Ian V D Weller, I.G. Williams
ABC of AIDS – Treatment of infections.
BMJ, June 2, 2001, pg.1350-1354.
Treatment of Pneumocystis carinii pneumonia
Co-trimoxazole (trimethoprim Component 15-20mg/kg per day
PO/IV in divided doses)
Nausea,vomiting, fever, rash, marrow suppression, raised
Intolerance common (25-50% of treated patients)
Pentamidine isethionate 4mg/kg per Day as slow intravenous infusion
Hypotension,hyper and hypoglycaemia, renal
failure,marrow suppression, nausea,vomiting, cardiac arrest.
80% of patients will respond to treatment
Trimetrexate 45mg/m2 IV and folinic
Marrow suppression raised transaminases rash, anaphylaxis.
Should only be used as third or fourth line treatment.
Adjuvant high dose steroids (e.g. prednisolone 40-60mg daily PO)
Indicated in severe disease.Optimal dose not determined
Mild to moderate disease
Clindamycin 600mg 6 hourly PO/IV and primaquine 15mg daily PO.
Diarrhoea, rash, nausea, Vomiting, marrow suppression, methaemoglo binaemia, hemolysis.
Clostridium difficile toxin associated diarrhoea is a frequent complication of clindamycin therapy.
Trimethoprim 20mg per kg/day
PO/IV in 2-3 divided doses and
Dapsone 100mg daily PO
Rash, nausea, methaemo globinaemia, marrow suppression.
Alternative regimens should be used in patients with G6PD deficiency.
Atovaquone suspension 750mg
Rash, raised transaminases, and neutropenia.
Must be taken with food
Consider combination with
IV pentamidine as resistance reported with mono therapy
Treatment of toxoplasmosis
Sulphadiazine 4-6g per day or clindamycin 600mg x 4 per day
Pyrimethamine 50-100 mg per day
Folinic acid 15mg per day
· Clarithromycin 2g per day or
· Atovaquone 750mg x 4 per day PO
Pyrimethamine 50-100mg per day PO.
Viral opportunistic infections
acyclovir 200mg 5x a day orally or10 mg/ kg 8 hourly IV.
Duration may be extended in severe infections.
Acyclovir 200mg 4 x day or 400mg 2 x day
Ganciclovir 5mg/kg twice a day iv
GCSF support may be required.
Cidofovir 5mg/kg IVOnce a week
Nephrotoxicity: impaired creatinine
neutropenia ocular toxicity
Co-administer with probenecid and adequate hydration to reduce risk of nephrotoxicity.
Foscarnet 180mg/kg daily
Nephrotoxicity, hypomagnesaemia Hyper-andhypo-
calcaemia, hyper and hypophosphataemia, hypokalaemia, nausea, vomiting, genital ulceration
Dose must be adjusted according to renal function.
Ganciclovir 3mg daily orally
Until CD4 count >100 x 106/1 on HAART
May be combined with intraoccular ganciclovir implants. Avoid in patients with diarrhoea Increases levels of didanosine
Cidofovir 5mg/kg once every 2 weeks
Until CD4 count >100x 106/1 on HAART
alternative secondary prophylaxis regimens include daily intravenous foscarnet or ganciclovir, intravitreal injections of ganciclovir or foscarnet, and intraoccular ganciclovir implants.
Nystatin oral suspension pastilles, miconazole oral gel, or amphotericin lozenges all 4-6 times a day.
Systemic therapy is commonly required
Ketoconazole 200mg a day (PO)
nausea (less if taken with food) abnormal liver function tests, hepatitis thrombocytopenia, rash.
In patients who remain severely immuno suppressed, relapse is common and maintenance therapy is required
Fluconazole 50-200mg a day (PO)
nausea, abnormal liver function tests.
Itraconzaole capsules or (PO)
nausea, abnormal liver function tests
0.7-1.0mg/kg/day(IV) ± flucytosine 75-100mg/kg/day in 3-4 divided doses
suppression, renal impairment, hypo-calcaemia
In patients who remain severely immuno
sup- pressed, relapse is common and maintenance therapy is required.
Liposomal preparations of amphotericin reduce risk of nephrotoxicity.
Fluconazole 800mg daily As above 1-3 days 600mg daily thereafter (PO or IV)
Treatment of Mycobacterium avium complex
Clarithromycin 1-2 g daily in divided doses
Ethambutol 1 5 mg/kg/day daily
Either Rifabutin 450 – 600mg daily
Rifampicin 450 – 600mg daily
Ciprofloxacin 500mg twice daily
Clofazimine 100mg daily
3 or 4 drug regimens are recommended.
Feng Ying C Lin, Vo Anh Ho et al
The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five year old children.
New Eng Jr.of Med. Vol.344, Apr.26, 2001, pg.1263
The licenced typhoid vaccines confer only about 70 percent immunity, do not protect young children and are not used for routine vaccination. A newly devised conjugate of the capsular polysaccharide of S.typhi, Vi, bound to nontoxic recombinant Ps.aeruginosa exotoxin A (rEPA) has enhanced immunogenicity in adults and children 5-14 years old and has elicited a booster response in children 2-4 years old.
The authors conducted a double-blind, randomized trial to evaluate safety, immunogenicity and efficacy of the Vi-rEPA vaccine in children 2-5 years old in 16 communes in Vietnam. Each child received 2 injections 6 weeks apart of either the vaccine or placebo. Efficacy was estimated by comparing the attack rate of typhoid in the vaccine group with that in the placebo group.
The conclusions were that the Vi-rEPA conjugate typhoid vaccine is safe and immunogenic and has more than 90 percent efficacy in children 2-5 years old. The antibody responses and the efficacy suggest that this vaccine should be at least as protective in persons who are more than 5 years old.
Richard L Guerrant and Margaret Kosek
Editorial – Polysaccharide conjugate typhoid vaccine.
New Eng J of Med. Vol.344, April.26, 2001, pg.1322.
The currently available typhoid vaccines have several drawbacks. Heat and phenol-inactivated typhoid vaccines that are 51-77 percent effective have been available for more than a century, but their frequent local and systemic side-effects limit their acceptance. They are the only currently available vaccines for children younger than 2 years old. The Vi polysaccharide vaccine is available for persons 2 years of age or older.
This new vaccine can also be expected to provide an improved alternative for protecting laboratory workers at risk, members of the military and travellers to areas where typhoid fever is endemic.
Bayer withdraws cerivastatin
Scrip No.2668, August 10, 2001. p.20
Bayer has withdrawn their lipid lowering agent Cerivastatin (Baycol/Lipobay) because of doubts about the safety. The decision to withdraw was voluntary and was made on the basis of side effects mainly rhabdomyolsis (muscle weakness).
Rival firms gain hepatitis C approvals
Scrip No.2668, August 10, 2001. p.20
Hepatitis C has become the world’s most important viral hepatitis and has displaced Hepatitis B as the most common hepatitis.
Schering-Plough has received US approval for the use of its pegylated alpha interferon product in combination with its antiviral ribavirin for treatment of Hepatitis C.
Barry Cookson, Sheldon Stone
Use alcohol hand rubs between patients: they reduce the transmission of infection
BMJ, Vol.323, 25 August 2001, p.411
Most doctors are not aware that they frequently transmit infection from one patient to another. It has been shown that alcohol hand rub in between patients reduce the transmission of the infection. The same applies to nurses.
The problem is not of informing doctors and nurses of this hygiene but it is to inculcate the practice as second nature.
S Sundar, G Agrawal, et al (Dept. of Medicine, NY)
Treatment of Indian Visceral Leishmaniasis with single or daily infusions of low dose liposomal amphotericin B: randomized trial.
BMJ, Vol.323, 25 August 2001,
The low dose liposomal amphotericin B (5mg/kg), given either as a five-day course or as a single infusion, seems to be effective for visceral leishmaniasis and warrants further testing.
M Petrie, J McMurray
Changes in notions about heart failure
The Lancet, Vol.358: 11 August 2001, p.432.
Chronic Heart Failure (CHF) has been traditionally thought of as a clinical syndrome of breathlessness, fatigue and salt and water retention. Until lately the focus has been on symptoms and left ventricular systolic dysfunction.
In large survey of 3960 patients, in person over 45 years, who were examined and investigated in great detail, it was found that approximately half the patients had no symptoms. Left ventricular ejection fraction was seen as diminished in 139 patients out of 3960. Ejection fraction was calculated by echocardiography and when followed up the 5-year mortality rate was 50-75%.
In treatment, ACE inhibitors were the drugs of choice given in adequate doses. Combination with beta blockers further improved the prognosis.
O.P.Asthana, J.S. Srivastava, et al
A multicentric study with Arteether in patients of uncomplicated Falciparum Malaria.
JAPI, Vol.49, July 2001, pg.692.
Arteether is an oil-based preparation obtained from the plant Artemisia annua (Quinghaosu). It rapidly kills asexual stages of the malarial parasite (schizontocidal activity).
This is a study of phase III clinical trial of Arteether in 267 patients of uncomplicated P. falciparum malaria. Arteether was given IM in a dose of 150mg/day for 3 consecutive days. Each patient was followed upto 28 days. The cure rate was 97% with fever clearance time between 1-7 days and parasite clearance time between 1-3 days. Parasite reappearance rate was found to be 3% and reported at 3 centres. No adverse effects were observed.
Urmila M Thatte
Editorial _ Arteetheer Therapy of Malaria
JAPI, Vol.49, July 2001, pg.687
Arteether has been selected by the Steering Committee of the Scientific Working Group on Malaria chemotherapy of WHO for further development and its early clinical development has been at Central Drug Research Institute, Lucknow.
Free radicals are generated through iron-mediated breakage of peroxide bridges in the structure of artemisine. These radicals bind to membrane proteins of the parasite and destroy it. Arteether is very effective in killing schizonts of P.falciparum, including those strains that are resistant to chloroquine and mefloquine. Arteether is twice as active as artemesine. Artemisinin resistance is not yet a clinical problem, however reports of resistance have already emerged from India. Artemisinin derivatives concentrate 300-fold in parasite infected RBCs.
Arteether has a long half-life (23-69 hours) and accumulates in brain, suggesting better efficacy in cerebral malaria. In a study in Zambia, efficacy and safety of intramuscular arteether was found to be comparable to intravenous quinine, and appears to be therapeutically equivalent to quinine for treatment of paediatric cerebral malaria.
Animal data indicates neurotoxicity and may produce impairment of posture, gait, autonomic regulation and eye movement disorders. But at therapeutic doses no reports of toxicity have been made. No data is available regarding use in pregnancy although children born to mothers who received IM injections of artemesine or artemether at 16 to 38 weeks of pregnancy showed no congenital deformities.
There are no studies comparing arteether with other antimalarial agents nor are there any studies in chloroquine resistant malaria. There are no indications of the benefits of drug combinations in India with these drugs.
A course of arteether would cost about Rs.300.
Artemisine and its derivative have a reserve status in the WHO essential drugs list indicating that they should be reserved for drug-resistant cases. Three days regimen appears to be sufficient in uncomplicated cases and should be used for at least 5 days in complicated malaria. To prevent resistance from developing secondary to indiscriminate use, chloroquine sensitivity tests on plasmodia may be necessary.
George J Fuchs
A better oral rehydration solution – an important step, but not a leap forward..
BMJ, 14 July, 2001: pg.59
For over 20 years the WHO and Unicef have recommended an oral rehydration solution containing 90 mmol/1 of sodium and 111 mmol/l of glucose. This solution is of established efficacy in treating children and adults with diarrhoea regardless of its cause. Acceptance of this solution by patients has been poor and other formulations have been developed. A major constraint of WHO oral rehydration solution is that it does not visibly reduce the severity of diarrhoea which is perceived as lack of efficacy.
In a meta-analysis, it was observed that compared with the standard WHO solution, reduced osmolarity rehydration solution resulted in fewer failures requiring the use of IV fluids. This is important because many of the most severe adverse effects related to rehydration are due to complications of IV fluids.
The rationale for reduced osmolarity solutions is the observation of improved net water absorption in animal and human perfusion studies. Reduced stool output is the primary aim for reduced osmolarity oral rehydration solution.
A major concern about reduced osmolarity solution has been that the reduced sodium content of these formulations might increase the risk of symptomatic hyponatraemia in patients with cholera. Definite information is not available. In this context, reduced osmolarity oral rehydration solution is an important and meaningful step but not a leap forward.
