2) Allium cepa (onion) – therapeutic effects attributed to sulphur compounds.

          

    (3) Allium satiuum (garlic) – known to have hypoglycaemic, hypocholesterolemic and hypolipidemic effects and protects against the development of atherosclerosis. The inhibition of cholesterol synthesis by garlic may be due to a mixture of multiple compounds of
    sulfur containing thiosulfinates, ajoenes and dithienes.

           

    (4) Aloe barbedensis – Lipid lowering agent lowers VLDL and LDL and increases HDL.

          

    (5) Capsicum annum (Red pepper). Red pepper or its active principle capsaicin prevented increase in cholesterol levels in rats.

          

    (6) Cicer arientinum – Bengal gram. Hypolipidemic effect
    – due to its isoflavonic component – Biochanin A.

           

    (7) Commiphora mukul – Crude guggul or its oleoresin lowers serum cholesterol in rabbits. Similar effect shown in patients with hypercholesterolemia. Long-term combination treatment with fraction A guggul and cholestyramine resulted in decrease in serum cholesterol and triglyceride levels.

         

    (8) Dolicos lablab – seeds used as pulse in diet. Reduces serum cholesterol in rats.

          

    (9) Emblica officinalis – Its fruit (amla) is probably the richest known natural source of vitamin C. Dietary supplementation with raw amla in normal and hypercholesterolemic subjects resulted in a decrease in cholesterol levels.

         

    (10) Medicago sativa : (Alfalfa). Alfalfa meals prevent hypercholesterolemia, triglyceridemia and atherogenesis in cholesterol fed rabbits.

         

    (11) Plantago ovata – They are a class of gel-forming, nonabsorbable, soluble fibres derived from oat or psyllium seed husk which have been shown to produce cholesterol lowering effects when added as dietary supplements. Addition of psyllium hydrophilic mucilloid to cholestyramine therapy may improve patient compliance by reducing drug-associated GI side-effects.

         

    (12) Terminalia arjuna – Powdered bark is used. Constituent of many Ayurvedic preparations shown to decrease serum cholesterol and blood sugar levels in experimental animals after 3 months of treatment. It is also reported to have antihypertensive and antiarrhythmic properties.

        

    (13) Terminalia belerica – Alcoholic extract has dose-dependent hypotensive effect. It is present in Triphala (T.belerica, T.chebula and E.officinalis).

         

    (14) Terminalia chebula – Reduces cholesterol levels in experimental atherosclerosis in rabbits.

         

    (15) Trichosanthes dioica – Fruit used. Hypoglycemic and hypocholesterolemic effects in normal and mildly diabetic humans.

          

    (16) Trigonella foenum graecum – The seeds (fenugreek)
    – caused cholesterol levels to decrease in diabetic hypercholesterolemic dogs. Also reduces hyperglycemia. Ethanol extract from defatted fenugreek seeds contained saponins that inhibit absorption of taurocholate and deoxycholate.

          

    In type I diabetes, fenugreek diet significantly reduced fasting blood sugar and improved glucose tolerance test. Serum cholesterol, LDL and VLDL and TG were significantly reduced but HDL was unchanged.

          

  • G A Fitzgerald and Carlo Patrono

    The Coxibs, Selective inhibitors of cyclooxygenase-2

    New Eng J of Med. August.9, 2001; pg.433

         

    The coxibs are selective inhibitors of Cox-2. Inhibition of Cox-2 has been more directly implicated in reducing inflammation, whereas inhibition of Cox-1 is related to adverse effects on GI tract. So, it was hoped that coxibs would be better tolerated than nonselective NSAIDs but equally efficacious. Cox-2 can be upregulated by cytokines, growth factors and tumour promoters, suggesting its relevance to inflammation and cancer. Though Cox-1 is a ‘housekeeping’ enzyme, its expression may also be regulated. Celecoxib and rofecoxib were the first drugs, others like valdecoxib and etoricoxib are being developed.

         

    Drug companies assess selectivity by in-vitro assays during screening, because these assays are relatively rapid and simple, but they do not reflect the complexity of drug-enzyme interaction in-vivo.

         

    Two large trials have addressed the efficacy of coxibs and the associated risk of GI complications – the Vioxx gastrointestinal outcomes research (VIGOR) and the celecoxib long-term arthritis safety study (CLASS) trial. The incidence of GI perforation, GI haemorrhage or symptomatic ulcer was 4.5% per 100 patient-years in the naproxen group and 2.1 per 100 patient – years in rofecoxib group, a difference of 54% (P<0.001). In the CLASS study there was no significant difference between the 2 groups.

         

    The distinct roles of 2 Cox enzymes in patients with peptic ulcers are not known. Both are found in apparently normal GI epithelium and may help to protect gastric mucosa. Results of both VIGOR and CLASS trials suggest that Cox-1 has the main cytoprotective role.

         

    Expression of GI epithelial Cox-2 is increased by traumatic and inflammatory stimuli, as well as by H.pylori infection. Expression is increased in the margin of healing ulcers and Cox-2 inhibitors impair ulcer healing in mice. We still have much to learn about potential risks of inhibition of Cox-2 in GI tract –e.g. Cox-2 inhibitors impair tolerance of dietary antigens and exacerbate experimental colitis in rodents.

         

    COXIBS and Cardiovascular disease – Cox-2 has an important role in increasing prostacyclin formation in clinical syndromes of platelet activation. Expression of both COX-1 and COX-2 is upregulated in foam cells and smooth muscle cells of ahterosclerotic plaques. Cox-2 may be important in physiological conditions also e.g. Cox-2 inhibitors decrease urinary excretion of prostacyclin metabolites in normal subjects indicating reduction of prostacyclin production. If Cox-2 inhibitors are associated with a risk of thrombosis, this risk should be small, because of presence of other substances like nitric oxide that protects against thrombosis. However, thrombosis may occur in patients who are already at risk of other underlying conditions –e.g. arterial thrombosis occurred after starting celecoxib therapy in 4 patients with lupus anticoagulant.

          

    Clearly more information is needed on cardiovascular effect of selective inhibitors of Cox-2 and their combination with antiplatelet drugs.

          

    Cox-2 and renal function : Cox-2 dependent prostaglandin formation is necessary for normal renal development. Little information is available on renal pharmacology of Cox-2 inhibitors. Both nonselective NSAIDS and celecoxib produced edema and hypertension to a similar extent. Controlled comparisons of coxibs with each other and with nonselective NSAIDs are necessary to assess risk of hypertension.

          

    Conclusions : In less than a decade after the discovery of Cox-2, clinical trials have demonstrated that selective Cox-2 inhibitors cause significantly fewer GI adverse events than nonselective NSAIDs. More selective coxibs are being developed. Given the cardiovascular findings of small but clinically relevant changes in BP, elucidation of cardiovascular and renal effects of these drugs and their interactions with potential adjuvant therapies, such as low-dose aspirin is necessary.

          

  • R J Norman 

    Commentary – Reproductive Consequences of COX-2 Inhibition 

    The Lancet October 20, 2001, Vol.358 (9290) Pg. 1287-1288

         


    Many reproductive processes-eg, ovulation, fertilisation, implantation, decidualisation, and parturition – depend on prostaglandin ligand-receptor interactions. 

         


    In experimental mice NSAIDs have been shown to induce infertility because of interference with reproductive processes. 

         


    There are many human case reports that infertility is produced by NSAIDs and COX-1/COX-2 inhibitors. However, fertility is restored by discontinuing these drugs. Women attempting to become pregnant should avoid taking these drugs.

          

  • Jan A Staessen, Ji-Guang Wang, Lutgarde Thijs 

    Cardiovascular Protection and Blood Pressure Reduction: A Meta-Analysis 

    The Lancet October 20, 2001, Vol.358 (9290) Pg. 1305-1315

         


    The authors’ conducted a meta-analysis of nine randomised trials comparing treatments in 62 605 hypertensive patients. Compared with old drugs (diuretics and b-blockers), calcium-channel blockers and angiotensin converting-enzyme inhibitors offered similar overall cardiovascular protection, but calcium-channel blockers provided more reduction in the risk of stroke (13.5%, 95% Cl 1.3-24.2, p=0.03) and less reduction in the risk of myocardial infarction (19.2%, 3.5-37.3, p=0.01). 

          


    The authors’ findings emphasise that blood pressure control is important. All antihypertensive drugs have similar long-term efficacy and safety.

          

  • Dinesh C Sharma 

    Policy and People – India to Regulate Indigenous Medicine Sector 

    The Lancet October 13, 2001, Vol.358 (9289) Pg. 1249

        


    India’s health ministry has taken steps to streamline the production of drugs extracted from medicinal plants. Such drugs form the basis of Indian traditional medicine-known as the Indian system of medicine (ISM) and includes Ayurvedic medicine – and will now be subject to quality control form cultivation to manufacture. 

       


    The government will create a register of farmers that grow medicinal plants, raw drug traders, laboratories, and manufacturers. Traders will be required to store medicinal plants properly and keep full records of their suppliers and stock. Drug licensing authorities will ask manufacturers to submit a list of the type and quantity of plant materials used to produce ISM drugs.

        


    Each state has its own set of rules and legislations. Because of this, movement of plant material from one part of the country to another may take several weeks, and volatile ingredients of the plant may get lost on the way.

         

  • C van Walraven, M M Mamdani, P S Wells, J I Williams 

    Inhibition of Serotonin Reuptake by Antidepressants and Upper Gastrointestinal Bleeding in Elderly Patients: Retrospective Cohort Study 

    BMJ No.7314, September 22, 2001, Pg. 655

        


    The aim of this study was to determine the association between inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding. It is a retrospective cohort study from population based databases. 

        


    317 824 elderly people were observed for more than 130 000 person years. Patients started taking an antidepressant between 1992 and 1998 and were grouped by how much the drug inhibited serotonin reuptake. Patients were observed until they stopped the drug, had an upper GI bleed or died or the study ended.

        


    The conclusions were that after age or previous upper GI bleeding were controlled for, antidepressants with high inhibition of serotonin reuptake increased the risk of upper GI bleeding. These increases are clinically important for elderly patients and those with previous GI bleeding.

          

  • Jayasree K Iyer, Wilbur K Milhous et al

    Plasmodium falciparum Cross-Resistance between Trimethoprim and Pyrimethamine 

    Lancet, Vol.358, September 29, 2001, Pg.1066

     


    Trimethoprim-sulfamethoxazole has been recommended as part of the standard package of care for people with HIV and AIDS in Africa.



    A similar antifolate combination, sulfadoxine-pyrimethamine, is now the first-line antimalarial drug in several African countries. 



    Authors present evidence of Plasmodium falciparum cross-resistance between trimethoprim and pyrimethamine at the molecular level. The impact of trimethoprim-sulfamethoxazole prophylaxis on the efficacy of sulfadoxine-pyrimethamine needs to be assessed and alternative antimalarial treatment should be considered for people on trimethoprim-sulfamethoxazole prophylaxis.

       

  • Catherine
    Vasilakis-Scaramozza, Hershel Jick 

    Risk of Venous Thromboembolism With Cyproterone or Levonorgestrel Contraceptives 

    Lancet, Vol.358, October 27, 2001, Pg. 1427-29



    Summary: Results of several small studies have shown that there is an excess risk of venous thromboembolism in users of oral contraceptives containing cyproterone compared with those containing levonorgestrel.



    The authors conducted a case-control study and the results suggest that risk of venous thromboembolism is increased 4 fold in women taking contraceptives containing cyproterone by comparison with those exposed to levonorgestrel.



    Contraceptives containing cyproterone are often prescribed for women with a history of hirsutism and acne. 

       

  • John A Farmer 

    Commentary: Learning From The Cerivastatin Experience 

    Lancet, Vol.358, October 27, 2001, Pg. 1383-85



    Summary: Statins have revolutionised the management of lipid disorders. They lower lipid concentrations and seem to be safe. Cerivastatin was withdrawn in August this year because of its adverse effects on muscle.



    Myotoxicity was one of the first clinically recognised adverse effects of statins. It ranges from a mild non-specific myalgia to myositis with raised concentrations of creatine kinase. Myositis can progress to the rare but life-threatening syndrome of acute rhabdomyolysis, which can lead to irreversible renal failure. The precise mechanism is not known.



    Statins inhibit HMG CoA reductase, the rate-limiting enzyme in cholesterol synthesis, and lead to secondary depletion of essential metabolic intermediates formed during cholesterol synthesis. Intracellular depletion of metabolic intermediates has been shown to be related to myotoxicity in laboratory work and supplementation of intermediate proteins ameliorated statin-associated toxic effects in in-vitro studies.



    Statins with good lipid solubility have been postulated to have an increased potential for toxicity because of enhanced ability to penetrate the myocyte. The role of reduced concentrations of synthetic intermediates is not studied in human beings, and there have been no clinical safety trials that compare statins directly.



    Myotoxicity may also be due to interaction with cytochrome P-450. The second-generation statins (atorvastatin, fluvastatin, cerivastatin) are synthetic and structurally dissimilar to first-generation statins (lovastatin, pravastatin, simvastatin).



    Although pre-marketing clinical trials of doses up to 0.4 mg/day did not indicate increased risk of rhabdomyolysis, post-marketing surveillance showed increased rates of rhabdomyolysis especially when it was given with gemfibrozil.



    US FDA issued a specific contraindication for this combination, yet cases of rhabdomyolysis continued and after 52 deaths were recorded worldwide, cerivastatin was withdrawn worldwide.



    In several cases associated with cerivastatin alone, the dose given had been the higher (0.8 mg) dose that had been recently approved for clinical use.

         

  • Anil Bharani and Hrishikesh Kumar

    Diabetes Insipidus Induced by Ofloxacin 

    BMJ No.7312, September 8, 2001, Pg. 547

         

    Summary : Nephrogenic diabetes insipidus occurs with agents such as lithium, methoxyfluorane, vitamin D and demeclocycline.

          


    The authors report a case of diabetes insipidus induced by ofloxacin.

        


    A male patient diagnosed bilateral lobar pneumonia acquired in the community after influenza was treated with multiple antibiotics and on the 3rd day after admission, as his response was poor, was given ofloxacin 200 mg twice daily. On the 5th day he developed polyuria (more than 20 litres per day) and excessive thirst. 

         


    Ofloxacin induced diabetes insipidus was suspected and the drug was stopped. Urine volume and thirst returned to normal within 36 hours. He was rechallenged with ofloxacin 400 mg daily and the symptoms of polyuria and polydipsia returned. Ofloxacin was stopped and the symptoms resolved after stopping the drug.

         


    The mechanism is not clear, it could be similar to that of lithium or demeclocycline which interfere with the action of antidiuretic hormone on the collecting ducts.

