UNMET THERAPEUTIC NEEDS IN THE MANAGEMENT OF ACUTE ISCHEMIA
Summary: Unstable angina and myocardial infarction (MI) continue to present a major challenge in clinical management. These acute ischemic coronary syndromes (AICS) are a spectrum of clinical presentations of the same pathophysiologic mechanism: thrombus formation superimposed on atherosclerotic plaque disruption or erosion. Current approaches to the management of AICS, which include both interventional and pharmacologic therapy, have been introduced to clinical practice during the past 20 years, and most of them have demonstrated efficacy in clinical studies. A common inadequacy of current therapies, however, is the lack of significant inhibition of platelet aggregation the crucial event in the formation of coronary thrombi and the pathogenesis of AICS. The final common pathway to platelet aggregation is the activation of the platelet glycoprotein (GP) IIb-IIIa receptor, which allows the cross-linking of adjacent platelets by the adhesive plasma proteins fibrinogen and von Willebrand's factor. The emergence of the GP IIb-IIIa receptor as a potential treatment target has led to the development of several inhibitors of its function. The inhibitors most advanced in clinical development are the chimeric monoclonal antibody abciximab (ReoPro) and the cyclic peptide eptifibatide (INTEGRILIN). In phase III clinical trials, both abciximab and eptifibatide have been shown to reduce the incidence of cardiac events in patients at risk for abrupt vessel closure after coronary angioplasty. Inhibition of the GP IIb-IIIa receptor is the most promising novel approach to the treatment of unstable angina and MI, and it may soon be an indispensable component of the management of patients with AICS.
Comment: Thrombus formation on the atherosclerotic plaques is certainly a key-step in the pathophysiologic chain of events of AICS. The newly-advented platelet GP IIb-IIIa receptor inhibitors, although promising, are not thoroughly investigated and are still unavailable in third world countries. Acetylsalicylic acid (ASA), which has served modern medicine for more than a century primarily as an antipyretic and pain-killer, now through its irreversible blockade of platelet-derived thromboxane-A2 production, is known as the standard antiplatelet aggregation agent in use. Many studies, however, revealed underutilization of this cheap, safe and efficient drug. Another recent study, indicated that more than half of the patients who had the definitive diagnosis of acute MI, had not received ASA in the emergency room (ER). Moreover, the same study disclosed that about 80% of those who did receive ASA, took it more than half an hour after arrival at the ER. To reduce the extent of pathology, whenever not contraindicated, administration of adequate ASA to a patient with suspected MI is suggested as soon as possible. Because tertiary-level medical facilities are not available readily in all areas of developing countries, and since in most of these centers, the door-to-needle time is usually markedly longer than that of developed countries, the used for early administration of ASA should be emphasized in the developing countries.
Farrokh Habibzadeh, M.D., Shiraz, Iran
Source: White HD. Am J Cardiol 1997; 80(4A):2B-10B
CLARITHROMYCIN-RESISTANT HELICOBACTER PYLORI IN PATIENTS WITH DUODENAL ULCER IN THE UNITED STATES
Summary: Background: Clarithromycin is a key component of several antimicrobial treatment regimens for Helicobacter pylori. Cure rates with clarithromycin-containing regimens are significantly decreased when resistance is present. Resistance develops by a point mutation in the ribosomal RNA of some organisms exposed to clarithromycin. We studied the prevalence of clarithromycin-resistant organisms in patients with duodenal ulcer in the United States from 1993-96. Methods: Patients with endoscopic evidence of a duodenal ulcer were studied. Gastric biopsies were culturer forH. pylori and antimicrobial sensitivity was determined by the E-test (epsilometer agar diffusion gradient). Results: In 1993-94, three of 78 patients (4%) had clarithromycin-resistant strains of H. pylori. In 1995-96, 44 of 348 patients (12.6%; p=0.025) had resistant strains of H. pylori. Patients who had previously failed antimicrobial treatment for H. pylori accounted for much of the increase in resistant strains (25%). Conclusions: Failed therapy with clarithromycin-based regimens is a growing cause of antimicrobial resistance in H. pylori in the United States. Whereas the overall rates of primary resistance are low, the increase in secondary resistance over a short period of time is worrisome. New treatments that prevent the emergence of resistance may be important in the future.
Comment: Clarithromycin, the most potent antibiotic available against H. pylori, is presently one of the major drugs used in combination therapy regimens for H. pylori eradication. It is usually prescribed along with amoxicillin or metronidazole and a proton pump blocker such as omeprazole. Clarithromycin is expensive and is not currently available in many developing countries including Iran.
Our experience has shown that the rate of in vitro primary resistance of H. pylori to clarithromycin is about 12% in Iran. This is 3 times higher than the rates reported in the USA. The rate of secondary resistance may rise even higher if the drug becomes widely available in Iran.
Meanwhile clinical trials in Iran and China have clearly shown that the cheap furazolidone a long known antibiotic is at least as effective as clarithromycin against H. pylori.
Till now our in vitro studies have detected no H. pylori strain resistant to furazolidone. The main drawback seems to be that up to 15% of patients cannot tolerate side effects caused by furazolidone.
We recommend that furazolidone be prescribed as a first line drug in combination therapies and that clarithromycin be used in instances where furazolidone could not be tolerated. This strategy is not only more cost effective but would defer the development of clarithromycin resistance.
Reza Malekzadeh, M.D., Tehran, Iran
Source: Vakil N, Hahn B, McSorley. Am J Gastroenterol 1998; 93:1432-5.