S J Proctor, A M Dickinson, et al
Editorial – Umbilical cord blood banks in the UK
Have proved their worth and now deserve a firmer foundation
BMJ, 14 July, 2001, pg.60
Allogeneic stem cell transplantation has revolutionized the outcome for a wide range of malignant and nonmalignant haematological conditions.
Of the sources of stem cells, umbilical cord blood, obtained from the placenta directly after delivery, is enriched in stem cells and has a higher proliferative capacity than cells obtained from bone marrow and peripheral blood. Like any blood product, however, stem cells from cord blood need an infrastructure for collecting, banking and matching the donations.
Jiri Chard and Paul Dieppe
Editorial – Glucosamine for osteoarthritis : magic, hype or confusion?
Its probably safe – but theres no good evidence that it works
BMJ, 16 June 2001, pg. 1439.
Glucosamine is a sugar, a sulphated amino monosaccharide, one of the constituents of the disaccharide units present in articular cartilage proteoglycans. In vitro work has shown that it can alter chondrocyte metabolism, and this is the rationale usually given for its use in osteoarthritis. It is unclear whether oral glucosamine can reach chondrocytes in vivo and in addition to the oral compound (commonly available form), injectables and local preparations have been subjected to clinical trial.
The most appropriate dose and route of administration remain unknown. We do not even seem to know how to classify it : is it a drug, a food supplement, a nutriceutical or a complementary therapy.
Osteoarthritis is a heterogenous and poorly understood condition. The origin of pain caused by osteoarthritis is unclear, and regional joint pain in older people is often due to periarticular lesions or referred pain rather than articular problems.
There is confusion about what we are trying to do when we treat people with osteoarthritis. A reasonable objective is the reduction of pain, stiffness and other symptoms that arise from a joint as a result of osteoarthritis and reduction in disability. But why should we expect an agent that affects articular cartilage to have any effect on symptoms ? There are no nerves in articular cartilage. An agent that affects cartilage might affect radiographic changes of osteoarthritis. But there is no relation between the severity of radiographic changes and clinical expression of disease. There is no good evidence that glucosamine alters either the symptomatic expression of osteoarthritis or its radiographic progression. Most of the trials are too small and much of the research is sponsored by companies making glucosamine.
Authors conclude that there is more confusion and hype than magic about glucosamine. The rationale for its use is unclear, the best dose and route of administration unknown and published trials do not allow any conclusion about its efficacy. We need large clinical trials, without company interference.
Gene Therapy shows promise for haemophilia
BMJ, 16 June 2001, pg. 1442
A new type of gene therapy boosted levels of factor VIII clotting factor in a small number of people with haemophilia, allowing 2 severely ill patients to go for 10 months without spontaneous bleeding. These results are far from the proof needed to bring the treatment to market. It is not clear if the effect lasts long enough to make the procedure practical, but the finding revives hopes that gene therapy written off by many scientists as a failure, may yet work.
Researchers used a factor VIII gene transfer method that avoided the traditional viral vectors and used a non-viral somatic cell, gene therapy system which they call transkaryotic implantation, in 6 patients with severe haemophilia. The procedure involved isolating dermal fibroblasts from a full thickness skin biopsy. These were transfected by electroporation with a plasmid containing the gene for factor VIII; the cells that expressed factor VIII were cloned, propagated and laparoscopically implanted into the omentum of patients.
According to the report, there were no significant adverse effects related to the procedure, none of the patients developed antibodies against factor VIII or a cellular immune response to the implanted transfected fibroblasts.
U. Chaudhari, P. Romano, et al
Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial.
Lancet. Vol.357, June 9, 2001, pg.1842
Currently available treatments for moderate to severe psoriasis are either incompletely effective in some patients or are associated with toxic effects. Since TNF-a is thought to have a role in pathogenesis of psoriasis, the authors did a double-blind, randomized trial to assess the clinical benefit and safety of infliximab a monoclonal antibody against TNF-a.
Patients receiving infliximab as monotherapy had a high degree of clinical benefit and rapid time to response in the treatment of moderate to severe plaque psoriasis compared with patients who received placebo. These findings suggest that TNF-a has a major role in the pathogenesis of psoriasis. There were no serious adverse events and infliximab was well tolerated. Infliximab was used in the doses of 5mg/kg and 10mg/kg IV at weeks 0, 2 and 6, and patients were assessed at 10 weeks.
Frank B Hu.
The role of N-3 polyunsaturated fatty acids in the prevention and treatment of cardiovascular disease.
Drugs of Today, 2001, 37(1): 49-56
Several long-term epidemiologic studies have found an inverse association between fish consumption and risk of coronary heart disease or stroke. Two secondary prevention trials have found that increasing fish consumption or fish oil supplementation significantly reduced coronary death among patients with existing MI. Epidemiologic and clinical studies have suggested that alpha-linoleic acid (ALA), a short-chain n3-3 fatty acid from plant sources may have similar cardiac benefits as long chain n-3 fatty acids from fish. Potential mechanisms through which n-3 polyunsaturated fatty acids protect against CVD include their antiarrhythmic and antithrombotic effects, and improving insulin sensitivity and endothelial function. Reduction of TG levels, reduction of platelet aggregation also contribute. There is growing evidence that fish oil may improve endothelial dysfunction.
Substantial evidence is there for beneficial effects of ALA on CVD. Flaxseed as well as other important dietary sources of ALA e.g. unhydrogenated canola, soyabean oil and walnuts can be incorporated into a healthy and balanced diet for prevention of CVD. This is especially important for persons who do not consume fish.
P C Hayes, A Lee
Commentary – What Progress with Artificial Livers?
The Lancet October 20, 2001, Vol.358 (9290) Pg. 1286-1287
Various procedures have been devised to treat acute liver failure. The results are not very impressive. Results with acute-on-chronic liver failure are somewhat better.
Although many procedures have been tried no system has been shown to be better than others.
D C G Skegg
Commentary – Hormone Therapy and Heart Disease After the Menopause
American Heart Association Recommendations on HRT and CVD
The Lancet October 13, 2001, Vol.358 (9289) Pg. 1196-1197
HRT should not be initiated for the secondary prevention of CVD.
Firm clinical recommendations for primary prevention await the results of ongoing randomised clinical trials.
There are insufficient data to suggest that HRT should be initiated for the sole purpose of primary prevention of CVD.
Initiation and continuation of HRT should be based on established noncoronary benefits and risks, possible coronary benefits.
F C Breedveld
Commentary – Is There a Place for Leflunomide in the Treatment of Rheumatoid Arthritis?
The Lancet October 13, 2001, Vol.358 (9289) Pg. 1198-1200
The manufacturer of leflunomide was alerting prescribers to changes in the summary of product characteristics and package leaflet made because of reports of 15 cases of severe liver injury (including hepatitis and a few cases of acute hepatic necrosis), some of which were fatal.
Randomised clinical trials of leflunomide for the treatment of rheumatoid arthritis showed that it was superior to placebo and similar to sulphasalazine or methotrexate in most measures.
The frequency of side-effects leading to the discontinuation of leflunomide was similar to that for the control drugs in the trials. Diarrhoea, reversible alopecia, allergic reactions, and increased serum concentrations of hepatic enzymes are known side-effects, and special care should be taken in patients who drink alcohol or have a history of liver disease.
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.
Alex van Belkum and Henri Verbrugh
40 Years of Methicillin Resistant Staphylococcus aureus
BMJ No.7314, September 22, 2001, Pg. 644.
Staphylococcus aureus is well adapted to human body. During infection the bacteria produce a large variety of virulence factors, for instance there are molecules which interfere with the chemotaxis of neutrophils to the site of infection. A particular worry has been the rise of MRSA.
There is a clinical need for an effective vaccine but strategies for developing vaccine are scarce. Biology of the organism is incompletely understood. MRSA emerged rapidly after the introduction of this antibiotic and primary route of spread of MRSA bacteria was shown to be through clonal dissemination.
Colonisation and infection were caused by spread of relatively small numbers of epidemic bacterial strains sometimes even between continents.
Hospitals have to invest in maintaining an adequate level of microbiological hygiene. Studies have shown that the rate at which MRSA colonises and infects patients is significantly correlated with the amount and nature of the antibiotics prescribed in clinics.
MRSA used to be primarily a problem of nosocomial spread, but recent reports indicate significantly rising numbers of MRSA in populations outside hospital.
The authors’ feel the need to find alternative strategies for eliminating MRSA carriage. Von Eiff et al have recently shown that S. aureus cells can be killed in vitro by shock waves that are used for extracorporeal lithothripsy. Its usefulness is doubtful.
Osmolyte stimulation of innate antimicrobial defence systems might be a more promising approach, but bacteriophage therapy or bacterial interference strategies which could lead to elimination of the ‘weakest’ strains should also be explored.
There are useful actions that clinicians can take Strict hand hygiene policies may already be achieving some success in the battle against nosocomial transmission of MRSA.
Von Eiff et al have shown that most infections caused by staphylococci can be traced back to prior nasal carriage by certain patients which suggests that elimination of nasal carriage still is a useful intervention.
PROGRESS Collaborative Group
Randomised Trial of A Perindopril-Based Blood-Pressure-Lowering Regimen Among 6105 Individuals With Previous Stroke or Transient Ischaemic Attack
Lancet, Vol.358, September 29, 2001, Pg.1033
Blood pressure is a determinant of the risk of stroke among both hypertensive and non-hypertensive individuals with cerebrovascular disease. There is uncertainty about the efficacy and safety of blood pressure lowering treatments for many such patients. The perindopril protection against recurrent stroke study (PROGRESS) was designed to determine the effects of a blood pressure lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or TIA.
6105 individuals from 172 centers in Asia, Australia and Europe were randomly assigned active treatment or placebo. Active treatment comprised a flexible regimen based on the ACE inhibitor perindopril (4 mg daily), with the addition of the diuretic indapamide at the discretion of treating physicians. The primary outcome was total stroke (fatal or non-fatal).
Over 4 years of follow-up, active treatment reduced blood pressure by 9/4 mm Hg. 307 (10%) individuals assigned active treatment suffered a stroke, compared with 420 (14%) assigned placebo. Active treatment also reduced the risk of total major vascular events.
There were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups. Combination therapy with perindopril plus indapamide reduced blood pressure by 12/5 mm Hg. and stroke risk by 43%. Single drug therapy reduced blood pressure by 5/3 mm Hg. and produced no discernable reduction in risk of stroke.
Treatment with these 2 agents should now be considered routinely for patients with a history of stroke or TIA, irrespective of their blood pressure.
Jan A Staessen, Jiguang Wang
Commentary – Blood Pressure Lowering for the Secondary Prevention of Stroke
Lancet, Vol.358, September 29, 2001, Pg.1026
In 1997, a quantitative overview of outcome trials of antihypertensive treatment among patients with stroke showed that among hypertensive stroke survivors, blood pressure lowering therapy decreased recurrence of fatal and non-fatal stroke by 28%.
The primary aim of PROGRESS trial was to find out the precise effects that a blood pressure lowering regimen based on a ACE inhibitor would have on stroke risk in patients with a history of TIA or minor strokes.
In PROGRESS trial, blood pressure cut-off points were 160 mm Hg systolic and 90 mm Hg diastolic. The threshold of systolic hypertension was 20 mm Hg higher than the definition of normotension. PROGRESS does not indicate the level to which blood pressure should be lowered or how blood pressure should be managed in patients with acute stroke.
Also PROGRESS findings cannot be extrapolated to patients with occlusive or stenotic disease of the main cerebral arteries, in whom cerebrovascular perfusion pressure is already decreased and whose risk of a first or recurrent brain infarct is substantially raised. Patients with occlusive or severe stenotic disease of the carotid arteries should be identified before blood pressure is reduced, to prevent recurrence of a stroke.
Unexpectedly, a pre-specified subgroup analysis revealed striking heterogeneity of treatment-effect sizes for stroke risk between participants who received perindopril plus indapamide and those who received perindopril alone.
If blood pressure and random variation do not explain the null results in the perindopril-only group in the PROGRESS trial, what could?