          

  • Catherine
    Vasilakis-Scaramozza, Hershel Jick 

    Risk of Venous Thromboembolism With Cyproterone or Levonorgestrel Contraceptives 

    Lancet, Vol.358, October 27, 2001, Pg. 1427-29

         


    Summary: Results of several small studies have shown that there is an excess risk of venous thromboembolism in users of oral contraceptives containing cyproterone compared with those containing levonorgestrel.

         


    The authors conducted a case-control study and the results suggest that risk of venous thromboembolism is increased 4 fold in women taking contraceptives containing cyproterone by comparison with those exposed to levonorgestrel.

         


    Contraceptives containing cyproterone are often prescribed for women with a history of hirsutism and acne. 

           

  • Bruce
    Zuraw

    Commentary – Bradykinin In Protection Against
    Left-Ventricular Hypertrophy

    Lancet, Vol. 358, October 6, 2001, Pg. 1116-18

         

    Summary : Left-Ventricular hypertrophy
    substantially increases risk of sudden death and other
    cardiovascular complications even after adjustment for
    other known risk factors.

        

    On the basis of pressor and remodeling effects of
    angiotensin II, the reninangiotensin system is widely
    thought to play an important part in the development
    of LVH. Efficacy of ACE inhibitors in lessening
    progressive LV remodeling and rates of sudden death in
    patient with LV dysfunction further proves the
    importance of this system.

          

    ACE generates angiotensin II but also degrades
    bradykinin, and bradykinin is the preferred ACE
    substrate. Of the 2 angiotensin receptors that have
    been identified, AT1 receptors mediates the
    pressor effect whereas AT2 receptor
    mediates hypotensive effects.

         

    David Brull and colleagues have reported that
    individuals with the greatest increase in LV mass had
    the highest concentration of ACE and the lowest
    concentration of B2 bradykinin receptor.
    These results strongly support an important role for
    bradykinin in the ACE medicated effect on LVH.

         

    Bradykinin mediates important cardiovascular effects,
    such as increased vascular permeability, enhanced
    myocardial glucose uptake, negative intropism and
    inhibition of myocardial growth. Bradykinin has been
    shown to play an intergral part in protecting
    ischaemic myocardium. Genetically ablating B2
    bradykinin receptors result in enhanced salt-induced
    hypertension and hypertropic cardiomyopathy.

         

    There is also evidence of interaction between
    bradykinin and rein-angiotesin system. It is now seems
    that bradykinin ia an important participant in the
    cardiac effects of the renin-angiotensis system and
    novel pharmaceutical approches to further increase
    bradykinin concentrations may be clinically
    beneficial.

        

    It is important to recognise that the ACE and B2
    bradykinin-receptor polymorphisms account for only a
    fraction of the total variability in the expression of
    LVH.

         

    A complete understanding of LVH variability is certain
    to be extremely complex, involving multiple gene
    interactions as well as gene-environment interactions.

             

  • J P O’Beirne, S R Cairns

    Drug Points: Cholestatic Hepatitis in Association with Celecoxib 

    BMJ Vol. 7303, 7 July 2001; Pg. 23

          

    Non-steroidal anti-inflammatory drugs, particularly diclofenac sodium, have been associated with serious hepatotoxicity. 

           

    In a review of controlled clinical trials involving 7400 patients, hepatic dysfunction occurred in 0.8% of those treated with celecoxib compared with 0.9% treated with placebo and 3.7% treated with diclofenac sodium. 

           

    Nimesulide, another non-steroidal anti-inflammatory drug with cyclo-oxygenase-2 selectivity, has been reported to cause fulminant hepatic failure, and celecoxib has been associated with hepatitis and pancreatitis.

           

  • L. E. Schnipper and T. B. Strom 

    Editorial: A Magic Bullet For Cancer – How Near and How far?

    The New England Journal of Medicine Vol. 345(4), 26 July 2001; Pg. 283-84

           

    Since even humanized chimeric monoclonal antibodies often provoke antibodies that nullify the therapeutic effects of engineered immunoglobulins, a way of making fully human antibodies in vitro has been sought.

          

    The most notable success to date has been achieved with rituximab, a humanized monoclonal antibody against the B-cell-specific antigen CD20. In patients with low-grade B-cell lymphoma who relapse after the usual therapy, rituximab frequently results in complete or partial remissions.

          

    In some patients with low-grade lymphoma, rituximab plus chemotherapy eliminates all detectable cells. 

           

    A different approach entails fusing the DNA sequences encoding antigen-binding antibody fragments with genes for bacterial toxins.

          

    CD22, a surface antigen of B cells, was genetically fused to a truncated pseudomonas toxin protein containing the translocation and toxin moieties. This genetically engineered immunotoxin was used to treat patients with hairy-cell leukemia, a B-cell neoplasm with abundant expression of surface CD22. In this trial, the anti-CD22 immunotoxin induced complete remissions in 69 percent of patients.

          

    Similar results have also been found with use of a fusion protein combining diphtheria toxin and interleukin-2 in patients with T-cell lymphomas that express interleukin-2 receptors.

          

    Despite the uncertainties and unsolved problems, the authors are confident that tumor-specific immunotherapy is more than a distant promise.

           

  • Positive Opinion for Novartis’s Glivec 

    Scrip No. 2665, August 1, 2001. Pg. 22 

          

    The EC CPMP has adopted a positive opinion on Novartis’s anticancer, Glivec (ST1571/imatinib mesilate) 50mg and 100mg, for the treatment of adults with Philadelphia chromosome (bcr-abl)-positive chronic myeloid leukemia (CML) in the chronic phase after failure of alpha-interferon or in the accelerated phase or blast crisis.

          

    The product – a tyrosine kinase inhibitor – is already available in the US (as Gleevec), where it was approved in record time.

          

  • More Positive Data For Xanelim

    Scrip No. 2666, August 3, 2001. Pg. 22 

        

    Genentech and Xoma have presented more encouraging Phase III data on their anti-CD11 a monoclonal antibody, Xanelim (efalizumab), suggesting it is safe and effective in the treatment of moderate to severe psoriasis.

          

  • Michael A Weber 

    Vasopeptidase Inhibitors 

    Lancet, Vol.358, November 3, 2001, Pg. 1525-32

          

    Summary : Vasopeptidase inhibitors are a new class of cardiovascular drugs that simultaneously inhibit neutral endopeptidase and angiotensin-converting enzyme (ACE). They increase the availability of peptides that have vasodilatory and other vascular effects; they also inhibit production of angiotensin II.

          

    In animal models, vasopeptidase inhibitors decrease blood pressure in low, medium, and high renin forms of hypertension, and they also appear to confer benefits in models of heart failure and ischaemic heart disease.

         

    They also have hypotensive effects. Omapatrilat has been studied and shown to be more effective than currently available ACE inhibitors or other widely used antihypertensive agents. These drugs have safety profiles similar to ACE inhibitors though frequency of side-effects such as angio-oedema and cough are to be established. Large trials are needed to establish their place in therapy of hypertension, heart failure, ischaemic heart disease and nephropathy.

          

  • Gusto V Investigators 

    Reperfusion Therapy for Acute Myocardial Infarction with Fibrinolytic Therapy or Combination Reduced Fibrinolytic Therapy and Platelet Glycoprotein IIb/IIIa Inhibition: The GUSTO V Randomised Trial 

    Lancet, Vol.357, June 16, 2001, Pg. 1905-14

          


    Summary : Plasminogen activator therapy for acute myocardial infarction is limited by lack of achievement of early, complete, and sustained reperfusion in a substantial proportion of patients. Many phase II trials have supported the potential of combined fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition for improving reperfusion.

           

    The authors’ did a randomised, open-label trial to compare the effect of reteplase alone with reteplase plus abciximab in patients with acute myocardial infarction.

          

    Interpretation: Although combined reteplase and abciximab was not superior to standard reteplase, the 0.3% absolute (5% relative) decrease in 30-day mortality fulfilled the criteria of non-inferiority. 

           

    Combination therapy led to a consistent reduction in key secondary complications of myocardial infarction including reinfarction, which was partly counterbalanced by increased non-intracranial bleeding complications.

            

  • Freek W A Verheugt

    Commentary: GUSTO V: The Bottom Line of Fibrinolytic Reperfusion Therapy 

    Lancet, Vol.357, June 16, 2001, Pg. 1898-99

          

    Summary : Several drugs that could provide additional benefit to thrombolytic therapy have been investigated. Addition of heparin has not improved early patency rates or prevented reocclusion and has increased frequency of bleeding especially cerebral bleeding.

          

    Hirudin, a direct inhibitor of thrombin was similar. Aspirin, in addition to streptokinase, decreased mortality and has shown benefit of inhibiting platelet aggregation.

           

    Antagonists to the glycoprotein IIb/IIIa receptor, such as abciximab, eptifibatide or tirofiban, block the final common pathway of platelet aggregation. These drugs given IV have improved outcome of fibrinolytic agent and a glycoprotein protein abciximab has been extensively evaluated.

           

    Addition of full-dose abciximab to half-dose alteplase or to half-dose reteplase resulted in nearly 80% of patients achieving complete reperfusion at 90 min without much increase in side-effects. Patency improved and ECG signs of tissue perfusion were also better with the combination.

          

    Results of GUSTO V has both good and bad news. The good news is the report of the lowest 30 day mortality (less than 6%) and bad news is that concept of an improvement in early patency rates leading to a decrease in mortality was not confirmed.

         

    Future management of MI with ST elevation may involve early medical treatment with a bolus of fibrinolytic or a combination of a fibrinolytic and a glycoprotein blocker- followed immediately by angioplasty.

           

  • The GUSTO IV-ACS Investigators 

    Effect of Glycoprotein IIb/IIIa Receptor Blocker Abciximab on Outocome in Patients with Acute Coronary Syndromes Without Early Coronary Revascularisation: The GUSTO IV-ACS Randomised Trial 

    Lancet, Vol.357, June 16, 2001, Pg. 1915-24

           

    Summary : Glycoprotein IIb/IIIa blockers reduce procedure-related thrombotic complications of percutaneous coronary intervention, and the risk of death and myocardial infarction in patients with acute coronary syndromes.

         

    The effect on risk of death and myocardial infarction is particularly apparent in patients undergoing early percutaneous coronary interventions.

         

    The authors did a randomised, multicentre trial to study the effect of the glycoprotein IIb/IIIa blocker abciximab on patients with acute coronary syndromes who were not undergoing early revascularisation.

         

    Interpretations : Although the explanations for the findings are unclear, this study indicates that abciximab is not beneficial as first-line medical treatment in patients admitted with acute coronary syndromes.

         

  • Jose L Rocha, Jorge Fernandez-Alonso

    Acute Tubulointerstitial Nephritis Associated with the Selective COX-2 Enzyme Inhibitor, Rofecoxib 

    Lancet, Vol.357, June 16, 2001, Pg. 1946-47

           

    Summary : The nephrotoxic effect of COX-2 selective inhibitors has not yet been established. The authors report a case of reversible acute renal failure due to acute tubulointerstitial nephritis, confirmed by histology of a renal biopsy sample, associated with taking rofecoxib, a selective cyclo-oxygenase-2 (COX-2) inhibitor.

          

    Post marketing surveillance by the manufacturer has found some cases of possible interstitial nephritis in patients taking rofecoxib, and 11 cases of possible interstitial nephritis have been reported to the manufacturer in patients receiving celecoxib, although a definite diagnosis was not made in any patients. A case of interstitial nephritis has been reported in a series of 19087 patients treated with meloxicam (a relatively selective NSAID).

          

    This report shows that selective COX-2 inhibitors can also be associated with acute tubulointerstitial nephritis in the same way as non-selective NSAIDS. Frequency of this effect is still unknown and can only be established by close pharmacovigilance.

         

  • David J Rowbotham 

    Commentary: Endogenous Opioids, Placebo Response, and Pain 

    Lancet, Vol.357, June 16, 2001, Pg. 1901-02

           

    Summary : Endogenous ligands for opioid receptors include enkephalins (d receptor), dynorphins (k receptor) and endorphins. Endogenous ligands with a high selectivity for the m receptor (endomorphins) were first identified in 1997.

           

    Endomorphin-1 and endomorphin-2 are both simple peptides of only 4 amino acids. They are involved in pain and analgesia.

           

    A new receptor, structurally similar to opioid receptors has been classified as opioid-receptor-like (ORL1) or OP4 and its natural ligand as orphanin FQ or nociceptin. This system is involved in several physiological processes such as the central modulation of pain. It is not implicated in respiratory depression. 

            

    The exciting potential of this discovery is the availability of analgesics with opioid efficacy and no effect on respiratory function. Investigations on selective antagonists to this receptor are in progress. 

            

  • Deborah Josefson 

    FDA Warns Merck Over Its Promotion of Rofecoxib

    BMJ, Vol.323 (7316), October 6, 2001, Pg. 767

         

    Summary: Rofecoxib, a selective COX 2 inhibitor was approved by the FDA in May 1999 for the relief of acute pain, osteoarthritis and dysmenorrhoea. It was heavily promoted by Merck as safer and superior to nonselective NSAIDS like ibuprofen and
    naproxen.

         

    In its letter the FDA criticized Merck for playing down the possible risk of stroke associated with rofecoxib and for minimizing potential drug interactions with warfarin.

           

    The risk of stroke was found in an analysis of a large study called VIGOR (Vioxx gastrointestinal outcomes research) trial, which compared rofecoxib 50 mg per day with naproxen 500 mg twice a day in patients with rheumatoid arthritis.

           

    Analysis of this study by cardiologist Eric Topol and colleagues at the Cleveland clinic in Ohio showed that patients taking rofecoxib had a higher relative risk of developing adverse cardiovascular events such as ischaemic strokes, unstable angina, and myocardial infarction than the patients taking naproxen.

          

  • Amar Alwitry and Iain Gardner

    Minerva 

    BMJ, Vol.323, 20 October, Pg. 944

           

    Summary : This is a case report of tamoxifen induced retinopathy in a 64 year old woman taking tamoxifen 20 mg/day for 8 years. The incidence of tamoxifen retinopathy is about 6% among patients who have taken the drug for 5 years. Stopping treatment prevents further deterioration but rarely allows complete recovery of visual function.

          

  • Lisa R. Grillone and Rene Lanz 

    Fomivirsen 

    Drugs of Today, Vol.37 (4), April 2001, Pg. 245-255

           

    Summary : Cytomegalovirus (CMV) retinitis can rapidly lead to blindness in patients with AIDS. Fomivirsen is a novel antisense drug. 

          

    It is a phosphorothioate oligonucleotide with a unique antisense mode of action. The 21-nucleotide sequence of fomivirsen is complementary to a sequence in mRNA of IE2 of human CMV. This region of mRNA encodes several proteins that are essential for the production of infectious CMV. Binding of fomivirsen to this target mRNA results in inhibition of IE2 protein synthesis, subsequently inhibiting viral replication.

           

    In patients with AIDS, fomivirsen has been shown to provide a safe and effective treatment, for newly diagnosed, peripheral CMV retinitis or relapsed CMV retinitis unresponsive to other therapies.

           

    No systemic adverse effects were seen. It is administered by intravitreal injection to ensure target-specific distribution. No drug is detected in systemic circulation. Local ocular adverse events were predominantly mild to moderate, transient and responded well to topical medications. 

           

    The dosing schedule is simple and combined with demonstrated safety and efficacy, fomivirsen is a valuable and convenient treatment, for patients with AIDS and newly diagnosed peripheral CMV retinitis or relapsed CMV retinitis unresponsive to other therapies.

            

  • Burke A. Cunha 

    Antimicrobial Selection in the Penicillin-Allergic Patient 

    Drugs of Today Vol.37 (6), June 2001, Pg. 377-383 

          

    Summary : Penicillin and b-lactam allergic reactions should be determined by a careful history and whether it is of an anaphylactic or nonanaphylactic variety. Most reactions to
    b-lactams are of the nonanaphylactic type and are usually manifested clinically as a mild maculopapular rash or drug fever. 

          

    Uncommonly, penicillin allergies are clinically manifested as anaphylactic reactions e.g. bronchospasm, laryngospasm, hypotension or hives. Patients hypersensitivity reactions tend to be stereotyped on rechallenge, which make the reactions predictable. Although monobactams and carbapenems are structurally related to
    b-lactams, they are unrelated in terms of allergic potential. 

          

    There is no cross-reactivity between monobactams or carbapenems with b-lactams. Because so many antibiotics are available that are allergically unrelated to
    b-lactams, b-lactam desensitization procedures are rarely necessary.

           

  • T. P. Le and Y-Q. Xiong 

    Gemifloxacin 

    Drugs of Today Vol.37 (6), June 2001, Pg. 401-410 

           

    Summary : Gemifloxacin is a novel antibiotic and the first fluoroquinolone with a pyrrolidine derivative at the C-7 position. Because of the added pyrrolidine substitute, gemifloxacin has an enhanced spectrum of activity against Gram- positive bacteria such as
    Streptococcus pneumoniae and Staphylococcus
    aureus
    , in addition to its activity against Gram-negative bacteria. It has excellent activity against Enterobacteriaceae and other respiratory pathogens. 

            

    It has potential activity in vitro against anaerobic bacteria. With a broad spectrum of activity, convenient once-daily administration, good bioavailability and tolerability, gemifloxacin is an important addition to the armamentarium against a wide range of infections, from UTI to community acquired pneumonia.

            

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Speciality Spotlight

 

           
Clinical Pharmacology
       

     

  • Leape LL, Cullen DJ, Clapp MD, et al [Harvard School of Public Health : Massachusetts Gen. Hospital; Brigham and Women’s Hosp., Boston]
    Pharmacist Participation on Physicians Rounds and Adverse Drug Events in the Intensive Care Unit
    JAMA 282: 267-270, 1999
       
    Although studies show that pharmacist review of ICU prescription orders prevents mistakes and lowers drug costs by reducing drug use, there have been no studies on the benefits of having a pharmacist present in the ICU at the time drugs are prescribed. The efficacy of pharmacist participation in a medical ICU in preventing adverse drug events [ADEs] was tested in a controlled clinical trial.
       
    Between February 1 and July 31, 1993 [Phase 1 Preintervention] and October 1, 1994 and July 7, 1995 [Phase 2 postintervention], the effect of pharmacist intervention was tested in a 17-bed ICU [the study unit] and compared with no pharmacist intervention in a 15-bed coronary care unit with similar occupancy rate [the control unit].
       
    ADEs were compared for 75 randomly selected patients in each of the 3 groups from amongst all patients admitted to the study unit in Phase 1 and 2, and all patients admitted to the control unit in Phase 2. An experienced pharmacist made daily morning rounds with ICU personnel in the study unit; an experienced pharmacist was available for consultation but did not make daily rounds in the control unit. Outcome measures included measurements of ADEs, interventions the pharmacist made, and the acceptance of pharmacist interventions by the physicians and nurses.
       
    The overall rate of preventable ordering and ADEs/1000 patient days decreased by 66% in the study unit from Phase 1 to 2, with significant savings in drugs costs. The rate of ADEs came down significantly in the study group from Phase 1 to 2. In the control group the rate of ADEs continued to remain high.
       
    Of the 398 pharmacist interventions reported, 366 were related to ordering and 362 were accepted by the physicians.  Pharmacist – initiated clarifications or correction of incomplete orders, wrong dose, wrong frequency, inappropriate choice, or duplicate therapy accounted for 46% of interventions. Drug interactions or adverse reactions were prevented in 22 cases.
       
    The presence of a pharmacist at rounds in ICUs significantly reduces incidence of ADEs and result in substantial cost savings.
          

  • Presented at XII International symposium on Atherosclerosis, Stockholm, Sweden.
    Superstatin boosts Astra Zeneca
    Scrip no.2554, July 5, 2000, p.18
       
    Rosuvastatin (ZD4522) is the most potent cholesterol lowering agent known. It lowers LDL cholesterol by 65% as compared to 25% by current statins.
      
    It does not produce hepatotoxicity or myotoxicity. Liver enzymes and CPK remain normal. It has a long half-life (once a day dosing). Rosuvastatin is not metabolised by the liver.
        

  • Caelyx approved in EC for cancer
    SCRIP No.2588, November 1st, 2000, pg.22
      
    Pegylated liposomal doxorubicin (Caelyx) also known as Doxil has been approved in the EC for ovarian cancer. It is administered intravenously once every 4 weeks. Although there have been concerns that results of clinical trials submitted to US NDA (FDA) were not very meaningful, there are no alternative advanced treatment options for ovarian cancer and the FDA advisory panel decided that the product may be useful.
         

  • R Gupta, Shalini Singhal. et al (Department of Medicine, Monilek Hospital and Research Centre, Jaipur)
    Antioxidant and Hypocholesterolaemic Effects of Terminalia arjuna Tree-Bark Powder: A Randomised Placebo-Controlled Trials.
    JAPI, Vol.49, February 2001, pg.231 – 235.
      
    One hundred and five successive patients with coronary heart disease were divided into 3 groups and treated with either placebo, vitamin E capsules 400 units/day or Terminalia arjuna 500mg/day in capsules.
      
    After 30 days follow-up, blood biochemistry was repeated. No significant changes in total cholesterol HDL, LDL and triglyceride were seen in the placebo group and vitamin E group.  In the group, who received terminalia arjuna there was significant fall in cholesterol and LDL cholesterol.
      
    Conclusion by the authors was that terminalia arjuna has significant antioxidant action and also has a significant cholesterol lowering effect.
       

  • HS Bawaskar, PH Bawaskar,
    Prazosin Therapy and Scorpion Envenomation
    JAPI 2000, VOL.48(12), P.1175.
      
    One of the most dangerous scorpions in the world is Mesobuthus tamulus. It is very common on the Western coast of India. It is known as the Indian red scorpion and is a very aggressive species of scorpion and scorpion stings are very common among agricultural workers. The fatality rate is very high. Most victims develop severe hypertension. Use of antivenim has given very poor results. The only effective treatment of proven value is Prazosin which is an alpha adrenergic-blocker.
      
    Response to Prazosin given initially by injection and later continued with oral doses at 3 hourly intervals prevented the development of severe acute hypertension and its consequent complications such as pulmonary edema. Prasozin should be now accepted as the standard treatment for scorpion envenomation.
       

  • S Singh, Department of Internal Medicine, PGIMER, Chandigarh
    Blood Glucose Changes Following Anticholinesterase Insecticide Poisoning.
    JAPI 2000,Vol.48(12),pg.1145
      
    Organophosphates (OPC’s) and carbamates are extensively used in India, especially by the farming community. Both these compounds are very toxic. Biochemically there is an accumulation of acetylcholine (ACH). Symptomatically the nervous system is affected with muscle paralysis, central nervous system dysfunction, bradycardia and endocrine changes. Approximately half the victims get hyperglycaemia and glycosuria. The biochemical based on hyperglycaemia is not known. It is still not clear as to the duration of hyperglycaemia. After acute episode, patients need to be followed up to determine the long-term implications.
       

  • R Locher, PM Suter, W Vetter (Univ Hosp, Zurich, Switzerland)
    Ethanol Suppresses Smooth Muscle Cell Proliferation in the Postprandial State:  A New Antiatherosclerotic Mechanism of Ethanol?
    Am J Clin Nutr 67 : 338-341, 1998
       
    It is known that smooth muscle cell proliferation in the postprandial state (after food) may lead to narrowing of arteries.  It is well known that ethanol (alcohol) raises HDL cholesterol and thereby gives protection against atherosclerosis and heart attack.  It now appears that ethanol (alcohol) also suppresses the proliferation of smooth muscle cells and thereby gives additional protection in patients against atherosclerosis.
      

  • BA Julian, Jr RR Brantley, CV Barker, et al (Univ of  Alabama, Birmingham)
    Losartan, an Angiotensin II type 1 Receptor Antagonist, Lowers Hematocrit in Posttransplant Erythrocytes.
    J Am Soc Nephrol 9:1104-1108, 1998.
      
    Losartan, significantly lowers hematocrit in patients with post-transplant Anaemia (PTE).  This suggests that angiotensin II has a pathogenic role in post-transplant Anaemia.
       

  • WJ Catalona, AW Partin, KM Slawin, et al (Washington Univ, St. Louis, Mo; Johns Hopkins Hosp, Baltimore Md; Baylor College of Medicine, Houston; et al)
    Use of the Percentage of Free Prostate-specific Antigen to Enhance Differentiation of Prostate Cancer from Benign Prostatic Disease: A Prospective Multicenter Clinical Trial.
    JAMA 279: 1542-1547, 1998.
       
    Free PSA percentage is a significant predictor of prostate cancer, with a sensitivity of 95% below a cutoff of 25%. Patients with prostate cancer and free PSA levels about the cutoff had less aggressive disease. Precentage of free PSA is an independent predictor of prostate cancer.

           

  • Shoseyov D, Bibi H, Shai P, et al (Hadassa Med School, Jerusalem, Israel; Brazilai Hosp, Ashkelon, Israel; SHIRAM Asaf Harofe Med Ctr, Zerifin, Israel; et al)
    Treatment with Hypertonic Saline versus Normal Saline Nasal Wash of Pediatric Chronic Sinusitis.
    J Allergy Clin Immunol 101: 602-605, 1998.
           
    Thirty patients were studied randomly with double-blind study. 
        
    Instilling 1 -mL hypertonic saline (HS) 3 times daily for 1 month improves the clinical and radiological conditions of children with chronic sinusitis. This treatment is tolerable and inexpensive.
         
    This is an interesting study supporting the use of HS. The exact mechanism is not known.
         

  • Personelle J, de Souza Pinto EB, Ruiz RO (Sao Paulo, Brazil)
    Injection of Vitamin A Acid, Vitamin E, and Vitamin C for Treatment of Tissue Necrosis.
    Aesthetic Plast Surg 22: 58-64, 1998.
        
    Experimental animals used were rats. Injection of ACE pool, composed of all-transretinoic acid, vitamin A, and vitamin E is useful for the treatment of necrosis after routine plastic surgery.
          
    The antioxidants and their general health effects were used orally in selected patients to better prepare their tissue for surgery by G.R. Holt and found this regimen to be useful. 
         
    Well controlled clinical trial is needed – G.R. Holt.
          

  • Ament PW, Paterson A (Latrobe Area Hosp, Penn)
    Drug Interactions with the Nonsedating Antihistamines
    Am Fam Physician 56: 223-230, 1997.
          
    The nonsedating antihistamines – which include astemizole, fexofenadine, loratadine and terfenadine – are very commonly prescribed drugs.
         
    Terfenadine and astemizole cause serious adverse effects in interaction with macrolide antibiotics or the antifungal agents, quinine Such interaction appears to be less likely with fexofenadine and Loratadine.
         
    To avoid an adverse effect (drug-drug interactions) one must avoid prescribing any medication that may influence cytochrome P450 system.
         

  • Marvez-Vals EG, Ernst AA, Gray J, et a (Louisiana State Univ, New Orleans; Vanderbilt Univ Med Ctr, Nashville, Tenn)
    The role of Betamethasone in the Treatment of Acute Exudative Pharyngitis.
    Acad Emerg Med 5: 567-572, 1998.
         
    The double-blind clinical trial was performed over 3 months. Forty-six patients were randomized to placebo and 46 to Betamethasone.
        
    Betamethasone, used as an adjunct to antibiotic therapy reduces the time to pain relief. Most effective in patients with streptococal positive.
           

  • Walter N Kernan, Catherine M Viscoli, et al
    Phenylpropanolamine and the Risk of Hemorrhagic Stroke
    New Eng J Med. Vol.343(25), December 21, 2000.
       
    Phenylpropanolamine is commonly found in appetite suprressants and cough or cold remedies. case reports have linked the use of products containing phenylpropanolamine to hemorrhagic stroke, often after the first use of these products. To study the association, the authors designed a case-control study.
      
    Men and women 18-49 years of age were recruited.  Eligibility criteria included occurrence of a subarachnoid or intracerebral haemorrhage within 30 days before enrollment and absence of previously diagnosed brain lesion.
       
    An analysis in men showed no increased risk of a hemorrhagic stroke in association with the use of cough or cold remedies containing phenylpropanolamine. No men reported the use of appetite suppressants.
      
    The results suggest that phenylpropanolamine in appetite suppressants and possibly in cough and cold remedies, is an independent risk factor for hemorrhagic stroke in women.
          

  • Christine A Haller and Neal L Benowitz
    Adverse Cardiovascular and Central Nervous System Events Associated with Dietary Supplements Containing Ephedra Alkaloids.
    BMJ, 343(25), 21 December 2000, p. 1833-8
      
    Dietary supplements that contain ephedra alkaloids (sometimes called ma huang) are widely promoted and used in USA as a means of losing weight and increasing energy. In the light of recently reported adverse events related to the use of these products, FDA has proposed limits on the dose and duration of use of such supplements.
       
    Authors reviewed 140 reports of adverse events related to the use of dietary supplements containing ephedra alkaloids. A standardised rating system for assessing causation was applied to each adverse event.
       
    The results revealed that hypertension was the most frequent adverse effect followed by palpitations, tachycardia or both, stroke and seizures. Ten events resulted in death, and 13 events produced permanent disability. It is concluded that, use of dietary supplements that contain ephedra alkaloids may pose a health risk to some persons.
         

  • Olli T Raitakari and David S Celermajer
    Flow-mediated dilatation
    Br.J.Clin Pharm. Vol.50, November 2000, pg.397-404
        
    This article describes a non-invasive method for measuring endothelial function.
        