Before randomisation doctors had to opt whether any individual patient would receive single-drug or combination therapy. Patients selected for the latter strategy were younger, predominantly male, had higher blood pressure at entry were more likely to be hypertensive or to have coronary artery disease, and were recruited sooner after their qualifying event. Statistical adjustment for the entry characteristics did not remove the heterogeneity.
Adverse Effects of Subclinical Hyperthyroidism
Lancet, Vol.358, September 15, 2001, Pg.856
Sensitive thyrotropin (sTSH) assays can measure very low concentrations (as low as 0.001 mU/L) of thyrotropin. Introduction of these assays has allowed clinicians to diagnose “subclinical hyperthyroidism” as a distinct disorder of a very low or undetactable thyrotropin concentration associated with normal concentrations of peripheral thyroid hormones.
Possible causes of a low serum thyrotropin concentration, such as treatment with dopamine, dobutamine, high doses of glucocorticoids or recovery from hyperthyroidism should be ruled out.
The most common cause is excess thyroid-hormone therapy. Thyroid autonomy due to autonomous adenoma or nodular goitre, early or mild Graves’ disease, silent or postpartum thyroiditis, subacute thyroiditis, and ingestion of pharmacological amounts of iodine are other causes.
For patients receiving thyroxine-replacement therapy, the dose must be adjusted to obtain a normal serum thyrotropin concentration.
Brent E. Wisse, and Michael Schwartz
Role of Melanocortins in Control of Obesity
Lancet, Vol.358, September 15, 2001, Pg. 857
The discovery in 1994 that deficiency of the adipocyte hormone, leptin, underlies genetic obesity in ob/ob mice, provided compelling support for the hypothesis that humoral signals generated in proportion to body-fat mass provide afferent input to critical brain areas that control energy intake and expenditure.
Melanocortins are neuropeptides such as a-MSH that are derived from pro-opiomelanocortin (POMC) – precursor polypeptide. When released from axon terminals in the hypothalamus, these peptides reduce food intake while increasing energy expenditure, mainly via activation of the neuronal Mc4r melanocortin receptor subtype, although Mc3r may also play a role. Opposing the neuronal action of a-MSH in this system is the endogenous Mc3/4r antagonist, agouti-related peptide (AgRP).
Both a-MSH and antagonist AgRP are synthesised within adjacent but distinct subgroups of hypothalamic neurons that are sensitive to input from adiposity-related signals such as leptin.
Efforts to introduce leptin as a treatment for obesity have proved disappointing, largely because obesity is associated with leptin resistance. Since drugs acting “downstream” of leptin may effectively bypass this resistance, they are particularly appealing.
Melanocortin receptor agonists are an example of this new class of drug and seem to promote weight loss even in leptin-resistant forms of obesity. Melanocortin receptors are expressed widely in the body, and are involved in functions as diverse as skin pigmentation (Mc1r) and secretion of adrenal hormones (Mc2r), an important challenge is to target neuronal melanocortin receptors selectively.
David M Lee and Michael E. Weinblatt
Review – Rheumatoid Arthritis
Lancet, Vol.358, September 15, 2001, Pg. 903
This is a review article discussing clinical features, pathophysiology and treatment. There is a paradigm shift in the treatment. Previous therapeutic approach involved conservative management with NSAIDS for several years and disease modifying antirheumatic drugs (DMARDs) were used only when erosions were seen. DMARDs were added individually as disease progressed.
This form of treatment has been changed by early start of DMARDs and combination DMARD therapy in patients with potential for progressive disease.
Methotrexate has been used as DMARD. It has been combined with ciclosporin, infliximab, etanercept, leflunomide, sulfasalazine, hydroxychloroquine and prednisolone.
The newly approved drugs are leflunomide and the TNF biological-response modifiers – etanercept and infliximab.
Leflunomide is an orally available inhibitor of dihydroorotate dehydrogenase – an enzyme required for de-novo pyrimidine synthesis. It affects lymphocyte function though its specific mechanism of action in rheumatoid arthritis is not known.
A loading dose of 100 mg daily is given over 3 days and then 10-20 mg orally daily. Theoretically the effects of leflunomide could complement those of methotrexate by affecting separate nucleic acid metabolic pathways.
Etanercept is generally well tolerated but may produce injection-site reaction. It is only available via parenteral route and standard dosing is a 25mg subcutaneous injection twice weekly.
Infliximab is also available only via parenteral route. FDA approved dosing schedule is 3 mg/kg at weeks 0, 2 and 6 followed by maintenance dosing every 8 weeks thereafter.
Excitement regarding usefulness of TNF-a biological response modifiers is tempered by potential for long-term side-effects and toxicity. Rare events include infections (Mycobacterium tuberculosis, fungal and bacterial sepsis), a lupus-like syndrome, and a demyelinating syndrome.
Eventually it might be possible to identify relevant inflammatory pathways operative within individual patients and tailor therapy accordingly.
Klaus Scheidtmann, Wolfgang Fries et al
Effect of Levodopa in Combination with Physiotherapy on Functional Motor Recovery After Stroke: A Prospective, Randomised, Double-blind Study
Lancet, Vol.358, September 8, 2001, Pg. 787-90
Summary: Physiotherapy has been the only way of improving motor function in hemiplegia after stroke. Administration of amphetamine in addition to exercise improves motor recovery in animals, probably by increasing the concentration of norepinephrine in the central nervous system. Aim of the present study was to find out whether levodopa could have similar effect.
The authors conducted a prospective, randomised, placebo-controlled double-blind study in 53 primary stroke patients. For the first 3 weeks patients received single doses of levodopa 100 mg or placebo daily in combination with physiotherapy. For the second 3 weeks patients had only physiotherapy. Motor function was quantitatively assessed every week with Rivermead motor assessment (RMA).
The interpretation of the study was that single dose of levodopa is well tolerated and when given in combination with physiotherapy, enhances motor recovery in patients with hemiplegia. In view of its minimal side-effects, levodopa will be a possible add on during stroke rehabilitation.
TREM-1 in Sepsis
Lancet, Vol.358, September 8, 2001, Pg. 776-78
Summary: Sepsis is characterised by a dysregulated host response to microbial components, such as lipopolysaccharide (in the case of gram-negative bacteria) and peptidoglycan or extracellular toxins (from gram-positive bacteria).
Neutrophils and monocyte / macrophages exposed to lipopolysaccharide are activated and release proinflammatory cytokines, such as tumor-necrosis factor (TNF) a and interleukin – 1b. Excessive production of these cytokines is believed to contribute to the multiorgan failure that is seen in septic patients.
Until recently little was known of the mechanism that linked bacteria on the outside of the cell with transcription of genes for cytokines in the cell nucleus. Triggering receptor expressed on myeloid cells (TREM)-1 is the most recent of a series of discoveries that have begun to open this particular black box.
TREM-1 is a member of the immunoglobulin super-family and is expressed on the cell surface of neutrophils and certain subpopulations of monocytes. It triggers secretion of proinflammatory cytokines. Expression of TREM-1 is greatly upregulated in presence of extracellular bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus. It amplifies host response to bacterial stimulus. When infected mice were treated with a fusion protein containing the extracellular domain of murine TREM-1 and human IgG Fc, TNF-a and interleukin-1b production was significantly reduced and mortality fell from 94% to 24%.
This protection was still effective when started up to 4 h after infection. TREM-1 is thus a mechanism by which innate immunity responds to the presence of bacterial components.
Some of these pathways represent potential therapeutic targets. Molecules such as E5531 that appear to interfere with lipopolysaccharide binding are already in clinical development, and blocking TREM-1 deserves further study because it seems to be active even after bacterial challenge.
A better understanding of the processes that cause bacteria to activate cells may shed light on why patients respond so differently to what seems to be the same insult.
Richard N. Channick, Gerald Simonneau et al
Effects of the Dual Endothelin-Receptor Antagonist Bosentan in Patients With Pulmonary Hypertension: A Randomised Placebo-Controlled Study
Lancet, Vol.358, October 6, 2001, Pg. 1119-23
Summary: Endothelin-1, a powerful vasoconstrictor and mitogen might be a cause of pulmonary hypertension. Bosentan (Ro 47-0203), an orally active non-peptide antagonist of both endothelin receptor subtypes (ETA and ETB) has been shown to decrease inflammatory reactions, prevent increase in permeability of pulmonary vessels and prevent development of fibrosis in animals with pulmonary inflammation.
This is a double-blind, placebo-controlled study in 32 patients with pulmonary hypertension (primary or associated with scleroderma). Patients were randomly assigned to bosentan or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening.
Interpretation of the study was that bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.
Patrick Tounian, Yacine Aggoun, et al
Presence of Increased Stiffness of the Common Carotid Artery and Endothelial Dysfunction in Severely Obese Children: A Prospective Study
Lancet, Vol.358, October 27, 2001, Pg. 1400-04
Summary: Epidemiological studies suggest that obesity induced atherosclerosis may start in childhood, but this process has never been demonstrated.
The authors looked for arterial changes and investigated their relation to cardiovascular risk factors in obese children.
Non-invasive ultrasonographic measurements were made in 48 severely obese children and 27 controls to investigate arterial mechanics and endothelial function. Plasma lipid concentrations, indices of insulin resistance, and body composition were assessed in obese children.
Severe obesity in children is associated with arterial wall stiffness and endothelial dysfunction. Low plasma apolipoprotein-A-I, insulin resistance, and android fat distribution may be the main risk factors for these arterial changes, which are of considerable concern as possible early events in the genesis of atheroma.
M. Naumann, N. J. Lowe, et al
Botulinum Toxin Type A in Treatment of Bilateral Primary Axillary Hyperhidrosis: Randomised, Parallel Group, Double Blind, Placebo Controlled Trial
BMJ No.7313, September 15, 2001, Pg. 596-9
Summary : This was a multicentre, randomised, parallel group, placebo controlled trial in patients aged 18-75 years with bilateral primary axillary hyperhidrosis sufficient to interfere with daily living, in 307 completed cases.
Patients received either botulinum toxin type A (Botox) 50 U per axilla or placebo by 10-15 intradermal injections evenly distributed within the hyperhidrotic area of each axilla, defined by Minor’s iodine starch test.
Percentage responders (patients with ³ 50% reduction from baseline of spontaneous axillary sweat production) at 4 weeks, patients’ global assessment of treatment satisfaction score, and adverse events were noted.
The results revealed that at 4 weeks, 94% of the botulinum toxin type A group had responded compared with 36% of the placebo group. By week 16, response rates were 82% and 21% respectively.
Results of all other measures of efficacy were significantly better in the botulinum toxin group than the placebo group. Significantly higher patient satisfaction was reported in the botulinum toxin type A group than the placebo group. Treatment related adverse events were reported by 27 patients in the botulinum toxin group and 4 in the placebo group.
Eleven patients in the botulinum toxin group perceived an increase in non-axillary sweating after treatment compared with none of the control group. All 11 were responders and increases were reported at various body sites.
Common Virus Holds Out Hope For People With HIV
BMJ No.7313, September 15, 2001, Pg. 592
Summary: An apparently harmless and relatively common virus discovered 6 years ago allows people infected with HIV to live substantially longer by slowing progression to full blown AIDS, researchers report in 2 new studies.
Infection with the virus, known as GB virus or hepatitis G virus, improves survival in patients infected with HIV by directly influencing HIV replication as reported in New England Journal of Medicine 2001; 345: 707-14 and 715-24.
The investigators also conducted in vitro studies of peripheral blood mononuclear cells infected with each virus separately and with the 2 viruses together. Cells infected with HIV 24 hours after being infected with GB virus C showed a 99% reduction in HIV replication 6 days after infection.
Doctors now worry that some people with HIV may be tempted to infect themselves with the virus in the hope of preventing the onset of AIDS. Doctors caution against that, because so little is known about the virus.
Any suggestion that the intentional infection of persons with GB virus C be explored as a therapeutic approach for HIV infection is premature.
Steven M. Edworthy
Telemedicine In Developing Countries
BMJ No.7312, September 8, 2001, Pg. 524-5
Summary: Telemedicine, a broad umbrella term for delivery of medical care at a distance, has reached around the world. Internet, e-mail, websites, chatlines, multimedia presentations and occasional opportunities for synchronous communication via internet phones and videoconferencing provide an opportunity for medical education, medical care and collegial support.