    Arterial endothelial dysfunction is an early event in atherogenesis and precedes structural atherosclerotic changes. It is also important in the late stages of obstructive atherosclerosis, predisposing to constriction and or thrombosis.
       
    Endothelial function can be measured in coronary arteries and in the periphery by measuring vasomotor function after intra-arterial infusion of pharmacologic agents, which release endothelial nitric oxide. A widely used method which is noninvasive uses ultrasound. Arterial diameter is measured in response to an increase in sheer stress, which causes endothelium dependent dilatation. Endothelial function assessed by this method correlates with invasive testing of coronary endothelial function, as well as with the severity and extent of coronary artherosclerosis. This technique provides valuable insights into early atherogenesis, as well as into potential reversibility of endothelial dysfunction by various strategies including drugs e.g. lipid lowering agents, ACE inhibitors, L-arginine and antioxidants.
       
    Diameter of target artery is measured by high resolution external vascular ultrasound in response to an increase in blood flow (causing shear stress) during reactive hyperaemia (induced by cuff inflation and then deflation). This leads to endothelium dependent dilatation, the response is contrasted with that to sublingual nitrogylcerin, an endothelium – independent dilator.
      

  • Manel Esteller, Jesus Garcia Foncillas et al
    Inactivation of the DNA repair gene MGMT and the clinical response of gliomas to alkylating agents.
    New Eng J Med. Vol.343, Nov.9, 2000,pg.1350.
       
    Summary : The DNA repair enzyme O6-methyl-guanine-DNA methyltransferase (MGMT) inhibits the killing of tumour cells by alkylating agents. MGMT activity is controlled by a promoter and methylation of the promoter silences the gene in cancer and the cells no longer produce MGMT. Authors examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumour to alkylating agents.

    MGMT promoter in tumour DNA was analysed by a specific PCR assay. Gliomas were obtained from patients treated with carmustine. Molecular data were correlated with the clinical outcome. MGMT promoter was methylated in 40% of gliomas and this was associated with regression of the tumour and prolonged overall and disease free survival. It was an independent and stronger prognostic factor than age, stage, tumour grade or performance status.

    The conclusion was that methylation of the MGMT promoter in gliomas is a useful predictor of responsiveness of the tumours to alkylating agents.
       
    Editorial : John N Weinsten, pg.1408
    Pharmacogenomics – Teaching old drugs new tricks.
    Summary: Traditionally, cancer treatments have been selected on the basis of tumour type, pathological features, clinical stage, the patient’s age and performance status and other nonmolecular considerations. The field of pharmacogenomics, through the study of large number of genes that influence drug activity, toxicity and metabolism, provides the opportunity to tailor drug treatments and to eliminate many of the uncertainties of current therapy for cancer.
      
    Strong support for this concept is provided by the study of genetic polymorphisms that influence drug metabolism. CYP2D6 affects metabolism of several drugs (beta-blockers, antidepressants, antipsychotics and opioids). Dihydropyrimidine dehydrogenase influences metabolism and therefore neurotoxicity of fluorouracil.
      
    Esteller and colleagues provide clinical evidence to explain the resistance of some gliomas to nitrosourea alkylating agents. Carmustine and other nitrosoureas kill by alkylating O6 position of guanine and thereby cross-linking adjacent strands of DNA. Formation of these cross-links can be prevented by MGMT, which rapidly reverses alkylation. About 30% of gliomas lack MGMT. A lack of MGMT appears to correlate with sensitivity to carmustine. Methylation of MGMT promoter could be used to predict responses to treatment with carmustine.
       
    Pharmacogenomics studies will produce benefits both for clinical research and standard practice. Potential advantages include discovery of better drugs, elimination of poor candidates early in the development process, and dramatic decrease in size and expense of clinical trials.
      

  • Scott Gottlieb, New York
    Cancer drug may cause heart failure
    BMJ, Vol.321, July 29, 2000, pg.259.
        
    Trastuzumab (Herceptin) is a monoclonal antibody that binds to a protein found on the surface of some cells. The protein, HER2, helps to regulate cell growth. By binding to tumour cells, trastuzumab inhibits growth of cancerous cells. It is currently approved for use in metastatic breast cancer.
      
    Editorial in ‘Circulation’ has reported that heart failure occurs in 7% of women taking trastuzumab alone and this rate increases to 28% in women taking the drug with other chemotherapy drugs.
      
    A team of researchers is calling for long-term studies investigating the risk of heart failure among women taking trastuzumab.
      

  • D R Morgan, M Trimble et al 
    Atrial Fibrillation associated with sumatriptan
    BMJ, Vol.321, July 29, 2000, pg.275
        
    This is a case report of a 34 year old man with a history of migraine, who presented with palpitations after taking sumatriptan by nasal spray for a severe headache. On examination, ventricular rate was 130 beats/min. The patient recalled having had a fast irregular pulse after taking sumatriptan previously. He reverted to sinus rhythm spontaneously within 12 hours of admission.
      
    Sumatriptan (5HT agonist at IB and ID receptors) may cause chest tightness and pain in upto 15% of patients. This is presumed to be due to vasoconstriction of coronary arteries. Myocardial infarction has been reported after sumatriptan treatment and its use is contraindicated in patients with IHD. Atrial fibrillation associated with sumatriptan is uncommon.
       

  • David C G Skegg
    Editorial – Third generation oral contraceptives – Caution is still justified.
    BMJ, Vol.321, July 22, 2000, pg.190-191
         
    I
    n October 1995, the Committee on Safety of medicines in UK warned that oral contraceptives containing desogestrel or gestodene carried a small increase in risk of venous thromboembolism compared with older preparations. Four well-designed studies gave the picture that women using 3rd generation oral contraceptives (OCs) had about twice the risk of venous thromboembolism of women using preparations containing levonorgestrel. These conclusions have been debated extensively.
      
    The absolute risks are small, but are they of no consequence ? Studies in Britain and New Zealand, where 3rd generation pills have been commonly used, estimate that the annual death rate from idiopathic venous thromboembolism in users of OC is about 1 in 100,000. Thus, the risk of dying of a woman using the pill for 2-3 years is of the same order of magnitude as the risk of fatal aplastic anaemia in a patient treated with chloramphenicol. Non-fatal events which can still have serious consequences may be at least 30 times more common.
       

  • Editorial – E Ernst
    Herbal medicines: where is the evidence ? 
    Growing evidence of effectiveness is counter balanced by inadequate regulation.
    BMJ, Vol.321, Aug.12, 2000, pg.395-396.  
        
    Sales of herbal medicines are booming. Fastest growth is for St. John’s wort, a herbal antidepressant. In a meta-analysis of 23 randomized trials with mild to moderate depression, the authors concluded that extracts of hypericum were significantly more effective than placebo and as effective as conventional antidepressants.
      
    Controlled trials of ginkgo biloba for dementia showed that ginkgo was more effective than placebo. A meta-analysis showed palmetto as a symptomatic treatment for benign prostatic hyperplasia. It improved urological symptoms and flow measures significantly more than placebo. Saw palmetto was as effective as finasteride and had fewer adverse effects. A systematic review of horse chestnut seed extracts for chronic venous insufficiency indicated equivalence with other active therapies.
      
    Even though herbal remedies may be effective, do their benefits outweigh the risks ? Most herbal remedies in UK and USA are sold as food supplements. Thus, they evade regulation of their quality and safety. Two British cases of severe nephropathy caused by Chinese herbal tea administered to treat eczema illustrate this. Huge variations exist in the quality of herbal medicinal preparations.
      
    A recent study of herbal creams in UK showed that 8 of 11 preparations contained undeclared dexamethasone.
      
    The possibility of herb-drug interactions is a further important issue. Ginseng, on its own, has few serious adverse effects. When combined with warfarin, its antiplatelet activity might cause over anticoagulation.
      
    There is need for reliable information on herbal medicines, and should be met by undergraduate and postgraduate education. Detailed questions about use of herbal drugs should form a part of taking medical history.
      

  • Wilson S Colucci, Uri Elkayam et al
    Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure.
    New Eng J Med, vol.343, July 27, 2000, pg.246.
        
    Intravenous infusion of nesiritide, a brain (B-type) natriuretic peptide, has beneficial hemodynamic effects in patients with decompensated congestive heart failure. Authros investigated the clinical use of nesiritide in such patients. Nesiritide was infused at rates of 0.015 and 0.03 ug per kg per minute. It decreased pulmonary capillary wedge pressure, reduced dyspnoea and fatigue.
      
    It was concluded that in patients hospitalized with decompensated congestive heart failure, nesiritide improves hemodynamic function and clinical status. Intravenous nesiritide is useful for short-term treatment of decompensated congestive heart failure.
            

  • Angela C Shore (Dept. of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, Univ. of Exeter)
    Capillaroscopy and the measurment of capillary pressure
    Br J Clin. Pharmacol, 50, 501-513
        
    Capillaries play a vital role in cardiovascular function as the point of exchange of nutrients and waste products, between tissues and circulation. Skin capillaries can be studied by the technique of capillaroscopy, which enables the investigator to assess morphology, density and blood flow velocity. It is also possible to estimate capillary pressure by direct cannulation using glass micropipettes.
      
    This is a review article, which describes the techniques used to make assessments and outlines some of the changes that are seen in health and disease.
          

  • Paul A Vasey (CRC Dept of Medical Oncology, Univ. of Glasgow)
    Immunotherapy for renal carcinoma: theoretical basis and current standard of care
    Br.J.Clin. Pharmacol 50, 521-529.
       
    There is no internationally recognised standard therapy for metastatic renal cancer and patients are treated with IFA or rIL-2 monotherapy or combinations. New approaches are needed.
       
    There are a number of preclinical studies which suggest that simultaneous exposure to both interferons and retinoids can result in enhanced antiproliferative and differentiation effects, compared with either agent alone. The EORTC are conducting a randomised trial of IFA in combination with 13-cis retinoic acid, a natural metabolite of vitamin A which has anticancer activity through a number of mechanisms including antiangiogenesis, differentiation induction and inhibition of IL-6.
        
    Immunostimulation by exogenously administered cytokines serves to enhance the function of the existing host immune system, rather than act as a cytotoxic agent that will eradicate or cure a disease process such as cancer. Continued development and exploration of novel therapies such as antiangiogenic compounds (e.g. thalidomide), differentiating agents, and newer immuno-stimulating agents will hopefully improve the outlook for patients in the future.
        

  • Kelly Morriss
    Macrodoctor, come meet the manodoctors
    Lancet, vol. 357, march 10, 2000, p.778
         
    In the 1996 film Fantastic Voyage, a mini-submarine of medics travels from vein to brain to laser a clot. The scenario remains science fiction, but emerging field of nanomedicine may make it a science fact.
      
    Billions of minute, self-assembling, computerised bioelectromechanical systems ‘nanobots’ swarming to the injury site, sensing, diagnosing and activating therapeutic systems and cellular repair is envisaged. Nanobots may be one day made with molecular nanotechnology.
       
    The team at Cornell University used tiny nickel nanopropellors to link with ATPase and is investigating ways to turn light energy into ATP, generating recyclable fuel that would render such devices autonomous.
       
    Tree-like polymers called dendrimers could deliver gene therapy or intracranial implants without eliciting immune response.
       
    Tejal Desai (Univ. of Chicago) has developed silicone based microcapsules with nanopores to deliver cells, drugs, proteins, peptides and nucleic acids. Similar type capsules may travel through bloodstream and release their contents at desired locations based on binding to cell-specific receptors.
       
    PEBBLES are probes encapsulated by biological, localised embedding-nanospheres 20-200 nm wide, delivered into cells with 99% viability, via liposomes, a gene gun, or even macrophage ingestion. An individual PEBBLE can measure pH, oxygen, electrolytes, nitric oxide or early changes of apoptosis.
       
    Lethal ‘nanobots’ do not sound comfortable, but safety requirements will be built into systems.
        
    The problem is whether we want to make nanorobotics a reality. An injection of nanorobots could completely clear a stroke clot in a time that is in the order of one blood circulation time. Such treatment needs to prove itself superior to thrombolysis.

    Eric Drexler (Chairman of ‘Foresight’) predicts that nanomedicine will dominate medocal technology research for at least half this century.
          

  • J M Trivier, J Caron, M Mahieu et al
    Fatal aplastic anaemia associated with clopidogrel.
    Lancet, vol.357, Feb.10, 2001, pg.446.
        
    Clopidogrel, an inhibitor of platelet aggregation was thought to be free of the side effects of ticlopidine. Authors describe a man who developed aplastic anaemia after 5 months of treatment with clopidogrel. There were no other plausible causes, and fatal aplastic anaemia might have been induced by clopidogrel.
         

  • Bruno Garcia, Fidy Ramahulimihaso et al
    Ischaemic colitis in a patient taking meloxicam
    Lancet, vol.357, March 3, 2001, pg.690
          
    The safety of cyclo-oxygenase 2 (Cox-2) preferential inhibitors such as meloxicam is debated. Authors describe a patient who presented with bloody diarrhoea after 15mg meloxicam daily for 10 days forosteoarthritis. The endoscopic and histological features were consistent with the diagnosis of ischaemic colitis. Symptoms and endoscopic lesions quickly regressed within 1 week of meloxicam withdrawl. Authors suggest that meloxicam might have intestinal toxic effects when taken in high doses, because of reduced Cox-2 selectivity.
       

  • Editorial –
    Animal research in the post-genome area.
    Lancet, vol.357, March 17, 2001, pg.817
      
    The intimidation in recent months of staff of and investors in Huntingdon Life Sciences, an animal-testing contractor, has brought the debate on animal research to the forefront in the UK.
      
    Regulations introduced 2 years ago require that an ethical review in terms of animal welfare be conducted before and during the project. The project also undergoes a cost benefit assessment to ensure that it will produce maximum benefit.
       
    The 3Rs approach to the problem is reducing number of animals used through better experimental design, refining procedures to minimise suffering to the animals, and replacing animal work with alternative methods.
       
    The unravelling of human genome could change trends drastically e.g. scientists can target specific genetic defects underlying disease instead of creating animal models. Genetic models of human disease are not easy to create and interaction between gene or genes and environment is likely to be more important than single gene defects in pathogenesis of disease.
       
    Animal work was also a requrement by licensing authorities. The authorities have begun to accept some replacement tests and in November last year, the requirement for LD50 for acute effects was dropped from OECD guidelines for testing of chemicals.
         

  • Abigail Pound
    E.coli engineered to mass-procedure erythromycin
    Lancet, vol.357, March 3, 2001, pg;692
        
    A team of researchers in USA, have genetically engineered Escherichia coli to produce polyketides – a group of complex natural products to which erythromycin belongs. At present, they can be produced only by fermentation. Blain Pfeifer and colleagues have reported in Science how E.coli is used to produce polyketides cheaply, quickly and in large quantities.
       

  • Scott Gottlieb
    Risk of ulcer soars with combination of arthritis drugs.
    BMJ, Feb.3, 2001, pg.258
      

    Alendronate and naproxen are commonly used in patients with osteoporosis. Although both drugs cause gastric ulcers when used individually, the authors found that when they are taken together, the incidence of stomach ulcers is far greater than would be expected. Stomach ulcers developed in 8% of the study participants receiving alendronate alone, in 12% of those receiving naproxen alone, and in 38% of the participants taking both alendronate and naproxen. Even in volunteers who did not develop ulcers, the damage to the lining of the stomach was significantly worse in those who received the combination of drugs than in those who took either drug alone.
      

  • Scott Gottlieb
    Methylphenidate works by increasing dopamine levels. 
    BMJ, Feb.3, 2001, pg.259
      
    Methylphenidate works in the treatment of attention deficit hyperactivity disorder by increasing dopamine in children’s brains according to a study reported in the Journal of Neuroscience.

    It raises the level of dopamine by blocking the activity of dopamine transporters which remove dopamine once it has been released. Dopamine decreases background firing rates and increases the signal to noise ratio in target neurones. As a result, methylphenidate may improve attention and decrease distractability in activities that normally do not hold the attention of children with attention deficit hyperactivity disorder.
      
    The drug increases dopamine levels like many addictive drugs (cocaine, alcohol, amphetamine) but the key difference may be the length of time that the drugs take to reach the brain. A drug must reach brain very quickly to become addictive. Oral methylphenidate takes about an hour to have effect on the brain, which prevents the drug from causing the ‘high’ produced by most drugs that stimulate dopamine. It could become addictive when tablets are crushed and then either snorted or injected which allows the drug to reach the brain more rapidly.
      

  • Jason M Kendall, Barnaby C Reeves, et al
    Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures.
    BMJ, Feb.3, 2001, pg.261
      
    Objective of the study was to compare the effectiveness of nasal diamorphine spray with intramuscular morphine for analgesia in children and teenagers with acute pain due to clinical fractures.

    Study was conducted in 404 patients. Onset of relief was faster in the spray group than in the intramuscular group, with lower pain scores at 5, 10, and 20 mins. after the treatment but no difference between the groups after 30 mins. 80% of patients given the spray showed no obvious discomfort compared with 9% given IM morphine.
       

  • Monica Escher, Jules Desmeules et al.
    Hepatitis associated with Kava, a herbal remedy for anxiety.
    BMJ, Jan.20, 2001, pg.139
      
    Kava, the rhizome of the pepper plant Piper methysticum, has been widely used in the South Pacific as a narcotic drink. Lactones, the major constituents of Kava, are considered to be active ingredients and sold in Europe and USA as standardised extracts for anxiety and tension.

    This is a case report of a 50-yr old man who presented with jaundice. He was taking 3-4 capsules of Kava extract daily for 2 months for anxiety (maximum recommended dose 3 capsules) corresponding to a dose of 210-280mg lactones. He took no other drugs and did not consume alcohol. Liver function tests were abnormal and he developed encephalopathy. He received a liver transplant 2 days later and recovered uneventfully. Histology of liver showed extensive and severe hepatocellular necrosis and extensive lobular and portal infiltration of lymphocytes and eosinophils. Assessment of causality according to the definitions of WHO is ‘probable’.
      

  • Ranjit Roy Chaudhury
    Commentary – Challenges in using traditional systems of medicine.
    BMJ. Jan.20, 2001, pg.167

    Integration of modern and traditional systems of medicine may result in loss of some of the basic concepts of the traditional systems of medicine. Purists in the traditional systems of medicine such as Ayurveda and Unani in India oppose this trend to ‘modernise’ their systems, particularly when such integration is carried out by experts in allopathy. They have no objection to the use of modern concepts of the methodology of clinical trials in evaluating the efficacy and side-effects of herbal preparations. Such clinical evaluation is essential to use these remedies in allopathic hospitals.
      
    However, carrying out randomised, double-blind, multicentred trials with standardised extracts is a slow and laborious process. Not all herbal medicines need to undergo vigorous trial because these preparations are already in use. The situation is complicated further because randomised trial may not be very appropriate for evaluation of medicines from traditional systems. Where Prakriti (Ayurveda) or Mijaj (Unani) of individual, determines specific therapy to be used.

    In the past 12 years, the Indian Council of Medical Research (ICMR) has set up a network for carrying out clinical trials of herbal medicines. Using this network, the council has shown the efficacy of several traditional medicines, including Picrorhiza kurroa in hepatitis and Pterocarpus marsupium in diabetes. As a result of these trials, these traditional medicines can be used in allopathic hospitals.

    The regulation of traditional systems of medicine, the products used in these systems, and the practitioners of these systems are weak in most countries. This leads to misuse of the medicines by unqualified practitioners and loss in the credibility of the system. WHO has initiated an effort in this direction and may be the appropriate body to help countries to develop a regulatory system and take steps to meet the obligations under Trade Related Intellectual Property Rights Agreement when these become applicable in the developing countries around 2005.
      

  • G.B. Bolli, David R Owens (Department of Internal Medicine, University of Perugia, Italy; Diabetic Research Unit, University of Wales College of Medicine, UK)
    Commentary – Insulin Glargine
    Lancet, vol.356, August 5, 2000, p.443-444
      
    Insulin glargine is a new long-acting insulin analogue, approved for use  in patients with type I and Type II diabetes mellitus. It is approved by US-FDA and also in Europe.
      

  • Tim Higenbottam, Tom Siddons et al  (Divison of Clincial Sciences sheffield University, UK)
    Commentary – A therapeutic role for chronic inhaled nitric oxide.
    Lancet, Vol.356, August 5, 2000, pg. 446-447.
      
    Inhaled nitric oxide (NO) is a unique selective pulmonary vasodilator, which rapidly combines with oxy-haemoglobin to form methaemoglobin and nitrate in the alveolar capillaries. This combination ensures that the predominant effects are on the pulmonary vessels.
      
    Inhaled NO is a potential treatment for the many forms of pulmonary hypertension. Acutely inhaled NO at maximum doses is about half as effective a pulmonary vasodilator as IV prostacyclin. In hypoxic lung disease such as COPD, pulmonary hypertension increases risk of death. Inhaled NO is about twice as effective a pulmonary vasodilator as oxygen.
       
    Preliminary results from a randomized controlled study in Vienna, Austria, have shown that administration of spiked inhaled NO to patients with COPD on long-term oxygen therapy causes a sustained decrease in pulmonary artery pressure at 3 months without causing hypoxia. Results of long-term studies of inhaled NO in COPD are awaited.
        

  • T.Abe, S Hayasaka, Y Nagaki, et al (Toyama Med and Pharmaceutical Univ, Japan)
    Pseudophakic Cystoid Macular Edema Treated With High-Dose Intravenous Methylprednisolone.
    J Cataract Refract Surg. 25: 1286-1288, 1999
       
    High-dose I.V. methylprednisolone was found to be effective in treating pseudophakic cystoid macular oedema (CME) in a study of 4 patients. Visual acuity improved in 3 of the 4 eyes.
        
    Each of the 4 patients had a ruptured posterior capsule for which anterior vitrectomy was done. The latter may also have played a role in improving visual acuity.
       

  • Rainer G, Menapace R, Schmetterer K, et al (Univ of Vienna)
    Effect of Dorzolamide and Latanoprost on Intraocular Pressure After Small Incision Cataract Surgery.
    J Cataract Refract Surg 25: 1624-1629, 1999.
       
    If there is elevated intraocular pressure (IOP) within 24 hrs. of cataract surgery, there may be a risk of developing corneal epithelial oedema, pain, retinal artery occlusion or anterior ischaemic optic neuropathy.
      
    In a study of 102 patients, it was found that both dorzolamide and latanoprost effectively reduced IOP rises after 6 hours. However only dorzolamide was of help after 20 to 24 hours.
      
    If untreated IOP rose about 5mmHg in 6 hrs and 1.5mm Hg within 24 hours. Using dorzolamide reduced the increase of IOP significantly. Latanoprost worked well only in the shorter term. Neither dorzolamide nor latanoprost could prevent IOP spikes of 30mm Hg or above.
       

  • Rasheed ES (El Maghraby Eye Ctr, Madina)
    Initial Trabeculectomy with Intraoperative Mitomycin-C Application in Primary Glaucomas
    Ophthalmic Surg Lasers 30: 360-366, 1999.
      
    Mitomycin C is an alkylating agent acting at all stages of the cell cycle. It reportedly inhibits fibroblast proliferation by preventing DNA synthesis, thereby decreasing the amount of scar tissue formation after trabeculectomy.
      
    The authors conducted a randomized study which compared the overall efficacy of the intraoperative application of Mitomycin C. They found that the use of intraoperative Mitomycin C may increase the success rate of glaucoma surgery. They felt that close follow-up and meticulous patient management are required, especially in the early post-operative period.
      
    Complications described are those that occur immediately postoperatively, related primarily to excessive filtration. Eyes with an overfiltering or leaking bleb are often uncomfortable to the patient. Vision is blurred due to low pressure and the excessive moisture on the corneal surface and the patient may suffer from photophobia.
      
    The late complications can be endophthalmitis, blebitis and hyptomy.
       

  • CD Hall, and the AIDS Clinical Trials Group 243 Team (Univ of North Carolina, Chapel Hill; Harvard School of Public Health, Boston; Mount Sinai School of Medicine, New York, et al )
    Failure of Cytarabine in Progressive Multifocal Leukoencephalopathy Associated with Human Immunodeficiency Virus Infection.
    N Engl J Med 338: 1345-1351, 1998.
      
    About 4% of patients with AIDS syndrome have progressive multifocal leukoencephalopathy (PML).  No therapy has been proven effective  for PML – survival after its diagnosis averages 3 months.
     
    In a study of 57 patients it was found that neither intrathecal nor intravenous cytarabine halted progression of PML better than antiretroviral therapy alone. Antiretroviral therapy itself offers no improvement in PML to these patients.
        

  • DM Treiman, for the Veterans Affairs Status Epilepticus Cooperative Study Group (Veterans Affairs Med Ctr, West Los Angeles; Veterans Affairs med Ctr, Bronx, NY; Veterans Affairs Med Ctr, Birmingham, Ala;  et al)
    A Comparison of Four Treatments for Generalized Convulsive Status Epilepticus.
    N Engl J Med 339 : 792-798, 1998.
         
    Three hundred eight-four patients with a verified diagnosis of status epilepticus and 134 patients with subtle generalized convulsive status epilepticus were enrolled in a 5-year randomized, double-blind, multicentre study.
        
    The four intravenous drugs used were (i) diazepam, 0.15mg/kg body weight followed by phenytoin, 18mg/kg (ii) Lorazepam, 0.1mg/kg   (iii) Phenobarbital 15mg/kg and (iv) Phenytoin, 18mg/kg.
         
    The author concludes that Lorazepam is more effective than phenytoin for the initial iv treatment of overt generalized convulsive status epilepticus. Lorazepam is easier to use than the other agents tested.
       

  • FE Dreifuss, NP Rosman, JC Cloyd, et al (Univ of Virginia, Chartlottesville; New England Med Ctr, Boston; Univ of Minnesota, Minneapolis, et al)
    A Comparison of Rectal Diazepam Gel and Placebo for Acute Repetitive Seizures.
    N Engl J Med 338: 1869-1875, 1998.
       
    Epilepsy affects about 2 million people in the United States. When the patient is actively convulsing, oral and sublingual administration is difficult and hazardous. Rectal diazepam is used to treat acute repetitive, prolonged and febrile seizures. It is effective, well tolerated and can be administered at home by trained caregivers.
       

  • D Gaist, I Tsiropoulos, SH Sindrup et al [Odense Univ, Denmark]
    Inappropriate Use of Sumatriptan : Polulation Based Register and Interview Study
    BMJ 316-1352-1353, 1998
      
    Sumatriptan succinate is a commonly prescribed headache drug in Denmark. The appropriateness of the use of this drug was assessed in a polulation-based interview study.
      
    The standard antimigraine drugs when taken in excessive amounts, are now known to either cause or sustain headache. Quite a few patients overuse sumatriptan and may in future, overuse the newer triptans as well.
       
    The study point out that, many overusers were using the medication for inappropriate types of headaches, namely tension-type and drug-induced headaches.
       
    Physicians must understand both the precise indications for the use of triptans and the danger of prescribing immoderate amounts. The quantity and frequency of use of these medications must be plainly specified to.
      

  • Miyake K, Ota I, Maekubo, et al (Miyake Eye Hosp, Nagoya, Japan)
    Latanoprost Accelerates Disruption of the Blood-Aqueous Barrier and the Incidence of Angiographic Cystoid Macular Edema in Early Postoperative Pseudophakias.
    Arch Ophthalmol 117: 34-40, 1999
       
    Latanoprost (prostaglandin F2) lowers intraocular pressure (IOP) by increasing uveoscleral outflow. In human models, latanoprost did not disrupt the blood-aqueous barrier and did not affect cystoid macular oedema (CME) formation in eyes with longstanding pseudophakias.
        
    However, endogenous prostaglandins synthesized in the anterior uvea DO have a role in disrupting the blood-aqueous barrier and in inducing CME after cataract extraction.
       
    In a randomized, double-blind trial for latanoprost, as well as an open-label controlled trial for studying the effects of NSA drops on latanoprost and its place, the authors found that latanoprost disrupts the blood aqueous barrier and increases the incidence of angiographic CME in early postoperative pseduophakia.
       
    Concurrent instillation of NSA drops (e.g. diclofenac) can prevent the adverse effects of latanoprost and thus maintain the decrease in IOP.
        

  • AAQ Aranjo, AP Wells, AD Dick, JV Forrester (Dept. of Ophthalmology, Aberdeen Royal Infirmary, Aberdeen)
    Early treatment with cyclosporin in serpiginous choroidopathy maintains remission and good visual outcome
    Br J Ophthalmol 2000; 84: 979-982.
       
    Serpiginous choroidopathy is characterised by geographic areas of choroidal atrophy (in both eyes), which occur around the optic disc and spread in a helicoid pattern along the major vascular arcades towards the macula. Recurrences are common.
       
    Visual disability may result from retinal lesions affecting the central macula, or from secondary choroidal neovascularization due to disruption of the Bruch’s membrane-retinal pigment epithelium.
      
    The authors present a case series of 14 eyes of seven patients with serpiginous choroidopathy with follow up ranging from 1.3 to 13 years.
      
    No patients suffered significant loss of acuity after starting systemic immunosuppression with cyclosporin as the primary agent. There were no serious complications from immunosuppression.
      
    Adequate immunosuppression can result in clinical remission and cessation of therapy in some patients.
       