One such example is a patient living in a hill community in Cambodia, who improved dramatically on prednisone after languishing for weeks with an undiagnosed illness. He was a suspected case of Henoch-Schonlein purpura (vasculitis) and a complete case history plus digital photographs of the lesions were sent.
Commentary: Prevention of Overwhelming Sepsis in Asplenic Patients: Could Do Better
Lancet, Vol.357, June 30, 2001, Pg. 2072
Summary : The spleen has an important function in the filtering, phagocytosis, and removal of bacteria from the circulation, and post-splenectomy or asplenic patients run a significantly increased risk of severe sepsis. There are guidelines for the prevention of infection in such patients but they are ignored.
The risk is considered greatest in the first 2-3 years after splenectomy but the risk is lifelong, so lifelong antimicrobial prophylaxis may be recommended. The recommendations for prevention include education of the patient, immunisation (pneumococcal vaccine) and antibiotic prophylaxis and specific advice concerning travel (increased risk of falciparum malaria), animal bites (risk of infection by the bacterium Capnocytophagia canimorsus), and tick bites (babesiosis).
Compliance with lifelong penicillin prophylaxis may be difficult and 3 G amoxicillin to be taken at the onset of a febrile illness may be recommended. Pneumococcal vaccine is important because of increasing resistance of Streptococcus pneumoniae to penicillin and macrolides.
Advice given to patients should be accompanied by an information fact sheet, patients should carry medi-alert bracelet, necklace or card and receive reminders for revaccination.
Improvement is needed to achieve best practice for the management of asplenic patients.
Franz-Josef Neumann, Adnan Kastrati et al
Treatment of Chlamydia pneumoniae Infection with Roxithromycin and Effect on Neointima Proliferation After Coronary Stent Placement (ISAR-3): A Randomised, Double-Blind, Placebo-Controlled Trial
Lancet, Vol.357, June 30, 2001, Pg. 2085-89
Summary : Vascular infection with Chlamydia pneumoniae might boost inflammatory responses that play an important role in neointima formation, which is the main cause of restenosis after stenting.
The aim of this study was to investigate whether or not treatment of Chlamydia pneumoniae infection with antibiotics prevents restenosis after stent placement.
The interpretation of this study was that non-selective use of roxithromycin is inadequate for prevention of restenosis after coronary stenting. There is a differential effect dependent on Chlamydia pneumoniae titres. In patients with high titres, roxithromycin reduced the rate of restenosis.
C. Varma and S J D Brecker
Predictors of Mortality in Acute Myocardial Infarction
Lancet, Vol.358, November 3, 2001, Pg. 1473-74
Summary : Initial treatment of myocardial infarction is aimed at establishing coronary artery patency, but it is myocardial viability that determines prognosis. Flow in the related artery is not always associated with myocardial perfusion because of microvascular damage.
Angioplasty is the most successful method of reperfusion, but it is restricted by logistical issues, and for most patients thrombolysis is the initial method of reperfusion.
The most reliable predictor of outcome after myocardial infarction is the concentration of troponin T. Troponin concentration may start to rise within 6 h of infarction, and takes only 20 min to measure. Other predictors are ST-segment elevation and increased concentrations of kinase. C reactive protein and myoglobin are also of prognostic value.
ECG is still the most widely used diagnostic tool and according to GUSTO-IIb study the 30-day incidence of death or myocardial reinfarction was 10.5% among those with ST-segment depression and 12.4% among those with ST elevation and depression. ST depression is also the strongest predictor of 1-year mortality among patients with acute coronary syndromes.
In a study reported by Klaus Schroder and colleagues, they found that mortality at 180 days was predicted by analysis of just 1 ECG lead (the one with maximum deviation at 90 min) and that the ST deviation (not resolution) in this single lead was a better predictor than sum STR.
Although the investigators used a lens-intensified calliper for their measurements, most of the measures are large enough not to require any special equipment.
Novel adjunctive therapies for reducing microvascular damage and improving myocardial perfusion (myocardium protective agents and vascular growth factors) are being investigated.
Klaus Schroder, Karl Wegscheider et al
Extent of ST-Segment Deviation in a Single Electrocardiogram Lead 90 Min After Thrombolysis as a Predictor of Medium-Term Mortality in Acute Myocardial Infarction
Lancet, Vol.358, November 3, 2001, Pg. 1479-86
Summary : In evolving myocardial infarction, assessment of the sum of early resolution of ST-segment elevation (sumSTR) has become an established method to predict outcome.
Authors have found previously that mortality is predicted more accurately by the existing ST-segment deviation in the single ECG lead with maximum deviation (maxSTE) 90 min after start of thrombolysis. Authors compared the power to predict medium-term mortality by these 2 approaches.
Interpretation of this study was that, maxSTE predicts early and medium-term mortality more accurately than does sumSTR. The prognosis for an individual patient can be accurately estimated simply by the ST-segment deviation present in one ECG lead recorded 90 min after thrombolysis.
Graham M Lord, Terry Cook et al
Urothelial Malignant Disease and Chinese Herbal Nephropathy
Lancet, Vol.358, November 3, 2001, Pg. 1515-16
Summary: Authors had previously reported occurrence of a specific type of nephropathy due to ingestion of Chinese herbs (Chinese herbal nephropathy) in 2 patients in the UK. These cases highlighted the role of aristolochic acid in causing this nephropathy, which was first described in a Belgian cohort.
In this article, the authors report development of invasive transitional cell carcinoma of the urinary tract associated with the presence of aristolochic acid-DNA adducts in one of these patients.
This work clearly shows the carcinogenic potential of aristolochic acid in this new type of nephropathy.
Ajit Lalvani, Ansar A Pathan et al
Enhanced Contact Tracing and Spatial Tracking of Mycobacterium tuberculosis Infection by Enumeration of Antigen-Specific T Cells
Lancet, Vol.357, June 23, 2001, Pg. 2017-21
Summary : Identification of individuals latently infected with Mycobacterium tuberculosis is an important part of tuberculosis control.
The current method, the tuberculin skin test (TST), has poor specificity because of the antigenic cross-reactivity of purified protein derivative (PPD) with M. bovis BCG vaccine and environmental bacteria. ESAT-6 is a secreted antigen that is highly specific for M. tuberculosis complex, but is absent from M. bovis BCG.
With an enzyme-linked immunospot (ELISPOT) assay for interferon gamma, the authors have identified ESAT-6-specific T cells as an accurate marker of M. tuberculosis infection.
This new antigen-specific T cell-based assay could allow more accurate identification of symptom-free individuals recently exposed to M. tuberculosis, and thereby help to improve tuberculosis control.
A. Gupta, R. Gupta, B. Lal
Effect of Trigonella foenum-graecum (Fenugreek) Seeds on Glycaemic Control and Insulin Resistance in Type 2 Diabetes Mellitus: A Double Blind Placebo Controlled Study
JAPI, Vol.49, November 200 1, Pg. 1057-1061
Summary : A double-blind placebo controlled study was performed in mild to moderate type 2 diabetes mellitus patients to evaluate the effects of Fenugreek seeds on glycaemic control and insulin resistance (determined by HOMA model).
A hydro-alcoholic extract of fenugreek seeds was used in the form of capsules, and patients were asked to take 2 capsules twice a day before meals, for 2 months. Twenty five newly diagnosed patients with type 2 diabetes (fasting glucose < 200 mg/dl) were randomly divided into 2 groups. Group 1 (n=12) received 1 gm/day hydro-alcoholic extract of fenugreek seeds and group 2 (n=13) received usual care (dietary control, exercise and placebo capsules).
Conclusions of the study were that adjunct use of fenugreek seeds improve glycaemic control and decrease insulin resistance in mild type 2 diabetic patients. The serum triglycerides decreased and HDL-cholesterol increased significantly in the group treated with fenugreek seeds.
V. Mohan and M. Balasubramanyam
Editorial: Fenugreek and Insulin Resistance
JAPI, Vol.49, November 2001, Pg. 1055-1056
Summary : The seeds of fenugreek comprising mucilaginous fibre (about 50% by weight) and steroid saponins (12% by weight) have been claimed to account for many of the beneficial effects of fenugreek. The steroid saponins are thought to inhibit cholesterol absorption and synthesis while the fibre may help lower blood sugar levels.
The available data suggests that it could be used as an adjunct therapy of type 2 diabetes, but most studies have been performed on small number of patients. Therefore, toxicity testing and large multicentre randomized clinical studies are necessary.
Recently, 4-hydroxyisoleucine, an amino acid extracted from fenugreek seeds has been shown to potentiate insulin secretion. Its action is very specific on beta-cells. Multiple beneficial effects of fenugreek on glucose and lipid metabolism indicate that it can serve as an effective supportive therapy in the clinical management of diabetes.
One should be cautioned that fenugreek may react adversely with a variety of medications including glipizide, heparin, insulin, ticlopidine and warfarin.
Jay S. Skyler, William T. Cefalu, et al
Efficacy of Inhaled Human Insulin in Type 1 Diabetes Mellitus: A Randomised Proof-of-Concept Study
Lancet Vol.357, February 3, 2001, Pg. 331-335
Summary : Effective glycaemic control in type 1 diabetes mellitus usually requires two or more insulin injections daily. Inhaled intrapulmonary delivery of insulin offers a potential new way to deliver meal-related insulin, eliminating the need for preprandial injections.
73 patients with type 1 diabetes mellitus were studied in an open-label, proof-of-concept, parallel-group randomised trial. Patients in the experimental group received preprandial inhaled insulin plus a bedtime subcutaneous ultralente insulin injection.
Patients in the control group received their usual insulin regimen of two to three injections per day. Participants monitored their blood glucose four times daily, and adjusted insulin doses weekly to achieve preprandial glucose targets of 5.6-8.9 mmol/L.
The primary outcome measure was change in glycosylated haemoglobin (HbA1c) after 12 weeks. Secondary outcomes were fasting and postprandial glucose response to a mixed meal; hypoglycaemia frequency and severity; pulmonary function; and patients satisfaction.
Changes in HbA1c were indistinguishable between groups (difference 0.2% [95% Cl – 0.2 to 0.5]). Changes in fasting and postprandial glucose concentrations, and occurrence and severity of hypoglycaemia were also similar between groups. Inhaled insulin was well tolerated and had no effect on pulmonary function (ie, spirometry, lung volumes, diffusion capacity, and oxygen saturation).
This proof-of-concept study shows that preprandial insulin can be given by inhalation in individuals with insulin-deficient type 1 diabetes as a less invasive alternative to conventional preprandial insulin injections.
Edwin A. M. Gale
Commentary: Two Cheers for Inhaled Insulin
Lancet Vol.357, February 3, 2001, Pg. 324-325
Summary : Jay Skyler and colleagues have shown by comparison between inhaled insulin and conventional therapy in patients with type 1 diabetes, that one daily injection of long-acting insulin plus 3 preprandial inhalations gives glucose control similar to that of 2 or 3 insulin injections a day.
First paper on inhaled insulin came out in 1924 and other routes, such as transdermal, oral, nasal, intestinal, and rectal, were also extensively investigated, but only a small and erratic fraction of the amount administered reaches circulation.
Inhalation has emerged as the most promising route for non-invasive administration of peptides or proteins. Insulin with a molecular weight of 5700, is absorbed well. Inhaled insulin peaks rapidly like a fast-acting analogue injected under the skin and has a longer duration of effect.
Intra-individual variability of absorption is similar to injected insulin. Some of the inhaled insulins in development contain bile salts, which enhance absorption, but the Pfizer preparation consists of dry insulin dispersed by aerosol into particles sufficiently fine to drift into distal twigs of respiratory tree.
Absence of an absorption enhancer reduces risk of adverse reactions but may also reduce bioavailability. Cigarette smoking is an effective means of increasing absorption of insulin but the finding is best ignored. On present evidence inhalation delivers a small and reproducible fraction of inhaled dose safely and rapidly in the blood stream.
Skylers study is a proof of concept, and inhaled insulin does not abolish the need for insulin injections, although it may allow people to get by on only one a day. Long-acting insulins are necessary in type I diabetes and still have to be given by injection.
It is too early to conclude that inhaled insulin is as good as conventional insulin, as the sample size has been too small.