  • L.M. Van Beck, M Mulder, N J van Haeringen, Aize Kijlstra. ( Dept of Ophthalmology, Leiden University, Netherlands; Dept of Allergy, CLB and Laboratory for Experimental and Clinical Immunology, Univ of Amsterdam, Netherlands).
    Topical ophthalmic b blockers may cause release of histamine through cytotoxic effects on inflammatory cells.
    Br. J Ophthalmol 2000; 84:1004-1007.
      
    A mixed leucyocyte and basophil preparation was obtained from venous blood of healthy non-atopic volunteers. Cell preparations were then incubated with betaxolol, metipranolol, timolol, or carteolol.
      
    One hour after incubation, the histamine content of the supernatant was analysed by automated fluorometric analysis. Cell viability was tested by measuring lactate dehydrogenase (LDH) concentrations.
      
    Betaxolol and metipranolol in concentrations between 10-2M and 10-3M liberated histamine from human blood cells in a dose dependent manner. Carteolol and timolol had NO effect on histamine at these concentrations.
      
    The authors conclude that betaxolol and metipranolol induce substantial histamine release from human leucocytes, probably as a result of their cytotoxic effect.
       
    This concurs with the observation that patients find timolol eye drops more comfortable than metripranolol or betaxolol eye drops.
       

  • C S Naylor, L Steele, et al 
    Cefotetan-induced hemolysis associated with antibiotic prophylaxis for cesarean delivery.
    Am J Obstet Gynecol 2000; 182: 1427-8
      
    The authors described 3 cases of antibiotic-induced hemolysis associated with cefotetan prophylaxis during cesarean delivery. Each of the 3 patients showed development of significant anemia with documented cefotetan-induced hemolysis. When postpartum anemia is associated with antibiotic use, immune hemolytic anemia should be considered and included in the differential diagnosis.
       

  • Lewis B Holmes, Elizabeth A Harvey, et al
    The Teratogenicity of Anticonvulsant Drugs
    NEJM, Vol.344, April 12, 2001, pg.1132-8.
       
    Major malformations, growth retardation, hypoplasia of the mid-face and fingers, known as anticonvulsant embryopathy is increased in infants exposed to anticonvulsant drugs in utero. Whether these abnormalities are caused by maternal epilepsy itself or by exposure to anticonvulsant drugs is not known.
       
    Authors screened 128,049 pregnant women at delivery to identify 3 groups of infants: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures and a control group. Infants were examined for presence of malformations.
       
    The conclusion of the study was that a distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself.

  • BL Charous, EF Halpern, GC Steven (Milwaukee Med Clinic, Wis)
    Hydroxychloroquine Improves Airflow and Lowers Circulating IgE Levels in Subjects With Moderate Symptomatic Asthma.
    J Allergy Clin Immunol 102: 198-203, 1998.

    Hydroxychloroquine, which is a disease-modifying agent, has an established efficacy in rheumatologic diseases. Its mechanism of action is thought to involve its ability to interfere with lysozome function and, thereby, inhibit of antigen processing and presentation, and subsequent T-cell activation.

    It has been used in asthma as a steroid sparing agent. Its uncommonly benign toxicity profile allows consideration of its use in these patients. The authors have conducted a double-blind, placebo-controlled trial of hydrochloroquine in patients with moderate symptomatic asthma.

    The authors have demonstrated the ability of hydrochloroquine to statistically significantly improve FEV1, morning and evening peak flows, and requirement for B2-agonists. Immune parameters that improved included the mean total IgE concentration. One final important comment is that as with hydrocholoroquine’s known mode of action in rheumatologic disease, the onset of efficacy in asthma was slow, and these changes did not occur until 30 weeks into the trial. A larger study group is required to further prove its efficacy.

  • E Pizzichini, MMM Pizzichini, P Gibson, et al (McMaster Univ, Hamilton, Ont; John Hunter Hosp, Newcastle, Australia; Mayo Clinic and Found, Rochester, Minn)
    Sputum Eosinophilia Predicts Benefit from Prednisone in Smokers With Chronic Obstructive Bronchitis.
    Am J Respir Crit Care Med 158: 1511-1517, 1998.

    Corticosteroid treatment has improved the on-doubt of its usefulness in patients with asthma and decreasing airway eosinophilia. However, its role in the treatment of chronic obstructive bronchitis is controversial. The authors present a placebo-controlled, crossover trial to determine whether the presence of sputum eosinophils predicts benefit from prednisone in 18 smokers with severe chronic obstructive bronchitis.

    Their findings that the presence of significantly elevated eosinophilia in the sputum identified a subset of patients who had objective improvements in effort, dyspnea, quality of life, and in their FEV1 interests us. It not only reduced sputum eosinophilia in these patients, but also reduced sputum fibrinogen concentrations. Thus supporting the concept that the use of prednisone may reduce airway fibrosis and remodeling, thereby slowing the progression of the disorder.

    In fact the findings of sputum eosinophilia may be further implemented in seeing if these patients do benefit with long term inhaled corticosteroids rather subject them to an exposure to systemic corticosteroids.

  • SD Aaron, RE Dales, B Pham (Univ of Ottawa, Ont)
    Management of Steroid-dependent Asthma with Methotrexate: A Meta-analysis of Randomized Clinial Trials.
    Respir Med 92: 1059-1065, 1998.
         
    Various alternatives to long-term steroid therapy are needed for the control of severe asthma. The efficacy of methotrexate as a steroid sparing agent was examined in a meta-analysis of randomized clinical trials.
        
    It was concluded from the study that methotrexate use enables modest decreases in oral corticosteroids in patients with severe asthma. However, the benefit is relatively small and the possibility of adverse effects should be always outweighed.
        
    There has been controversy concerning methotrexate’s usefulness as a steroid-sparing modality. Different blinded studies have had diametrically opposed results. This meta-analysis, combining experiences with 250 patients, showed a 6.0% improvement in forced expiratory volume over placebo, and an 18.2% decrease in prednisone dose. 
         
    This is relatively small advantage over the effort which has been applied in the entire study and it remains to be seen whether it is really helpful as the patients were subjected to methotrexate therapy were not without risk as two of them developed pneumonias and 1 had hepatic dysfunction as side effects which was an incidence at 1.2% . For a benefit of 6.0% improvement if there is going to be a risk of 1.2% then probably is not worth the effort.
           

  • S Elwany, M Bassiouny, (Alexandria Univ, Egypt)
    Topical Levocabastine for the Treatment of Perennial Allergic Rhinitis
    J Laryngol Otol 111: 935-940, 1997.
      
    Oral H1-receptor antagonists which have found the primary treatment for chronic allergic rhinitis are associated with severe systemic side effects. Topical therapy should theoretically avoid these events, while producing a higher concentration at the site. A study reported shows the use of a nasal spray containing levocabastine which is a potent and highly selective H1-receptor antagonist, on the nasal mucosa in patients with chronic allergic rhinitis.
       
    The study has some remarkable findings in that there has been a reappearance of normal cilia and microvilli and more acinar cells in the post-treatment specimens collected in the biopsy. The number and activity of goblet cells and serous glands decreased as was the evidence of vascular congestion. These changes reduced the formation of edema fluid, and the reduction in the number of pinocytotic vesicles reduced the transmission of fluid across epithelial cells. Degranulated mast cells and eosinophils however, were still present at the end of the short study. 
       
    Although perhaps not as impressive as topical corticosteroids induced changes, the reported findings certainly suggest moderate anti-inflammatory properties of this topical antihistamine. Hence one should look beyond just the antihistaminic actions of these agents by probably combining with leukotriene and lipoxygenase inhibition studies.
       

  • Sheena McCormack, Richard Hayes et al 
    Microbicides in HIV prevention
    BMJ, Vol.322, Feb. 17, 2001, p.410-413
        
    Although the use of condoms has slowly increased in countries most severely affected by the HIV epidemic, many vulnerable women are unable to ensure they are used. An effective and affordable vaginal microbicide, whose use could be controlled by women, would represent an important addition to the armamentarium against HIV infection. This article examines current progress in microbicide development and discusses their future role in HIV control.
       
    Potential microbicides currently in human trials:
       

      Activity

      Product groups and active agents          Anti-STI     Spermicidal             Human trials

    Broad spectrum activity

    Non-ionic surfactants:

    Nonoxinol  9*                                                           ++                     +                                    Efficacy

    Chlorhexidine                                                           ++                     +                       Efficacy (vertical transmission)

    Octoxinol  9*                                                            ++                     +                                      Safety

    Anionic surfactants

    Docusate sodium *                                                  ++                     NA                                   Safety

    Cationic surfactants:

    Glyminox (C31G)*                                                    ++                     +                                      Safety

    Benzalkonium chloride*                                           ++                     NA                                   Safety

    Geda plus *   

    Acid buffers:

    Buffer gel                                                                 ++                    +/ –                                  Safety

    Plant extracts:

    Praneem polyherbal                                                 ++                    +                                      Safety

    Gossypol                                                                  NA                   +                                      Safety

    Bacteria:

    Lactobacilli                                                                                                                            Safety

    Peptides:

    IB367 (protegrin)                                                       +                      NA                                 Safety

    Inhibitors of viral entry

    Sulphated polysaccharides:

    Dextrin sulphate                                                        +                                                           Safety

    Carrageenan                                                            ++                    NA                                  Safety

    Cellulose sulphate                                                    ++                                                          Safety

    Sulphonated polymers:

    PRO 2000                                                                ++                                                          Safety

    Inhibitors of viral replication

    Reverse transcriptase inhibitors:

    Tenofovir (PMPA)                                                                                                    Safety (oral administration)

        
       
    STI = sexually transmitted infection.   NA = not assessed.  * known to be cytotoxic to HIV

  • Patrick M.M.Bossuyt
    Better standards for reporting of RCTs.
    A revised CONSORT statement should further improve standards of reporting
    BMJ, June 2, 2001, pg.1317-1318

    Randomised clinical trial (RCT) are regarded as the best tools for gathering evidence on the effectiveness of health care interventions. To remedy deficiencies in trial reporting, several scientists and editors of bio-medical journals developed the CONSORT statement (the consolidated standards of reporting trials). CONSORT comprises a short checklist of essential items and a flow diagram to be used in reporting trials.

    A revised version of the 1996 statement has been published simultaneously in JAMA, Lancet and Annals of Internal Medicine and is also found on the internet (www.consort.statement.org) 
         

  • Yoshiki Sawa
    Therapeutic angiogenesis with gene transfection for ischaemic heart disease.
    Drugs of Today, 2001, 37(1), pg.67-71
       
    Genetic engineering studies conducted in the field of cardiovascular medicine have lead to the use of gene therapy as a means of treating ischaemic disease. Folkman et al have shown that tumour growth is facilitated by revascularisation and revascularization factors are involved in tumour growth. The first revascularisation factor used for therapeutic angiogenesis was basic fibroblast growth factor (bFGF). In a rabbit model of acute leg ischaemia, 14 day IM treatment with bFGF at a dose of 1 or 3 mg promoted the formation of collaterals in the legs. Possibility of treating myocardial infarction has also been reported. Intramyocardial injection of vascular endothelial growth factor (VEGF) on induction of myocardial revascularisation has been shown in dogs and pigs.
        
    Clinical trials of gene therapy using VEGF have started at Tufts University in U.S. This therapy is designed to treat severe ischemic disease with revascularisation. VEGF genes were injected locally into myocardium after small thoracotomy. More than 70 patients have undergone this therapy and revascularisation and improved regional blood flow as assessed by angiography and myocardial scintigraphy has been reported. Crystal and coworkers at Cornell University have administered VEGF cDNA on an adenovirus vector into the myocardia of about 30 patients, with or without coronary artery bypass grafting, and reported revascularising effect and safety of this therapy. 
        
    Revascularising effects of HGF:- Hepatocyte growth factor has been shown to be specific to vascular endothelium and does not affect proliferation of vascular smooth muscle.
       
    Studies in rats have shown that HGF increases the number of newly formed blood vessels. HGF is more potent than VEGF and clinically useful. Introduction of HGF gene, which is a revascularisation factor produced endogenously, may be a new means of treating severe ischaemic heart disease.
        

  • S.L. Udupa
    Indigenous drugs and atherosclerosis
    Drugs of Today 2001, 37(1), 37-47
         

    An encouraging field for the application of indigenous drugs is regression of atherosclerosis. Vitamins C and E, carotenoids, flavonoids, terpenoids present in indigenous drugs have been shown to slow down progression of experimental atherosclerosis. Potassium and magnesium found in herbals are also beneficial.
         
    This is a review of some of the Indian indigenous drugs, found to be antiatherogenic. 
         
    The drugs included are: 
    (1) Achyranthus aspera – contains triterpenoids. Hypocholesterolemic effect in rats. 
         
    (2) Allium cepa (onion) – therapeutic effects attributed to sulphur compounds.
          
    (3) Allium satiuum (garlic) – known to have hypoglycaemic, hypocholesterolemic and hypolipidemic effects and protects against the development of atherosclerosis. The inhibition of cholesterol synthesis by garlic may be due to a mixture of multiple compounds of sulfur containing thiosulfinates, ajoenes and dithienes.
           
    (4) Aloe barbedensis – Lipid lowering agent lowers VLDL and LDL and increases HDL.
          
    (5) Capsicum annum (Red pepper). Red pepper or its active principle capsaicin prevented increase in cholesterol levels in rats.
          
    (6) Cicer arientinum – Bengal gram. Hypolipidemic effect – due to its isoflavonic component – Biochanin A.
           
    (7) Commiphora mukul – Crude guggul or its oleoresin lowers serum cholesterol in rabbits. Similar effect shown in patients with hypercholesterolemia. Long-term combination treatment with fraction A guggul and cholestyramine resulted in decrease in serum cholesterol and triglyceride levels.
         
    (8) Dolicos lablab – seeds used as pulse in diet. Reduces serum cholesterol in rats.
          
    (9) Emblica officinalis – Its fruit (amla) is probably the richest known natural source of vitamin C. Dietary supplementation with raw amla in normal and hypercholesterolemic subjects resulted in a decrease in cholesterol levels.
         
    (10) Medicago sativa : (Alfalfa). Alfalfa meals prevent hypercholesterolemia, triglyceridemia and atherogenesis in cholesterol fed rabbits.
         
    (11) Plantago ovata – They are a class of gel-forming, nonabsorbable, soluble fibres derived from oat or psyllium seed husk which have been shown to produce cholesterol lowering effects when added as dietary supplements. Addition of psyllium hydrophilic mucilloid to cholestyramine therapy may improve patient compliance by reducing drug-associated GI side-effects.
         
    (12) Terminalia arjuna – Powdered bark is used. Constituent of many Ayurvedic preparations shown to decrease serum cholesterol and blood sugar levels in experimental animals after 3 months of treatment. It is also reported to have antihypertensive and antiarrhythmic properties.
        
    (13) Terminalia belerica – Alcoholic extract has dose-dependent hypotensive effect. It is present in Triphala (T.belerica, T.chebula and E.officinalis).
         
    (14) Terminalia chebula – Reduces cholesterol levels in experimental atherosclerosis in rabbits.
         
    (15) Trichosanthes dioica – Fruit used. Hypoglycemic and hypocholesterolemic effects in normal and mildly diabetic humans.
          
    (16) Trigonella foenum graecum – The seeds (fenugreek) – caused cholesterol levels to decrease in diabetic hypercholesterolemic dogs. Also reduces hyperglycemia. Ethanol extract from defatted fenugreek seeds contained saponins that inhibit absorption of taurocholate and deoxycholate.
          
    In type I diabetes, fenugreek diet significantly reduced fasting blood sugar and improved glucose tolerance test. Serum cholesterol, LDL and VLDL and TG were significantly reduced but HDL was unchanged.
          

  • G A Fitzgerald and Carlo Patrono
    The Coxibs, Selective inhibitors of cyclooxygenase-2
    New Eng J of Med. August.9, 2001; pg.433
         
    The coxibs are selective inhibitors of Cox-2. Inhibition of Cox-2 has been more directly implicated in reducing inflammation, whereas inhibition of Cox-1 is related to adverse effects on GI tract. So, it was hoped that coxibs would be better tolerated than nonselective NSAIDs but equally efficacious. Cox-2 can be upregulated by cytokines, growth factors and tumour promoters, suggesting its relevance to inflammation and cancer. Though Cox-1 is a ‘housekeeping’ enzyme, its expression may also be regulated. Celecoxib and rofecoxib were the first drugs, others like valdecoxib and etoricoxib are being developed.
         
    Drug companies assess selectivity by in-vitro assays during screening, because these assays are relatively rapid and simple, but they do not reflect the complexity of drug-enzyme interaction in-vivo.
         
    Two large trials have addressed the efficacy of coxibs and the associated risk of GI complications – the Vioxx gastrointestinal outcomes research (VIGOR) and the celecoxib long-term arthritis safety study (CLASS) trial. The incidence of GI perforation, GI haemorrhage or symptomatic ulcer was 4.5% per 100 patient-years in the naproxen group and 2.1 per 100 patient – years in rofecoxib group, a difference of 54% (P<0.001). In the CLASS study there was no significant difference between the 2 groups.
         
    The distinct roles of 2 Cox enzymes in patients with peptic ulcers are not known. Both are found in apparently normal GI epithelium and may help to protect gastric mucosa. Results of both VIGOR and CLASS trials suggest that Cox-1 has the main cytoprotective role.
         
    Expression of GI epithelial Cox-2 is increased by traumatic and inflammatory stimuli, as well as by H.pylori infection. Expression is increased in the margin of healing ulcers and Cox-2 inhibitors impair ulcer healing in mice. We still have much to learn about potential risks of inhibition of Cox-2 in GI tract –e.g. Cox-2 inhibitors impair tolerance of dietary antigens and exacerbate experimental colitis in rodents.
         
    COXIBS and Cardiovascular disease – Cox-2 has an important role in increasing prostacyclin formation in clinical syndromes of platelet activation. Expression of both COX-1 and COX-2 is upregulated in foam cells and smooth muscle cells of ahterosclerotic plaques. Cox-2 may be important in physiological conditions also e.g. Cox-2 inhibitors decrease urinary excretion of prostacyclin metabolites in normal subjects indicating reduction of prostacyclin production. If Cox-2 inhibitors are associated with a risk of thrombosis, this risk should be small, because of presence of other substances like nitric oxide that protects against thrombosis. However, thrombosis may occur in patients who are already at risk of other underlying conditions –e.g. arterial thrombosis occurred after starting celecoxib therapy in 4 patients with lupus anticoagulant.
          
    Clearly more information is needed on cardiovascular effect of selective inhibitors of Cox-2 and their combination with antiplatelet drugs.
          
    Cox-2 and renal function : Cox-2 dependent prostaglandin formation is necessary for normal renal development. Little information is available on renal pharmacology of Cox-2 inhibitors. Both nonselective NSAIDS and celecoxib produced edema and hypertension to a similar extent. Controlled comparisons of coxibs with each other and with nonselective NSAIDs are necessary to assess risk of hypertension.
          
    Conclusions : In less than a decade after the discovery of Cox-2, clinical trials have demonstrated that selective Cox-2 inhibitors cause significantly fewer GI adverse events than nonselective NSAIDs. More selective coxibs are being developed. Given the cardiovascular findings of small but clinically relevant changes in BP, elucidation of cardiovascular and renal effects of these drugs and their interactions with potential adjuvant therapies, such as low-dose aspirin is necessary.
          

  • R J Norman 
    Commentary – Reproductive Consequences of COX-2 Inhibition 
    The Lancet October 20, 2001, Vol.358 (9290) Pg. 1287-1288
         
    Many reproductive processes-eg, ovulation, fertilisation, implantation, decidualisation, and parturition – depend on prostaglandin ligand-receptor interactions. 
         
    In experimental mice NSAIDs have been shown to induce infertility because of interference with reproductive processes. 
         
    There are many human case reports that infertility is produced by NSAIDs and COX-1/COX-2 inhibitors. However, fertility is restored by discontinuing these drugs. Women attempting to become pregnant should avoid taking these drugs.
          

  • Jan A Staessen, Ji-Guang Wang, Lutgarde Thijs 
    Cardiovascular Protection and Blood Pressure Reduction: A Meta-Analysis 
    The Lancet October 20, 2001, Vol.358 (9290) Pg. 1305-1315
         
    The authors’ conducted a meta-analysis of nine randomised trials comparing treatments in 62 605 hypertensive patients. Compared with old drugs (diuretics and b-blockers), calcium-channel blockers and angiotensin converting-enzyme inhibitors offered similar overall cardiovascular protection, but calcium-channel blockers provided more reduction in the risk of stroke (13.5%, 95% Cl 1.3-24.2, p=0.03) and less reduction in the risk of myocardial infarction (19.2%, 3.5-37.3, p=0.01). 
          
    The authors’ findings emphasise that blood pressure control is important. All antihypertensive drugs have similar long-term efficacy and safety.
          

  • Dinesh C Sharma 
    Policy and People – India to Regulate Indigenous Medicine Sector 
    The Lancet October 13, 2001, Vol.358 (9289) Pg. 1249
        
    India’s health ministry has taken steps to streamline the production of drugs extracted from medicinal plants. Such drugs form the basis of Indian traditional medicine-known as the Indian system of medicine (ISM) and includes Ayurvedic medicine – and will now be subject to quality control form cultivation to manufacture. 
       
    The government will create a register of farmers that grow medicinal plants, raw drug traders, laboratories, and manufacturers. Traders will be required to store medicinal plants properly and keep full records of their suppliers and stock. Drug licensing authorities will ask manufacturers to submit a list of the type and quantity of plant materials used to produce ISM drugs.
        
    Each state has its own set of rules and legislations. Because of this, movement of plant material from one part of the country to another may take several weeks, and volatile ingredients of the plant may get lost on the way.
         

  • C van Walraven, M M Mamdani, P S Wells, J I Williams 
    Inhibition of Serotonin Reuptake by Antidepressants and Upper Gastrointestinal Bleeding in Elderly Patients: Retrospective Cohort Study 
    BMJ No.7314, September 22, 2001, Pg. 655
        
    The aim of this study was to determine the association between inhibition of serotonin reuptake by antidepressants and upper gastrointestinal bleeding. It is a retrospective cohort study from population based databases. 
        
    317 824 elderly people were observed for more than 130 000 person years. Patients started taking an antidepressant between 1992 and 1998 and were grouped by how much the drug inhibited serotonin reuptake. Patients were observed until they stopped the drug, had an upper GI bleed or died or the study ended.
        
    The conclusions were that after age or previous upper GI bleeding were controlled for, antidepressants with high inhibition of serotonin reuptake increased the risk of upper GI bleeding. These increases are clinically important for elderly patients and those with previous GI bleeding.
          

  • Jayasree K Iyer, Wilbur K Milhous et al
    Plasmodium falciparum Cross-Resistance between Trimethoprim and Pyrimethamine 
    Lancet, Vol.358, September 29, 2001, Pg.1066
     
    Trimethoprim-sulfamethoxazole has been recommended as part of the standard package of care for people with HIV and AIDS in Africa.

    A similar antifolate combination, sulfadoxine-pyrimethamine, is now the first-line antimalarial drug in several African countries. 

    Authors present evidence of Plasmodium falciparum cross-resistance between trimethoprim and pyrimethamine at the molecular level. The impact of trimethoprim-sulfamethoxazole prophylaxis on the efficacy of sulfadoxine-pyrimethamine needs to be assessed and alternative antimalarial treatment should be considered for people on trimethoprim-sulfamethoxazole prophylaxis.
       

  • Catherine Vasilakis-Scaramozza, Hershel Jick 
    Risk of Venous Thromboembolism With Cyproterone or Levonorgestrel Contraceptives 
    Lancet, Vol.358, October 27, 2001, Pg. 1427-29

    Summary: Results of several small studies have shown that there is an excess risk of venous thromboembolism in users of oral contraceptives containing cyproterone compared with those containing levonorgestrel.

    The authors conducted a case-control study and the results suggest that risk of venous thromboembolism is increased 4 fold in women taking contraceptives containing cyproterone by comparison with those exposed to levonorgestrel.

    Contraceptives containing cyproterone are often prescribed for women with a history of hirsutism and acne. 
       

  • John A Farmer 
    Commentary: Learning From The Cerivastatin Experience 
    Lancet, Vol.358, October 27, 2001, Pg. 1383-85

    Summary: Statins have revolutionised the management of lipid disorders. They lower lipid concentrations and seem to be safe. Cerivastatin was withdrawn in August this year because of its adverse effects on muscle.

    Myotoxicity was one of the first clinically recognised adverse effects of statins. It ranges from a mild non-specific myalgia to myositis with raised concentrations of creatine kinase. Myositis can progress to the rare but life-threatening syndrome of acute rhabdomyolysis, which can lead to irreversible renal failure. The precise mechanism is not known.

    Statins inhibit HMG CoA reductase, the rate-limiting enzyme in cholesterol synthesis, and lead to secondary depletion of essential metabolic intermediates formed during cholesterol synthesis. Intracellular depletion of metabolic intermediates has been shown to be related to myotoxicity in laboratory work and supplementation of intermediate proteins ameliorated statin-associated toxic effects in in-vitro studies.

    Statins with good lipid solubility have been postulated to have an increased potential for toxicity because of enhanced ability to penetrate the myocyte. The role of reduced concentrations of synthetic intermediates is not studied in human beings, and there have been no clinical safety trials that compare statins directly.

    Myotoxicity may also be due to interaction with cytochrome P-450. The second-generation statins (atorvastatin, fluvastatin, cerivastatin) are synthetic and structurally dissimilar to first-generation statins (lovastatin, pravastatin, simvastatin).

    Although pre-marketing clinical trials of doses up to 0.4 mg/day did not indicate increased risk of rhabdomyolysis, post-marketing surveillance showed increased rates of rhabdomyolysis especially when it was given with gemfibrozil.

    US FDA issued a specific contraindication for this combination, yet cases of rhabdomyolysis continued and after 52 deaths were recorded worldwide, cerivastatin was withdrawn worldwide.

    In several cases associated with cerivastatin alone, the dose given had been the higher (0.8 mg) dose that had been recently approved for clinical use.
         

  • Anil Bharani and Hrishikesh Kumar
    Diabetes Insipidus Induced by Ofloxacin 
    BMJ No.7312, September 8, 2001, Pg. 547
         
    Summary : Nephrogenic diabetes insipidus occurs with agents such as lithium, methoxyfluorane, vitamin D and demeclocycline.
          
    The authors report a case of diabetes insipidus induced by ofloxacin.
        
    A male patient diagnosed bilateral lobar pneumonia acquired in the community after influenza was treated with multiple antibiotics and on the 3rd day after admission, as his response was poor, was given ofloxacin 200 mg twice daily. On the 5th day he developed polyuria (more than 20 litres per day) and excessive thirst. 
         
    Ofloxacin induced diabetes insipidus was suspected and the drug was stopped. Urine volume and thirst returned to normal within 36 hours. He was rechallenged with ofloxacin 400 mg daily and the symptoms of polyuria and polydipsia returned. Ofloxacin was stopped and the symptoms resolved after stopping the drug.
         
    The mechanism is not clear, it could be similar to that of lithium or demeclocycline which interfere with the action of antidiuretic hormone on the collecting ducts.
          

  • Catherine Vasilakis-Scaramozza, Hershel Jick 
    Risk of Venous Thromboembolism With Cyproterone or Levonorgestrel Contraceptives 
    Lancet, Vol.358, October 27, 2001, Pg. 1427-29
         
    Summary: Results of several small studies have shown that there is an excess risk of venous thromboembolism in users of oral contraceptives containing cyproterone compared with those containing levonorgestrel.
         
    The authors conducted a case-control study and the results suggest that risk of venous thromboembolism is increased 4 fold in women taking contraceptives containing cyproterone by comparison with those exposed to levonorgestrel.
         
    Contraceptives containing cyproterone are often prescribed for women with a history of hirsutism and acne. 
           

  • Bruce Zuraw
    Commentary – Bradykinin In Protection Against Left-Ventricular Hypertrophy
    Lancet, Vol. 358, October 6, 2001, Pg. 1116-18
         
    Summary : Left-Ventricular hypertrophy substantially increases risk of sudden death and other cardiovascular complications even after adjustment for other known risk factors.
        
    On the basis of pressor and remodeling effects of angiotensin II, the reninangiotensin system is widely thought to play an important part in the development of LVH. Efficacy of ACE inhibitors in lessening progressive LV remodeling and rates of sudden death in patient with LV dysfunction further proves the importance of this system.
          
    ACE generates angiotensin II but also degrades bradykinin, and bradykinin is the preferred ACE substrate. Of the 2 angiotensin receptors that have been identified, AT1 receptors mediates the pressor effect whereas AT2 receptor mediates hypotensive effects.
         
    David Brull and colleagues have reported that individuals with the greatest increase in LV mass had the highest concentration of ACE and the lowest concentration of B2 bradykinin receptor. These results strongly support an important role for bradykinin in the ACE medicated effect on LVH.
         
    Bradykinin mediates important cardiovascular effects, such as increased vascular permeability, enhanced myocardial glucose uptake, negative intropism and inhibition of myocardial growth. Bradykinin has been shown to play an intergral part in protecting ischaemic myocardium. Genetically ablating B2 bradykinin receptors result in enhanced salt-induced hypertension and hypertropic cardiomyopathy.
         
    There is also evidence of interaction between bradykinin and rein-angiotesin system. It is now seems that bradykinin ia an important participant in the cardiac effects of the renin-angiotensis system and novel pharmaceutical approches to further increase bradykinin concentrations may be clinically beneficial.
        