Lorraine Kyne, Michel Warny et al
Association Between Antibody Response to Toxin A and Protection Against Recurrent Clostridium difficile Diarrhoea
Lancet Vol.357, January 20, 2001, Pg. 189-193
Summary : Clostridium difficile associated diarrhoea is a common iatrogenic, nosocomial disease associated with substantial morbidity and mortality. Pathogenic strains of C. difficile produce the protein exotoxins toxin A and toxin B.
These cytotoxic, enterotoxic and proinflammatory toxins induce colonial mucosal injury, diarrhoea and in severe cases, pseudomembranous colitis. The aim of this study was to determine whether an acquired immune response to toxin A, during an episode of C. difficile diarrhoea, influences risk of recurrence.
Authors studied 63 patients with nosocomial C. difficile diarrhoea. Serial serum IgA, IgG and IgM concentrations against C. difficile toxin A, toxin B or non-toxin antigens were measured by ELISA. Individuals were followed for 60 days.
Interpretation of the study was that a serum antibody response to toxin A, during an initial episode of C. difficile diarrhoea, is associated with protection against recurrence.
Mark Wilcox, Jane Minton
Commentary – Role of Antibody Response in Outcome of Antibiotic-associated Diarrhoea
Lancet Vol.357, January 20, 2001, Pg. 158-159
Summary : The observations of Lorraine Kyne and colleagues report significantly higher concentrations of both serum IgM and IgG antibodies against toxin A in patients who experienced one episode than in those with multiple episodes of C. difficile diarrhoea.
They have also highlighted the protective role of serum IgG antibodies against C. difficile in those patients who remained symptom-free despite being colonised.
Thus, not only composition of the gut flora but also ability to mount a specific antibody response influences patients susceptibility to infection.
Jean L Rouleau, Marc A Pfeffer et al
Comparison of vasopeptidase inhibitor, omapatrilat and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomized trial.
Lancet, vol.356, Aug.19, 2000, pg.615
Background: Authors aimed to assess in patients with congestive heart failure whether dual inhibition of neutral endopeptidase and angiotensin-converting enzyme (ACE) with the vasopeptidase inhibitor, omapatrilat is better than ACE inhibition alone with lisinopril on functional capacity and clinical outcome.
Methods : Authors did a prospective, randomised, double-blind, parallel trial of 573 patients with New York Heart Association (NYHA) class II-IV congestive heart failure, left-ventricular ejection fraction of 40% or less, and receiving an ACE inhibitor. Patients were randomly assigned omapatrilat at a daily target dose of 40mg (n=289) or lisinopril at a daily target dose of 20 mg (n=284) for 24 weeks. The primary endpoint was improvement in maximum exercise treadmill test (ETT) at week 12. Secondary endpoints included death and comorbid events indicative of worsening heart failure.
Omapatrilat improved NYHA class more than lisinopril in patients who had NYHA class III and IV, but not if patients with NYHA class II were included.
Interpretation : Findings suggest that omapartilat could have some advantages over lisinopril in the treatment of patients with congestive heart failure. Thus use of vasopeptidase inhibitors could constitute a potentially important treatment for further improving the prognosis and well being of patients with this disorder.
Franz H Messerli, Jurg Nussberger
Commentary – Vasopeptidase inhibition and angio-oedema
Lancet, vol.356, Aug.19, 2000, pg.608
Omapatrilat affects the cardiovascular system by inhibiting the ACE (and thereby interrupting the renin-angiotensin-aldosterone cascade), and by inhibiting the neutral endopeptidase (NEP) (and thereby increasing the concentration of natriuretic peptides). Both these enzymes also inactivate bradykinin, and ACE inhibitors alone have been shown to increase plasma kinin concentrations. Bradykinin is probably the mediator of the angio-oedema associated with ACE inhibitors. Plasma bradykinin concentrations can rise more than 10 fold during attacks of angio-oedema associated with an ACE inhibitor. The US FDA has raised concern about this adverse effect and the manufacturer withdrew the application temporarily.
Angio-oedema is a well documented, but rare, adverse event in patients taking ACE inhibitors. It can first appear from a few hours to 8 years after an ACE inhibitor is first taken.
Omapatrilat apart from conferring potential cardiovascular benefits, may be of advantage in CHF patients with renal impairment. But as a dual ACE and NEP inhibitor, omapatrilat also carries a higher risk of life-threatening angio-oedema than do ACE inhibitors alone. For omapatrilat, as for any therapy, the risk/benefit ratio must be quantified before it becomes generally available.
L. H. Opie
Commentary: Renoprotection by Angiotensin-Receptor Blockers and ACE Inhibitors in Hypertension
Lancet, Vol. 358, December 2001, Pg. 1829-1831
Effects of antihypertensive agents on renal variables have been generally ignored but the position has changed with publication of the results of 3 trials with hard renal endpoints such as serum creatinine concentrations and end-stage renal disease.
These trials strongly support that renin-angiotensin inhibition gives renoprotection and has disease-retarding effects independent of blood-pressure reduction. Further benefit can be expected in patients with proteinuria exceeding IG/day from BP dependent effects.
Data from losartan and irbesartan show that protection from end-stage renal disease in type 2 diabetes with nephropathy is possible by the use of angiotensin-type I receptor antagonists (ARBS).
These studies are not perfect, in one of these studies the add-on drugs – furosemide, doxazosin, clonidine, hydralazine and minoxidil are unlikely ever to be used.
The ARBS are the first-line of treatment for hypertensive patients with type-2 diabetes with nephropathy, whether overt or incipient, with ACE inhibitors a close next choice and with calcium channel blockers being kept for add-on therapy to reduce BP adequately.
Why is ACE inhibitor better at renoprotection than amlodipine and why is irbesartan better than amlodipine?. Physiological observations provide the explanation. First, by causing vasodilatation of afferent renal arterioles, calcium blockers of the dihydropyridine type increase intraglomerular pressure and therefore promote proteinuria.
There is good evidence that increasing degree of proteinuria reflects increasing renal damage. Second, the dihydropyridines generally increase sympathetic activity, which is already high in renal disease.
On the other hand, the ACE inhibitors by promoting dilatation of both afferent and efferent renal arterioles could be expected to reduce intraglomerular pressure and hence lessen proteinuria. ACE inhibitors also reduce sympathetic activity.
These features of dihydropyridines may not apply to non-dihydropyridines verapamil and diltiazem. In next generation of renal trials there has to be a direct comparison between ARBS and ACE inhibitors.
Helen F. Cross, Melang Haarbrink, et al
Severe Reactions to Filarial Chemotherapy and Release Wolbachia Endosymbionts into Blood
Lancet, Vol. 358, December 2001, Pg. 1873-1875
Severe systemic inflammatory reactions to diethylcarbamazine in individuals with B. malayi infection have been associated with high levels of microfilariaemia before treatment and with increased post treatment concentrations of interleukins 6 and 10, lipopolysaccharide binding protein (LBP) and soluble TNF-a receptors.
Interleukin 6 and LBP were most significantly associated with severe reactions. Most of the inflammatory activity of B. malayi is mediated by lipopolysaccharide-like molecules derived from endosymbiotic Wolbachia bacteria.
Authors investigated whether similar mechanisms account for the presentation of severe systemic inflammatory reactions in human lymphatic filariasis.
The observations show that in patients with high microfilarial loads, the release of endosymbionts into the blood from parasites killed or damaged by DEC treatment coincides with the development of severe systemic inflammatory reactions.
These reactions associated with increases in proinflammatory cytokines including TNF-a and interleukin 6 have also been reported in bancroftian filariasis and onchocerciasis.
The reactions are likely to be caused by partial adulticidal activity of DEC and subsequent release of endosymbiotic bacteria. In onchocerciasis, antibiotics have been used to target filarial Wolbachia as an alternative to current antifilarial treatments.
Treatment with doxycycline resulted in long-term clearance of endosymbionts, which led to profound embryotoxicity and sterility of adult worms.
Carmine Zoccali, Stefanie M. Bode-Boger, et al
Plasma Concentration of Asymmetrical Dimethylarginine and Mortality in Patients With End-Stage Renal Disease: A Prospective Study
Lancet Vol.358, December 22/29, 2001, Pg. 2113-2117
The plasma concentration of asymmetrical dimethylarginine (ADMA), an inhibitor of nitric-oxide synthase, which has been linked to endothelial dysfunction and atherosclerosis in the general population, is raised in patients with end-stage renal disease and could contribute to the high cardiovascular risk in patients with chronic renal failure.
The authors investigated the relation between cardiovascular risk factors and plasma ADMA concentration in a cohort of haemodialysis patients (n=225), and tested the predictive power of ADMA for mortality and cardiovascular outcomes.
On univariate analysis, ADMA concentration in plasma was directly related to concentrations of fibrinogen and L-arginine in plasma, duration of dialysis treatment, and serum cholesterol concentration, and was inversely related to serum albumin concentration.
Interpretation of this study was that, in haemodialysis patients, plasma ADMA is a strong and independent predictor of overall mortality and cardiovascular outcome. These findings lend support to the hypothesis that accumulation of ADMA is an important risk factor for cardiovascular disease in chronic renal failure.
Commentary: Importance of Asymmetrical Dimethylarginine in Cardiovascular Risk
Lancet Vol.358, December 22/29, 2001, Pg. 2096-2097
Over the past 10 years nitric oxide has emerged as a vital signalling molecule in virtually every organ system. Its synthesis from L-arginine can be blocked by N-monomethyl-L-arginine (L-NMMA), a structural analogue of arginine.
In the cardiovascular system L-NMMA vasoconstricts, causes hypertension, increases platelet activation and enhances atherogenesis. Asymmetrical dimethylarginine (ADMA) also inhibits nitric-oxide synthase and produces near-identical effects to L-NMMA.
Both L-NMMA and ADMA are naturally occurring compounds that circulate in plasma and are excreted in urine. ADMA is found in far higher concentration than L-NMMA. The first disease in which an increase of ADMA was implicated was renal failure. ADMA would act as a uraemic toxin linking the degree of renal failure to multisystem abnormalities and C. Zoccali and colleagues place ADMA center stage as a potential mediator of cardiovascular abnormality in renal disease.
In this study, plasma ADMA concentrations emerged second only to age as a predictor of both overall mortality and cardiovascular events in patients with chronic renal impairment.
What are the implications of these findings for patients with renal failure? Whether long-term dietary supplementation with arginine affects cardiovascular risk in patients with renal failure? However, it is important to recognise that arginine does more than act as substrate for nitric-oxide synthases and that supplementation in individuals with renal failure can lead to detrimental increases in potassium concentrations. ADMA fulfils many of the characteristics of a uraemic toxin.
A research letter in Lancent reports a relation between risk of acute coronary events and ADMA concentration among middle-aged men in Finland. Since renal function in this group was not impaired and excretion of ADMA was presumably normal, DDAH (dimethyl arginine dimethyl aminohydrolase) dysfunction is strongly implicated as a primary mechanism.
Veli-Pekka Valkonen, Hannu Paiva, et al
Risk of Acute Coronary Events and Serum Concentration of Asymmetrical Dimethylarginine
Lancet Vol.358, December 22/29, 2001, Pg. 2127-2128
Asymmetrical dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor, which has been suggested to be a novel independent risk factor for endothelial dysfunction and coronary heart disease.
The authors investigated the association of ADMA concentration in serum with risk of acute coronary events. They did a prospective, nested, case-control study in middle-aged men from eastern Finland. In an analysis of men who did not smoke, those who were in the highest quartile for ADMA (> 0.62 mmol/L) had a 3.9-fold (95% C1 1.25-12.3, p=0.02) increase in risk of acute coronary events compared with the other quartiles. Their findings suggest that ADMA is a predictor of acute coronary events.
Nirupa Chaudhari and Sue C. Kinnamon
Molecular Basis of the Sweet Tooth?
Lancet Vol.358, December 22/29, 2001, Pg. 2101-2102
What the taste-buds detect as sweet includes aminoacids such as D-phenylalanine and even same proteins. There are therapeutic applications of sweet compounds. Sucrose has been used to counter the innately bitter taste of many medicines, but recent studies suggest that sucrose releases endorphins, which can be used in pain management, particularly in newborns, for whom many analgesics are not suitable.
Contrary to the “tongue maps” commonly displayed in text-books, all areas of the tongue respond to all taste qualities (e.g. sweet, salty) although with variable efficiency.