    It is important to recognise that the ACE and B2 bradykinin-receptor polymorphisms account for only a fraction of the total variability in the expression of LVH.
         
    A complete understanding of LVH variability is certain to be extremely complex, involving multiple gene interactions as well as gene-environment interactions.
             

  • J P O’Beirne, S R Cairns
    Drug Points: Cholestatic Hepatitis in Association with Celecoxib 
    BMJ Vol. 7303, 7 July 2001; Pg. 23
          
    Non-steroidal anti-inflammatory drugs, particularly diclofenac sodium, have been associated with serious hepatotoxicity. 
           
    In a review of controlled clinical trials involving 7400 patients, hepatic dysfunction occurred in 0.8% of those treated with celecoxib compared with 0.9% treated with placebo and 3.7% treated with diclofenac sodium. 
           
    Nimesulide, another non-steroidal anti-inflammatory drug with cyclo-oxygenase-2 selectivity, has been reported to cause fulminant hepatic failure, and celecoxib has been associated with hepatitis and pancreatitis.
           

  • L. E. Schnipper and T. B. Strom 
    Editorial: A Magic Bullet For Cancer – How Near and How far?
    The New England Journal of Medicine Vol. 345(4), 26 July 2001; Pg. 283-84
           
    Since even humanized chimeric monoclonal antibodies often provoke antibodies that nullify the therapeutic effects of engineered immunoglobulins, a way of making fully human antibodies in vitro has been sought.
          
    The most notable success to date has been achieved with rituximab, a humanized monoclonal antibody against the B-cell-specific antigen CD20. In patients with low-grade B-cell lymphoma who relapse after the usual therapy, rituximab frequently results in complete or partial remissions.
          
    In some patients with low-grade lymphoma, rituximab plus chemotherapy eliminates all detectable cells. 
           
    A different approach entails fusing the DNA sequences encoding antigen-binding antibody fragments with genes for bacterial toxins.
          
    CD22, a surface antigen of B cells, was genetically fused to a truncated pseudomonas toxin protein containing the translocation and toxin moieties. This genetically engineered immunotoxin was used to treat patients with hairy-cell leukemia, a B-cell neoplasm with abundant expression of surface CD22. In this trial, the anti-CD22 immunotoxin induced complete remissions in 69 percent of patients.
          
    Similar results have also been found with use of a fusion protein combining diphtheria toxin and interleukin-2 in patients with T-cell lymphomas that express interleukin-2 receptors.
          
    Despite the uncertainties and unsolved problems, the authors are confident that tumor-specific immunotherapy is more than a distant promise.
           

  • Positive Opinion for Novartis’s Glivec 
    Scrip No. 2665, August 1, 2001. Pg. 22 
          
    The EC CPMP has adopted a positive opinion on Novartis’s anticancer, Glivec (ST1571/imatinib mesilate) 50mg and 100mg, for the treatment of adults with Philadelphia chromosome (bcr-abl)-positive chronic myeloid leukemia (CML) in the chronic phase after failure of alpha-interferon or in the accelerated phase or blast crisis.
          
    The product – a tyrosine kinase inhibitor – is already available in the US (as Gleevec), where it was approved in record time.
          

  • More Positive Data For Xanelim
    Scrip No. 2666, August 3, 2001. Pg. 22 
        
    Genentech and Xoma have presented more encouraging Phase III data on their anti-CD11 a monoclonal antibody, Xanelim (efalizumab), suggesting it is safe and effective in the treatment of moderate to severe psoriasis.
          

  • Michael A Weber 
    Vasopeptidase Inhibitors 
    Lancet, Vol.358, November 3, 2001, Pg. 1525-32
          
    Summary : Vasopeptidase inhibitors are a new class of cardiovascular drugs that simultaneously inhibit neutral endopeptidase and angiotensin-converting enzyme (ACE). They increase the availability of peptides that have vasodilatory and other vascular effects; they also inhibit production of angiotensin II.
          
    In animal models, vasopeptidase inhibitors decrease blood pressure in low, medium, and high renin forms of hypertension, and they also appear to confer benefits in models of heart failure and ischaemic heart disease.
         
    They also have hypotensive effects. Omapatrilat has been studied and shown to be more effective than currently available ACE inhibitors or other widely used antihypertensive agents. These drugs have safety profiles similar to ACE inhibitors though frequency of side-effects such as angio-oedema and cough are to be established. Large trials are needed to establish their place in therapy of hypertension, heart failure, ischaemic heart disease and nephropathy.
          

  • Gusto V Investigators 
    Reperfusion Therapy for Acute Myocardial Infarction with Fibrinolytic Therapy or Combination Reduced Fibrinolytic Therapy and Platelet Glycoprotein IIb/IIIa Inhibition: The GUSTO V Randomised Trial 
    Lancet, Vol.357, June 16, 2001, Pg. 1905-14
          

    Summary : Plasminogen activator therapy for acute myocardial infarction is limited by lack of achievement of early, complete, and sustained reperfusion in a substantial proportion of patients. Many phase II trials have supported the potential of combined fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition for improving reperfusion.
           
    The authors’ did a randomised, open-label trial to compare the effect of reteplase alone with reteplase plus abciximab in patients with acute myocardial infarction.
          
    Interpretation: Although combined reteplase and abciximab was not superior to standard reteplase, the 0.3% absolute (5% relative) decrease in 30-day mortality fulfilled the criteria of non-inferiority. 
           
    Combination therapy led to a consistent reduction in key secondary complications of myocardial infarction including reinfarction, which was partly counterbalanced by increased non-intracranial bleeding complications.
            

  • Freek W A Verheugt
    Commentary: GUSTO V: The Bottom Line of Fibrinolytic Reperfusion Therapy 
    Lancet, Vol.357, June 16, 2001, Pg. 1898-99
          
    Summary : Several drugs that could provide additional benefit to thrombolytic therapy have been investigated. Addition of heparin has not improved early patency rates or prevented reocclusion and has increased frequency of bleeding especially cerebral bleeding.
          
    Hirudin, a direct inhibitor of thrombin was similar. Aspirin, in addition to streptokinase, decreased mortality and has shown benefit of inhibiting platelet aggregation.
           
    Antagonists to the glycoprotein IIb/IIIa receptor, such as abciximab, eptifibatide or tirofiban, block the final common pathway of platelet aggregation. These drugs given IV have improved outcome of fibrinolytic agent and a glycoprotein protein abciximab has been extensively evaluated.
           
    Addition of full-dose abciximab to half-dose alteplase or to half-dose reteplase resulted in nearly 80% of patients achieving complete reperfusion at 90 min without much increase in side-effects. Patency improved and ECG signs of tissue perfusion were also better with the combination.
          
    Results of GUSTO V has both good and bad news. The good news is the report of the lowest 30 day mortality (less than 6%) and bad news is that concept of an improvement in early patency rates leading to a decrease in mortality was not confirmed.
         
    Future management of MI with ST elevation may involve early medical treatment with a bolus of fibrinolytic or a combination of a fibrinolytic and a glycoprotein blocker- followed immediately by angioplasty.
           

  • The GUSTO IV-ACS Investigators 
    Effect of Glycoprotein IIb/IIIa Receptor Blocker Abciximab on Outocome in Patients with Acute Coronary Syndromes Without Early Coronary Revascularisation: The GUSTO IV-ACS Randomised Trial 
    Lancet, Vol.357, June 16, 2001, Pg. 1915-24
           
    Summary : Glycoprotein IIb/IIIa blockers reduce procedure-related thrombotic complications of percutaneous coronary intervention, and the risk of death and myocardial infarction in patients with acute coronary syndromes.
         
    The effect on risk of death and myocardial infarction is particularly apparent in patients undergoing early percutaneous coronary interventions.
         
    The authors did a randomised, multicentre trial to study the effect of the glycoprotein IIb/IIIa blocker abciximab on patients with acute coronary syndromes who were not undergoing early revascularisation.
         
    Interpretations : Although the explanations for the findings are unclear, this study indicates that abciximab is not beneficial as first-line medical treatment in patients admitted with acute coronary syndromes.
         

  • Jose L Rocha, Jorge Fernandez-Alonso
    Acute Tubulointerstitial Nephritis Associated with the Selective COX-2 Enzyme Inhibitor, Rofecoxib 
    Lancet, Vol.357, June 16, 2001, Pg. 1946-47
           
    Summary : The nephrotoxic effect of COX-2 selective inhibitors has not yet been established. The authors report a case of reversible acute renal failure due to acute tubulointerstitial nephritis, confirmed by histology of a renal biopsy sample, associated with taking rofecoxib, a selective cyclo-oxygenase-2 (COX-2) inhibitor.
          
    Post marketing surveillance by the manufacturer has found some cases of possible interstitial nephritis in patients taking rofecoxib, and 11 cases of possible interstitial nephritis have been reported to the manufacturer in patients receiving celecoxib, although a definite diagnosis was not made in any patients. A case of interstitial nephritis has been reported in a series of 19087 patients treated with meloxicam (a relatively selective NSAID).
          
    This report shows that selective COX-2 inhibitors can also be associated with acute tubulointerstitial nephritis in the same way as non-selective NSAIDS. Frequency of this effect is still unknown and can only be established by close pharmacovigilance.
         

  • David J Rowbotham 
    Commentary: Endogenous Opioids, Placebo Response, and Pain 
    Lancet, Vol.357, June 16, 2001, Pg. 1901-02
           
    Summary : Endogenous ligands for opioid receptors include enkephalins (d receptor), dynorphins (k receptor) and endorphins. Endogenous ligands with a high selectivity for the m receptor (endomorphins) were first identified in 1997.
           
    Endomorphin-1 and endomorphin-2 are both simple peptides of only 4 amino acids. They are involved in pain and analgesia.
           
    A new receptor, structurally similar to opioid receptors has been classified as opioid-receptor-like (ORL1) or OP4 and its natural ligand as orphanin FQ or nociceptin. This system is involved in several physiological processes such as the central modulation of pain. It is not implicated in respiratory depression. 
            
    The exciting potential of this discovery is the availability of analgesics with opioid efficacy and no effect on respiratory function. Investigations on selective antagonists to this receptor are in progress. 
            

  • Deborah Josefson 
    FDA Warns Merck Over Its Promotion of Rofecoxib
    BMJ, Vol.323 (7316), October 6, 2001, Pg. 767
         
    Summary: Rofecoxib, a selective COX 2 inhibitor was approved by the FDA in May 1999 for the relief of acute pain, osteoarthritis and dysmenorrhoea. It was heavily promoted by Merck as safer and superior to nonselective NSAIDS like ibuprofen and naproxen.
         
    In its letter the FDA criticized Merck for playing down the possible risk of stroke associated with rofecoxib and for minimizing potential drug interactions with warfarin.
           
    The risk of stroke was found in an analysis of a large study called VIGOR (Vioxx gastrointestinal outcomes research) trial, which compared rofecoxib 50 mg per day with naproxen 500 mg twice a day in patients with rheumatoid arthritis.
           
    Analysis of this study by cardiologist Eric Topol and colleagues at the Cleveland clinic in Ohio showed that patients taking rofecoxib had a higher relative risk of developing adverse cardiovascular events such as ischaemic strokes, unstable angina, and myocardial infarction than the patients taking naproxen.
          

  • Amar Alwitry and Iain Gardner
    Minerva 
    BMJ, Vol.323, 20 October, Pg. 944
           
    Summary : This is a case report of tamoxifen induced retinopathy in a 64 year old woman taking tamoxifen 20 mg/day for 8 years. The incidence of tamoxifen retinopathy is about 6% among patients who have taken the drug for 5 years. Stopping treatment prevents further deterioration but rarely allows complete recovery of visual function.
          

  • Lisa R. Grillone and Rene Lanz 
    Fomivirsen 
    Drugs of Today, Vol.37 (4), April 2001, Pg. 245-255
           
    Summary : Cytomegalovirus (CMV) retinitis can rapidly lead to blindness in patients with AIDS. Fomivirsen is a novel antisense drug. 
          
    It is a phosphorothioate oligonucleotide with a unique antisense mode of action. The 21-nucleotide sequence of fomivirsen is complementary to a sequence in mRNA of IE2 of human CMV. This region of mRNA encodes several proteins that are essential for the production of infectious CMV. Binding of fomivirsen to this target mRNA results in inhibition of IE2 protein synthesis, subsequently inhibiting viral replication.
           
    In patients with AIDS, fomivirsen has been shown to provide a safe and effective treatment, for newly diagnosed, peripheral CMV retinitis or relapsed CMV retinitis unresponsive to other therapies.
           
    No systemic adverse effects were seen. It is administered by intravitreal injection to ensure target-specific distribution. No drug is detected in systemic circulation. Local ocular adverse events were predominantly mild to moderate, transient and responded well to topical medications. 
           
    The dosing schedule is simple and combined with demonstrated safety and efficacy, fomivirsen is a valuable and convenient treatment, for patients with AIDS and newly diagnosed peripheral CMV retinitis or relapsed CMV retinitis unresponsive to other therapies.
            

  • Burke A. Cunha 
    Antimicrobial Selection in the Penicillin-Allergic Patient 
    Drugs of Today Vol.37 (6), June 2001, Pg. 377-383 
          
    Summary : Penicillin and b-lactam allergic reactions should be determined by a careful history and whether it is of an anaphylactic or nonanaphylactic variety. Most reactions to b-lactams are of the nonanaphylactic type and are usually manifested clinically as a mild maculopapular rash or drug fever. 
          
    Uncommonly, penicillin allergies are clinically manifested as anaphylactic reactions e.g. bronchospasm, laryngospasm, hypotension or hives. Patients hypersensitivity reactions tend to be stereotyped on rechallenge, which make the reactions predictable. Although monobactams and carbapenems are structurally related to b-lactams, they are unrelated in terms of allergic potential. 
          
    There is no cross-reactivity between monobactams or carbapenems with b-lactams. Because so many antibiotics are available that are allergically unrelated to b-lactams, b-lactam desensitization procedures are rarely necessary.
           

  • T. P. Le and Y-Q. Xiong 
    Gemifloxacin 
    Drugs of Today Vol.37 (6), June 2001, Pg. 401-410 
           
    Summary : Gemifloxacin is a novel antibiotic and the first fluoroquinolone with a pyrrolidine derivative at the C-7 position. Because of the added pyrrolidine substitute, gemifloxacin has an enhanced spectrum of activity against Gram- positive bacteria such as Streptococcus pneumoniae and Staphylococcus aureus, in addition to its activity against Gram-negative bacteria. It has excellent activity against Enterobacteriaceae and other respiratory pathogens. 
            
    It has potential activity in vitro against anaerobic bacteria. With a broad spectrum of activity, convenient once-daily administration, good bioavailability and tolerability, gemifloxacin is an important addition to the armamentarium against a wide range of infections, from UTI to community acquired pneumonia.
            

 

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