Recent advances were made possible by discovery over a decade ago that inbred strains of mice have a diminished preference for sweetness such as sucrose and saccharin. By contrast, taster strains of mice have a higher preference for sweetness compared with non-taster strains.
These differences stem from a locus, sac, near the distal end of mouse chromosome 4. Tas1r3 in human genome corresponds to sac gene. The gene Tas1r3 encodes a novel G-protein coupled receptor T1R3. So does T1R3 function as a membrane receptor for sweet substances?
The chemosensory G protein, gustducin, has been implicated in signalling pathways because of decreased sweet responses in gustducin-knockout mice.
Knowledge of the molecular structure of sweet-taste receptor and its binding site should facilitate the design of novel non-caloric sweeteners that have a cleaner sweet taste and help prevent problems associated with sugars.
It might lead to the synthesis of new compounds that activate sweet receptors so efficiently that pancreatic release of insulin can be avoided. Such compounds may be useful for antagonising bitter medicines and alleviating pain in infants.
Judith R Thompson, Patrick F Gerald, et al
Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood : a case-control study.
The Lancet, Dec. 8, 2001, vol.358, pg.1935-40
Acute lymphoblastic leukaemia is the most common childhood cancer in more-developed countries but it has few recognized risk factors or preventive measures. Authors aimed to determine and assess the risk factors associated with this disease.
From 1984 to 1992, authors investigated known and suspected risk factors for common acute lymphoblastic leukaemia diagnosed in a population-based case-control study of children aged 0-14 years in Western Australia.
Results, though unexpected, suggest that folate supplementation in pregnancy reduces the risk of common acute lymphoblastic leukaemia in the child.
Basil Rigas, Izhar Hasan, et al
Effect on treatment outcome of coinfection with SEN viruses in patients with hepatitis C.
The Lancet, vol.358, Dec.8.2001, pg.1961-62
Five hepatitis viruses (A-E) cause more than 80% of cases of viral hepatitis, and efforts are underway to identify the agents responsible for the remainder. Primi and colleagues recently described the SEN family of eight new viruses (SEN A-H), which are single-stranded, circular, non-enveloped DNA viruses, on average 3900 nucleotides in length, similar to circoviruses. SEN D and SEN H are transmitted parenterally and can cause post-transfusion hepatitis. Authors assessed whether these two viruses infect patients with chronic hepatitis C and whether such coinfection influences the outcome of therapy.
The newly discovered SEN D and SEN H viruses are transmitted parenterally and can cause post-transfusion hepatitis. Authors assessed whether coinfection of patients with chronic hepatitis C and SEN D or SEN H correlates with the outcome of treatment with interferon and ribavirin. Of 31 patients with hepatitis C studied, six were positive for SEN D and seven for SEN H (one was positive for both). All of those positive for SEN D and five of those positive for SEN H failed to respond to therapy. Overall response (RNA titre and alanine aminotransferase concentration after treatment) was lower in SEN-infected patients than uninfected patients (p=0.025). They conclude that coinfection with SEN viruses is frequent in chronic hepatitis C patients and might adversely affect the outcome of treatment with interferon and ribavirin.
Daniel J Diekema, Ronald N Jones
The Lancet, vol.358, Dec.8 2001, pg.1975
Many common gram-positive pathogens (e.g.Staphylococcus aureus, Enterococcus spp, and Streptococcus pneumoniae) have become increasingly resistant to antimicrobial agents and new drugs with activity against gram-positive bacteria are urgently needed. The oxazolidinones, a new chemical class of synthetic antimicrobial agent, have a unique mechanism of inhibiting bacterial protein synthesis. Linezolid, the first oxazolidinone to be approved for clinical use, displays in-vitro activity (generally bacteriostatic) against many important resistant pathogens, including meticillin resistant Staph aureus, vancomycin-resistant enterococci, and penicillin-resistant Strep pneumoniae. Linezolid is a parenteral agent that also possesses near-complete oral bioavailability plus favourable pharmacokinetic and toxic effect profiles. Clinical trials confirm the activity of linezolid in the setting of pneumonia, skin and soft-tissue infections, and infections due to vancomycin-resistant enterococci. Linezolid shows promise as an alternative to glycopeptides and streptogramins to treat serious infections due to resistant gram-positive organisms. New agents with greater potency and new spectra of activity could arise from further modification of the oxazolidinone nucleus.
Brian Wharton and Ian Booth
Editorial – Fortification of flour with folic acid
BMJ, Vol.323, Nov.24, 2001, pg.1198
Thirty-three years ago Hibbard and Smithells linked folate deficiency in pregnancy with neural tube defects. Improving folate status from before conception to 12 weeks of pregnancy by increasing folic acid intake from foods and supplements has been carried out by Health education authority in the UK The Dept. of Health Committee in the U.K. has now recommended universal fortification of flour in the UK. The benefits are clear but possible harm of such a policy is not, and it is necessary to be cautious in implementing such a policy.
For example, in people with Vit.B12 deficiency consumption of folate may mask megaloblastic anaemia, an important manifestation of Vit.B12 deficiency, which then may progress undetected to subacute combined degeneration of the spinal cord.
Tim Lancaster, and Michael Moher
Updating guidelines on stable angina – Beta blockers are the first choice for regular treatment.
BMJ, Vol.323, Nov.24, 2001, pg.1202
The guideline advises b-blockers as the first choice for patients needing regular treatment. This guideline is based on trial evidence showing that b-blcokers reduce morbidity in patients with stable angina. Verapamil remains the preferred alternative for those who cannot tolerate b-blcokers. The guideline continues to highlight the importance of aspirin for secondary prevention. There are minor changes for modifying weight, physical activity and smoking. There is a new emphasis on a Mediterranean diet and on fatty fish intake, though the guideline points out that the trials in which these diets reduced mortality were conducted in survivors of myocardial infarction. The guideline avoids specific recommendations on cholesterol lowering drugs.
Kalifa A Bojang, Paul JM Milligan, et al
Efficacy of RTS,S/ASO2 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in the Gambia: a randomised trial.
The Lancet, vol.358, 8 Dec.2001, pg. 1927-34.
RTS,S/ASO2 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HbsAg, incorporating a new adjuvant (ASO2). Authors did a randomised trial of the efficacy of RTS,S/ASO2 against natural P.falciparum infection in semi immune adult men in The Gambia.
Three hundred and six men aged 18-45 years were randomly assigned three doses of either RTS,S/ASO2 or rabies vaccine (control). Volunteers were given sulfadoxine/ pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P.falciparum. Analysis was per protocol.
Interpretation: Of the study was that RTS, S/ASO2 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P.falciparum infection.
I.M.Cropley, Diana NJ, Lockwood et al
Rapid diagnosis of falciparum malaria by using the ParaSight F test in travellers returning to the United Kingdom: prospective study
BMJ, Vol.321, 19-26 August 2000, p.484.
A simple diagnostic strip test for Plasmodium falciparum malaria (ParaSight F test, Becton Dickinson Advanced Diagnostics) detects a water soluble antigen, histidine rich protein 2, which is produced by blood stages of P.falciparum. High sensitivity and specificity have been reported for the test in areas where malaria is endemic. Authors compared the test with standard blood film microscopy in febrile travellers returning to the United Kingdom from such areas.
The ParaSight F test is simple, rapid, and has adequate sensitivity and specificity for initial assessment of P falciparum infection in returning travellers. It identified all patients with P.falciparum apart from one patient with a low parasitaemia of <0.01% and two patients with parasites not detected on initial microscopy.
The test does not remove the need for blood film examination as it is not 100% sensitive at low parasitaemias, and repeated daily testing may be necessary to establish the diagnosis. Nor does the test give any indication of density of parasites, essential in planning management.
Jurg Utzinger, Eliezer K NGoran et al
Oral artemether for prevention of Schistosoma mansoni infection: randomised controlled trial.
The Lancet, vol.355, April 15, 2000, pg.1320-25
Chemotherapy with praziquantel is the current strategy of choice to control schistosomiasis. However, in view of concern about praziquantel tolerance or resistance, new drugs are needed. Artemether, a derivative of the antimalarial drug artemisinin, kills immature schistosomes of Schistosoma japonicum, and reduces the incidence of infection in field trials. Laboratory studies have also showed activity by this drug against S mansoni. Authors report a randomised double-blind placebo-controlled clinical trial of artemether to prevent S mansoni infection.
Interpretation of this study is that oral artemether is safe and shows a prophylactic effect against S mansoni. The use of artemether may be recommended in appropriated situations as an additional tool for more effective schistosomiasis control measures. However the application needs to be carefully assessed especially in view of the concern that it could select for resistant plasmodia
Praziquantel is the drug of choice – it is active against all schistosome species, can be easily administered, has high cure and egg-reduction rates, and no or only mild side-effects. However, field studies in a community in Senegal exposed to a very intense focus of Schistosoma mansoni showed unexpected low cure rates after praziquantel.
These observations raised concern about praziquantel tolerance or resistance. oxamniquine (for S mansoni) and metrifonate (for S haematobium) are effective but are difficult to obtain in some African countries. The production of oxamniquine has been reduced and metrifonate has been withdrawn from the market.
For schistosomiasis, a drug that kills immature worms can be defined as chemoprophylaxis, because it prevents the development of the mature female worms that cause damage to the human host as a result of egg secretion.
Derivatives of artemisinin (the Chinese drug qinghaosu) were tested in the laboratory and showed highest activity against immature worms.
For S mansoni, the killing of immature worms by artemether was shown in vitro, and is well documented in mice with worm-reduction rates of 97-100%. The highest efficacy was seen between days 7 and 28 after the mice had been infected. This is the period when praziquantel and other schistosomicides are less effective.
The study showed that oral artemether is safe and has a clear prophylactic effect against S mansoni. The incidence of S mansoni infection was 50% lower in those children who received artemether rather than placebo. The intensity of infection among the positive children was also reduced significantly.
In the case of schistosomiasis, control measures could be improved and may even lead to higher cure rates by combination therapy with drugs with different modes of action; one acting against immature worms, e.g. artemether, and the other against adult worms, eg. praziquantel. Such an approach could also reduce the risk of developing resistance.
Daniel W Fitzgerald, Moise Desvarieux et al
Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1 infected individuals: a randomised trial
The Lancet, 2000; 356: 1470-74
Patients with HIV-1 infection respond well to treatment for active tuberculosis, but whether such patients are at increased risk of disease recurrence after complete cure is uncertain. A randomised trial was carried out in Port au Prince, Haiti, to determine whether recurrent tuberculosis after curative tuberculosis treatment is more common in HIV-1 infected individuals than HIV-1-uninfected individuals, and to determine whether post-treatment isoniazid prophylaxis decreases the risk of recurrent tuberculosis.
Interpretation of the study was that, the rate of recurrent tuberculosis is higher in HIV-1-positive individuals than in HIV-1-negative individuals, and is strongly associated with a history of symptomatic HIV-1 disease before initial tuberculosis diagnosis. Post-treatment isoniazid prophylaxis decreases the risk of recurrence in HIV-1-positive individuals, and should be considered for HIV-1-positive individuals with a history of HIV-1-related symptoms at the time of tuberculosis diagnosis.
Gary L Davis
Treatment of Chronic Hepatitis C
Combination therapy permanently eradicates the virus in at least 40% of patients.
BMJ, 17 Nov.01, 323, 1141
Chronic hepatitis C virus infections have become very common because of the use of blood transfusion and surgeries. Prognosis of hepatitis C is as bad as hepatitis B. While Lamivudine is very effective in hepatitis B infections, it is not effective against hepatitis C infections. After various studies it has now been found that the combination of interferon and ribavirin is effective for treating chronic hepatitis C. Overall, hepatitis C virus is permanently eradicated in about 40% of patients treated with combination therapy in doses appropriate to viral genotype.
Responses are genotype dependent and are sustained in 42-46% in patients infected with genotype 1 and 76-82% in genotype 2 or 3.
Duncan P Thomas
Thromboprophylaxis after replacement arthroplasty
Anticoagulants are more effective than aspirin
BMJ, 24 Mar, 01, vol.322, pg.686
Arthroplasty either total hip arthroplasty or knee arthroplasty is notorious for producing venous thromboembolism. The usual treatments are warfarin and heparin both of which are effective but both of which carry the risk of bleeding. In addition, warfarin requires careful monitoring frequently which is difficult for patients outside hospital. Unfortunately, aspirin does not seem to be effective as an anticoagulant for venous thromboembolism after hip and knee replacement.
The CAPRICORN Investigators
Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction.
The Lancet, vol.357 (9266), 5 May 2001, pg.1385
The beneficial effects of b-blockers on long-term outcome after acute myocardial infarction were shown before the introduction of thrombolysis and angiotensin-converting-enzyme (ACE) inhibitors. Generally, the patients recruited to these trials were at low risk: few had heart failure, and none had measurements of left-ventricular function taken. The long-term efficacy of carvedilol on morbidity and mortality was investigated in patients with left-ventricular dysfunction after acute myocardial infarction treated according to current evidence-based practice.
In a multicentre, randomised placebo-controlled trial, 1959 patients with a proven acute myocardial infarction and a left-ventricular ejection fraction of > 40% were randomly assigned 6.25mg carvedilol (n=975) or placebo (n=984). Study medication was progressively increased to a maximum of 25mg twice daily during the next 4-6 weeks, and patients were followed up until the requisite number of primary endpoints had occurred. The primary endpoint was all-cause mortality or hospital admission for cardiovascular problems. Analysis was by intention to treat.
In patients treated long-term after an acute myocardial infarction complicated by left-ventricular systolic dysfunction, carvedilol reduced the frequency of all-cause and cardiovascular mortality, and recurrent, non-fatal myocardial infarctions. These beneficial effects are additional to those of evidence-based treatments for acute myocardial infarction including ACE inhibitors.
Commentary – Prophylactic effect of Malarone against malaria: all good news?
Lancet, vol.356, Dec.2, 2000, pg.1864.
Birthe Hogh colleagues report the results of a large, detailed, and well-conducted trial of Malarone (Glaxo-Wellcome) for the prophylaxis of malaria in travellers. This fixed combination of atovaquone and proguanil was a safe and effective prophylactic agent in travellers. To people trying to combat increasing drug resistance in Plasmodium falciparum, this finding seems like good news – or is it?
The main component of the combination (atovaquone) belongs to a family of anti-infective compounds, the hydroxynaphthoquinones, which has been known for over 50 years to be active against P.falciparum. The first studies in human beings were disappointing, and the prototypes of this group of drugs were not studied further.
Meanwhile, when it became clear that P.facliparum was developing resistance to other classes of drugs at an alarming pace, the antimalarial property of atovaquone was re-explored.
Mass chemoprophylaxis is not recommended currently (except in pregnancy) for fear of encouraging resistance, and the drug is far too expensive for poor tropical countries.
For the treatment of P.falciparum infections, Malarone (if affordable) could prove very valuable in areas where the parasite is becoming resistant to all other drugs.
By inhibiting mitochondrial electron transport in the parasite, atovaquone reduces pyrimidine synthesis and causes collapse of the mitochondrial membrane potential. Despite the combination with proguanil, atovaquone is clearly vulnerable to resistance, as shown in clinical studies. New, safe, and the affordable antimalarial drugs are unlikely to be developed in the near future, so malarone needs to be protected. Protection can be achieved by judicious use and by combining Malarone with an artemisinin derivative. Thus, the finding that Malarone is safe and effective in protecting wealthy travellers is good news, but not necessarily for the millions living (and dying) with malaria in the tropics.
Camilla S Graham and Margaret James Koziel
Why should hepatitis C affect immune reconstitution in HIV-1 infected patients?
Lancet, vol.356, Dec.2, 2000, pg.1865.
Hepatitis C virus (HCV) is a common infection associated with HIV-1 infection. HCV shares the parenteral route of transmission with HIV-1, and co-infection rates are 60-90% in injection drug users and people with haemophilia. Now that life-expectancy in patients with HIV-1 infection is increasing, thanks in part to highly active antiretroviral therapy (HAART) , such patients may face the complications associated with lengthy HCV infection, which include cirrhosis, decompensated liver disease, and hepatocellular carcinoma.
A major feature of HIV-1 infection is the progressive decline in CD4-cell counts but the mechanisms for the depletion are controversial.
HCV might alter either production or apoptosis of T cells, thus blunting the expected increase in CD-4-positive cells.
Another possible explanation is that HCV sensitizes cells to apoptosis. HIV-1 and HCV may act synergistically to increase apoptosis of CD4-positive cells.
If HCV does have deleterious effects on CD4-cell responses with HAART, the implication is that patients with HCV/HIV-1 coinfection may benefit from anti-HCV therapy, both to decrease incidence of HCV-related advanced liver disease and to increase the effectiveness of HAART.
Ralf Koster, Dieter Vieluf, et al
Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis.
The Lancet, vol.356, Dec.2, 2000, pg.1895
Coronary in-stent restenosis might be triggered by contact allergy to nickel, chromate, or molybdenum ions released from stainless-steel stents. Authors investigated the association between allergic reactions to stent components and the occurrence of in-stent restenosis.
Patients with allergic patch-test reactions to nickel and molybdenum had a higher frequency of in-stent restenoses than patients without hypersensitivity. Allergic reactions to nickel and molybdenum released from stents may be one of the triggering mechanisms for in-stent restenosis.
The hidden potential of statins
Lancet, vol.356, Dec.2, 2000, pg.1906
Francois Mach (Geneva Medical School, Switzerland) and colleagues reveal this week that statins, the most powerful class of lipid lowering drugs available, inhibit the expression of MHC-II by some antigen-presenting cells. This will not affect the way statins are used for heart-disease patients but ‘it may open up new clinical indications for statin treatment’, says Mach, ‘such as the prevention of graft atherosclerosis after organ transplants”.
Joachim Schrader and Stephan Luders
High risk patients should receive ramipril irrespective of their blood pressure.
BMJ, 23 March 2002, vol.324, pg.687
The Heart Outcomes Prevention Evaluation study (HOPE), has shown beneficial effects of the angiotensin converting enzyme inhibitor ramipril on cardiovascular events and disease progression. In this issue the investigators describe the results of preventing stroke. The findings clearly show that ramipril substantially decreased the risk of stroke and transient ischaemic attacks in 9297 patients with high cardiovascular risk. A 32% relative risk reduction was found, while the reduction in blood pressure was only 3.8mmHg (systolic) and 2.8mm Hg (diastolic). This benefit was greater than expected from prior meta-analyses of epidemiological studies or trials in hypertension studies. The results have important implications for the primary and secondary prevention of stroke.
The protective effects of these drugs on the vascular wall are possibly explained by decreased oxidative stress and decreased proliferative and inflammatory responses resulting in a beneficial effect on the progression of atherosclerotic plaques. The anti-inflammatory response of angiotensin converting enzyme inhibition may lead to more plaque stabilization.
These causal concepts are supported by the SECURE study, a substudy in which progression of atherosclerosis was significantly reduced by ramipril compared with placebo. Importantly, the effect of a 10mg dose, as used in the HOPE study, was better than 2.5mg. This underlines the need for titrating ramipril to a higher dose to exploit its full preventive potential.
Since acetylsalicylic acid is one of the best documented treatments in secondary prophylaxis of stroke, the effectiveness of its combination with angiotensin converting enzyme inhibitors must be urgently proved.
Recombinant human parathyroid hormone
Osteoporosis is proving amenable to treatment
BMJ Vol.324, Feb.23, 2002, pg.435
On 27 July the US Food and Drug Administration held a public hearing on an application for a licence for the use of recombinant human parathyroid hormone in the treatment of postmenopausal osteoporosis. The application, from Eli Lilly, is for teriparatide (Forsteo), the N-terminal fragment rhPTH(1-34). The hearing’s advisory panel voted unanimously in favour of the parathyroid hormone. The parathyroid hormone given as a daily injection for several weeks or months in experimental animals, increases bone mass and strength. This evidence led to a multicentre randomised controlled trial in women with osteoporosis, which showed that treatment with parathyroid hormone reduced spine fractures by 66% to 90% and other fractures by 50%.
What can we hope of parathyroid hormone for the future? Currently it seems to be the most effective treatment for osteoporosis, although this apparent advantage will certainly be contested by the promoters of biphosphonates. Side effects have been few and mild. The need to inject the hormone with a penlike device, as used for insulin, is a slight nuisance, though perhaps preferable to the dyspepsia caused in some by biphosphonates. A licence application for Europe is pending. Authors still need to evaluate the effectiveness of parathyroid hormone in other forms of osteoporosis, and already data indicate that it is effective in steroid induced osteoporosis and osteoporosis in men.
Parathyroid hormone’s biggest untested impact might be in the prevention of hip fractures, because it expands the bony envelope in the hip and elsewhere. From being one of medicine’s most untreatable disorders, osteoporosis is following in the footsteps of hypertension and proving amenable to treatment through several targets: oestrogen receptors, osteoclasts (by targeting them with bisphosphonates) and now parathyroid hormone receptors. A fourth target just over the horizon might be the promotion of local nitric oxide synthesis in bone by statins.
Gwen L Zornberg, Hershel Jick
Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study.
The Lancet, vol.356; Oct.7, 2000: 1219-23
Aim of the study was to assess the risk of venous thromboembolism in users of conventional antipsychotic drugs who had been diagnosed with first-time, idiopathic venous thromboembolism.
Current exposure to conventional antipsychotic drugs was associated with a significantly increased risk of idiopathic venous thromboembolism compared with non-use. Although, authors found no difference between phenothiazines, thioxanthenes, or other conventional antipsychotic drugs, low potency antipsychotic drugs such as chlorpromazine and thioridazine were more strongly associated with venous thromboembolism than were high potency antipsychotic drugs such as haloperidol. The risk for venous thrombosis was highest during the first few months of conventional antipsychotic drug use.
Interpretation of this study is that current exposure to conventional antipsychotic drugs significantly increases the risk of idiopathic venous thromboembolism in men and women younger than 60 years of age.
Victor E Tapson
Commentary – Risk of venous thromboembolism with use of antipsychotic agents.
The Lancet, vol.356, Oct.7, 2000, pg.1206
The relation between antipsychotic medicines and venous thromboembolism (VTE) was first suggested about four decades ago, only a few years after the introduction of phenothiazines and reserpine. Despite these early descriptions and subsequent reports, the evidence for a true link has not yet been deemed sufficient for inclusion in lists of risk factors in standard textbooks or review articles on venous throboembolism. Many of the early studies lacked controls and convincing evidence of the absence of concomitant thrombogenic risk factors.
The case-control analysis by Gwen Zornberg and Hershel Jick reported in the Lancet suggests that this association should be re-examined.
Although this clinical study suffers from the usual limitations of a case-control design, the cohort was large (nearly 30000) and the observation period was long (mean 6.8 years). Also, the diagnosis of VTE was confirmed by objective tests, and patients with certain disease states that have not been clearly identified as risk factors (e.g. diabetes, cystic fibrosis, disorders due to alcohol and substance misuse) were also excluded, but this point would probably have affected both cases and controls equally. The attempt to exclude patients with other risk factors and to identify more clearly use of antipsychotic agents as a risk factor is important. However, it is quite possible that, in the presence of additional risk factors such as previous VTE, obesity, or cancer, antipsychotic agents may further enhance the risk of thromboembolism.
Commentary – Vagal nerve stimulation for epilepsy
Lancet, vol.357, June 2, 2001, pg.1726
Vagal-nerve stimulation (VNS) stops strychnine-induced seizures in dogs and pentylenetetrazol-induced seizures in rats. Chronic stimulation of the vagal nerve reduces the frequency of spontaneous seizures in monkeys with alumina-gel foci. The device consists of a pulse generator, a bipolar lead to stimulate the nerve, and a programming wand and software with handheld magnets capable of switching the stimulator on or off. The device is implanted to stimulate the left, rather than the right, vagal nerve, since stimulation on this side is less likely to cause cardiac effects.
This new technology has been well publicized in the media as an alternative to an increase in antiepileptic drugs in patients with chronic refractory epilepsy. The device can be easily implanted as a day-case procedure.
Current device shows that VNS has an unequivocal although modest therapeutic effect against complex partial seizures. A more complete understanding of VNS across the disorder of epilepsy is needed before its contribution to care can be assessed.
Chris Silagy, Neil Formica
Place of bupropion in smoking-cessation therapy.
The Lancet, vol.357, May 19, 2001, pg.1550
Reducing the number of current smokers is the single most important behavioural change that would substantially reduce morbidity and mortality associated with cigarette smoking. However, no effort to find a cure for tobacco dependence has led to strategies (pharmacological or non-pharmacological) close to fulfilling this role. The mainstays of therapy for tobacco dependence have focused on increasing successful quit attempts through the use of behavioural approaches and/or some form of nicotine-replacement therapy. Although such strategies have relative effectiveness approaching twice that of placebo, the absolute success rates are still small (5-15%), with increasing absolute success related to the intensity of therapy and follow-up. There has been little to differentiate the various forms of nicotine-replacement therapy from each other in clinical effectiveness, mainly because of lack of head-to-head trials with adequate follow-up.
In recent years interest has grown in the potential role of antidepressants as an effective aid to smoking cessation. Despite lack of evidence to support an effect of some of these agents (such as fluoxetine), others (such as nortryptiline and bupropion) have shown more promise. Their exact mode of action in smoking cessation is unclear but is thought to reflect their capacity to inhibit neuronal uptake of norepinephrine and dopamine rather than antidepressant activity.
Bupropion is the first antidepressant to be formally registered for use as a treatment for tobacco dependence.
The study reported in Lancet by D P Tashkin and colleagues is a placebo-controlled trial of bupropion among heavy smokers with chronic obstructive pulmonary disease. Although the relative effectiveness of the drug is similar to that in published studies, the absolute cessation rates are smaller (despite similar levels of counseling and only 6 months of follow-up data available so far). When taken into account with the existing data on the drug, this study provides further confirmation that bupropion is more effective than placebo.
Until the required research is done, the choice of whether or not to use bupropion as a first-line agent for smoking cessation will depend as much on whether it is available locally (and at what cost), as it will on the delicate trade-offs between the apparent evidence of benefit, set against the potential risk of serious side-effects, the need for supportive counseling, and the relative effectiveness compared with the more accessible and established forms of nicotine-replacement therapy.
Statins for stroke prevention
Lancet, vol.357, May 19, 2001, pg.1548
Cholesterol reduction by treatment with an HMG co-A reductase inhibitor (statin) seems to reduce the risk of stroke. A reduction in the risk of stroke was apparent only among patients with a history of coronary heart disease (CHD).
The first difficulty is that the rationale for cholesterol reduction to prevent stroke is not strong.
The available data therefore suggest that any patient with a history of ischaemic stroke or TIA and CHD and a cholesterol concentration greater than 5.0 mmol/L (or LDL cholesterol >3 mmol/L) is likely to benefit from cholesterol reduction with a statin. By constrast, it is premature to recommend routine use of statins for patients with ischaemic stroke or TIA (irrespective of age, or the presence of carotid atheroma) and no history of CHD, until the current trials and meta-analyses are available.
Targeted drugs taken center stage at US Cancer Meeting
Lancet, vol.357, May 19, 2001, pg.1593
Researchers attending this years annual meeting of the American Society of Clinical Oncology (ASCO) were clearly excited by results of several early phase I and phase II trials that suggest that new drugs that target specific molecular abnormalities in cancer cells may be extremely potent weapons against various cancers.
These new drugs, which target abnormal growth factor receptors and other cancer-causing proteins, will change the way doctors treat cancer in much the same way the discovery of antibiotics changed the way doctors treated infections, said Larry Norton head of the Division of Solid Tumour Oncology at Memorial Sloan-Kettering Cancer Centre (New York)
The studies that gained the greatest attention were trials of the compound imatinib mesylate. This drug,which is being marketed in the USA as Gleevec, was granted accelerated approval by the US Food and Drug Administration (FDA) after it had been shown to be extremely potent against chronic myelogenous leukaemia (CML). The compound is a small molecule that blocks an abnormal tyrosine kinase, BCL-ABL, that seems to be the key molecular defect leading to uncontrolled cell growth in CML.
Earlier this year, Brian Druker of Oregon Health Sciences University (Portland, OR, USA) reported the results of a dose-escalating phase I study that indicated that a dose of 300 mg per day induced complete haematological responses in 53 of 54 patients for whom standard CML treatment with interferon ? had previously been ineffective or not tolerated. And a related study showed the drug could also induce responses in patients with CML and acute lymphoblastic leukaemia who were in blast crises.
The new studies presented at the ASCO meeting were phase I and phase II trials of imatinib mesylate in patients with a rare form of tumours, called gastrointestinal stromal tumours (GISTs) which arise from the precursor cells of the connective tissue of the gut. Another abnormal tyrosine kinase growth factor, C-KIT, is thought to play a key role in the pathogenesis of these tumours. GISTs usually do not respond to chemotherapy or radiation therapy and if not resected successfully are usually rapidly fatal.
In another phase II trial reported at the meeting, cetuximab was found to shrink metastatic colorectal cancer tumours in patients with chemotherapy-resistant disease. Cetuximab is a monoclonal antibody that blocks epidermal growth factor receptors (EGFR), cell membrane proteins found in colon and several other tumours that when stimulated drive cancer cell division and protect the cells from apoptosis. All of the 121 patients in the trial had tumours that had failed to respond to courses of standard chemotherapy with fluorouracil and irinotecan. All patients had tumours that expressed EGFR.
In the trial, the patients were treated with irinotecan again but this time in combination with cetuximab. 27 (22.5%) of the patients had a partial response, which was defined as a greater than 50% reduction in tumour size.
Results from the trials of the antiangiogenesis drugs were less encouraging. Several trials suggested that the drugs clearly have antitumour activity but that the extent of the activity will vary not only from patient to patient but from tumour to tumour and even within a tumour.
Science, medicine and the future – Microdialysis
BMJ, VOL.324, March 9, 2002, pg.588
Monitoring tissue chemistry in patients by microdialysis is likely to become routine in clinical paractice.
Many diagnostic and therapeutic decisions in medical practice are based on measuring blood concentration of endogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Assessing tissue chemistry should theoretically provide more accurate data, and this can now be achieved relatively cheaply and minimally invasively with microdialysis.
Principles of microdialysis
In vivo microdialysis measures the chemical composition of the interstitial tissue fluid- that is, the fluid to which cells and other target structures are directly exposed. In contrast to imaging techniques or biosensors, which serve as detecting tools, microdialysis is a sampling tool and needs to be linked to an analytical device. Depending on the availability of an appropriate analytical assay, virtually every soluble molecule in the interstitial space fluid can be measured by microdialysis. In recent years, the use of microdialysis has moved from preclinical evaluation and validation to clinical application, reflected by a considerable growth in the literature.
The concept of microdialysis goes back to the early 1960s, when push-pull cannulas, dialysis sacs, and dialytrodes were inserted into animal tissues to study tissue biochemistry directly.
Microdialysis enables the in vivo measurement of tissue chemistry in humans and is feasible in virtually every human organ.
It is currently being used to monitor brain ischaemia and metabolic control.
The technique is set to become a standard tool in drug monitoring and development.
In the future “bedside” microdialysis will allow monitoring of tissue metabolism in a wide range of diseases.
Current clinical research applications of microdialysis
Elucidating the chemical basis for initiation of seizures (such as pre-epileptic increase in glutamate and a consecutive surge in γ-aminobutyric acid).
Studying neurochemical patterns in defined brain areas (such as increased dopamine release in human amygdala during performance of cognitive tasks).
Studying local physiology of adipose tissue, muscle, and skin.
Measuring peptides and metabolites at site of action or release and describing paracrine regulations in select organs or tissues such as the ovary and subcutaneous fat.
Administering drug locally by microdialysis without inducing systemic side effects and simultaneously measuring the corresponding tissue response, such as catecholamine induced lipolysis.
Robert S. Rosenson (Northwestern University Medical School, Preventive Cardiology Center, Division of Cardiology, Chicago, U.S.A.)
Lipid Lowering Therapy as an Important Adjunct to Stroke Prevention in Coronary Heart Disease Patients
Drugs of Today, Vol. 37(11), November 2001, Pg. 731-738
Lipid altering pharmacotherapy has been shown to reduce stroke in coronary heart disease (CHD) patients. Several mechanisms of cerebrovascular protection attributed to these agents include reduction in embolic stroke from cardiac, aortic and carotid sites, delayed progression of carotid stenoses, stabilization of vulnerable carotid atherosclerotic plaque and improvement in cerebral blood flow.
Hypercholesterolemia has not been considered an important risk factor for stroke. Nevertheless, clinical trials of lipid altering pharmacotherapies in CHD patients have been accompanied by reductions in strokes and/or transient cerebral ischemia and the need for carotid endarterectomy.
Retrospective analysis of clinical trials in CHD patients demonstrates that lipid lowering therapy (statins, nicotinic acid and fibric acid derivatives) reduce stroke and transient ischemic attacks. Until prospective clinical trials of stroke prevention are completed in subjects without established CHD, prevention of further myocardial damage with lipid lowering therapies will decrease left ventricular dysfunction, mural thrombus and cardioembolic stroke.
Statins delay progression of carotid atherosclerosis, stabilize carotid atherosclerotic plaque and reduce the propensity for plaque rupture, an important distinguishing feature in symptomatic carotid artery disease and rapid growth of atherosclerotic lesions.
Lipid altering pharmacotherapy should be used for long-term preventive therapy in the stroke-prone patient. In experimental animal studies, statin therapy has a beneficial effect in acute stroke through NO mediated improvement in cerebral blood flow and consequent reduction in stroke size and less neurological deficits.
It remains to be determined whether lipid-altering therapies prevent stroke or limit cerebral infarction and neurological deficits in humans at high risk for stroke.
A. R. Chogle
Editorial – Multidrug Resistant Salmonellosis: An Escalating Problem
JAPI, Vol. 50, March 2002, Pg. 375-377
Multidrug resistant (MDR) Salmonella typhi has been prevalent in India since 1989. These bacteria are resistant to chloramphenicol, ampicillin and trimethoprim/sulfamethoxazole.
Like chloramphenicol resistance, resistance to ampicillin and trimethoprim is plasmid encoded. In 1990, there were epidemic outbreaks of multidrug resistant Salmonella typhi in different parts of India and three reports from urban hospitals in Delhi, Calcutta and Bombay were published in the Journal in 1991.
Adhikari and Baliga report a case of ciprofloxacin resistant typhoid fever in a 17 years old male who showed an incomplete response to cefotaxime. This report highlights several important issues in the management of typhoid fever but more importantly it raises the possibility that the problem of multidrug resistance in Salmonella is escalating.
Fluoroquinolone-resistant Enterobacteriaceae took 10 years to emerge clinically. To these vancomycin-insensitive Staphylococcus aureus and erythromycin-resistant Strep. Pyogenes can be added.
Patients infected with NARST strains need to be treated with higher doses of ciprofloxacin or longer courses of ofloxacin or with other antibiotics to which the strains are sensitive.
Fourth, once resistance appears, it is likely to decline slowly, if at all. There are no counter-selective measures against resistant bacteria. The slow loss of resistance is linked to poorly reversible genetic and environmental factors.
However, recent reports from centres in India have shown increase in sensitivity of Salmonella typhi to chloramphenicol, ampicillin and co-trimoxazole which have been rarely used in treatment of typhoid in the last few years.
Fifty, the use of antibiotics by any one person affects others in the extended as well as the immediate environment. In this context, it is pertinent to note that in the case reported by Adhikari and Baliga two of the patient’s cousins had recently suffered from ciprofloxacin-resistant typhoid proven by blood culture.
Ceftriaxone, cefotaxime, ceftazidine and cefoperazone are some of the third generation cephalosporins, which have been used in the treatment of typhoid. These are expensive drugs and should be used discreetly. Indications for their use are
a) Ciprofloxacin – resistant typhoid.
b) Typhoid meningitis
c) Typhoid fever in pregnancy, children less than 17 years of age, and G6PD deficiency, where quinolones are contraindicated.
d) When quinolone therapy produces or aggravates psychosis.
In India particularly, ciprofloxacin is widely available sometimes even without a prescription. As a result of this there is a misuse of this drug even for viral infections. Prevention of such type of misuse will lower the probability of drug resistance and result in protection of susceptible commensal bacteria in the environment which are the chief allies in reversing the crisis of multidrug resistance.