MOSQUITOES AND MOSQUITO REPELLENTS: A CLINICIAN'S GUIDE
Summary: This paper is intended to provide the clinician with the detailed and scientific information needed to advise patients who seek safe and effective ways of preventing mosquito bites. For this review, clinical and analytical data were selected from peer-reviewed research studies and review articles, case reports, entomology texts and journals, and government and industry publications. Relevant information was identified through a search of the MED-LINE database, the World Wide Web, the Mosquito-L electronic mailing list, and the Extension Toxicology Network database; selected U.S. Army, U.S. Environmental Protection Agency, and U.S. Department of Agriculture publications were also reviewed.
N, N-diethyl-3-methylbanzamide (DEET) is the most effective, and best studied, insect repellent currently on the market. This substance has a remarkable safety profile after 40 years of worldwide use, but toxic reactions can occur (usually when the product is misused). When DEET-based repellents are applied in combination with permethrin-treated clothing, protection against bites of nearly 100% can be achieved. Plant-based repellents are generally less effective than DEET-based products. Ultra-sonic devices, outdoor bug "zappers," and bat houses are not effective against mosquitoes. Highly sensitive persons may want to take oral antihistamines to minimize cutaneous reactions to mosquito bites.
Comment: As mentioned in the abstract, this is a review article on insect repellents, in particular DEET, in the prevention of mosquito bites. After elaborating on the importance of mosquito borne diseases (700 million cases annually), the role of personal protection by use of insect repellents, and the mosquito life cycle, the author describes stimuli that attract mosquitoes and the way insect repellents counteract some of these attractants. Among these repellents, DEET is claimed as the most effective chemical and a table gives the list of repellents that contain DEET, their formulation, their efficacy relative to the formulation and concentration of DEET. The best ones are those containing 35% of this chemical. The damaging effect of DEET on plastics (such as eye glass frames), some synthetic fabrics, leather and other materials are described. DEET is quite safe, but when used, the whole exposed skin should be cured. Some other repellents available on the market in the USA are also discussed, including plant-derived repellents containing repellent oils such as citronella, geranium, pine, thyme garlic and others, but none of these are as effective as DEET. The author believes that the best protection is to wear perthrin impregnated clothing and to use DEET containing repellents on exposed skin. None of the DEET containing materials mentioned in the paper are available on the Iranian market.
Abolhassan Nadim, M.D., Tehran, Iran
Source: Fradin MS. Ann Intern Med 1998; 128:931-40.
SINGLE DOSE VITAMIN A TREATMENT IN ACUTE SHIGELLOSIS IN BANGLADESHI CHILDREN: RANDOMISED DOUBLE BLIND CONTROLLED TRIAL
Summary: Objective: to evaluate the efficacy of a single large oral dose of vitamin A in treating acute shigellosis in children in Bangladesh. Design: Randomized double blind controlled clinical trial. Setting: Dhaka Hospital, International Center for Diarrhoeal Disease Research, Bangladesh. Subjects: 83 children aged 1-7 years with bacteriologically proved shigellosis but no clinical signs of vitamin A deficiency; 42 were randomized to treatment with vitamin A and 41 formed a control group. Intervention: Children were given single oral dose of 200000 IU of vitamin A plus 25 IU vitamin E or a control preparation of 25 IU vitamin E. Main outcome measures: Clinical cure on study day 5 and bacteriological cure. Results: Baseline characteristics of the subjects in the two treatment groups were similar. Significantly more children in the vitamin A group than in the control group achieved clinical cure 19/42 (45%) v 8/14 (20%); c 2=514,1 df, p=0.02; risk ratio -0.68 (95% confidence interval: 0.50 to 0.93). When cure was determined bacteriologically, the groups had similar rates (16/42 (38%) v 16/41 (39%); c 2 =0.02,1 df, p= 0.89; risk ratio=0.98 (0.70 to 1.39). Conclusions: Vitamin A reduces the severity of acute shigellosis in children living in areas where vitamin A deficiency is a major public health problem.
Comment: It is evident that the mortality/morbidity rate of infectious diseases increases in the presence of protein and vitamin deficiency and currently some of the vitamins including vitamin E are used as anti-oxidants. Among these vitamins the role vitamin A plays in the health and integrity of the mucosae has been identified,the best example is xerophthalmia caused by vitamin A deficiency which prones the eyes to the infectious agents leading to blindness. According to this article, vitamin A has no direct effect on Shigella. Although vitamin A supplementation in malnourished patients (including vitamin A deficiency) with shigella potentiate the mucosal repair and give better therapeutic results, its effectiveness in the absence of vitamin A deficiency is not clear. It must be considered that not only vitamin A but also all deficient nutritional elements must be identified and replaced in malnourished patients with infectious disease to improve prognosis and further reduce mortality and morbidity from infectious processes.
Ali Reza Yalda, M.D., Tehran, Iran
Source: Hossain S, Biswas R, Kabir I, et al. BMJ 1998; 316(7):422-5.
INTERFERON ALFA-2b ALONE OR IN COMBINATION WITH RIBAVIRIN AS INITIAL TREATMENT FOR CHRONIC HEPATITIS C
Summary: Background: Only 15 to 20 percent of patients with chronic hepatitis C have a Sustained virologic response to interferon therapy. We compared the efficacy and safety of recombinant interferon alfa-2b alone with those of a combination of interferon alfa-2b and ribavirin for the initial treatment of patients with chronic hepatitis C. Methods: We randomly assigned 912 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin (1000 or 1200 mg orally per day, depending on body weight) for 24 or 48 weeks. Efficacy was assessed by measurements of serum hepatitis C virus (HCV) RNA and serum aminotransferase and by liver biopsy. Results: The rate of sustained virologic response (defined as an undetectable serum HCV RNA level 24 weeks after treatment was completed) was higher among patients who received combination therapy for either 24 weeks (70 of 228 patients, 31 percent) or 48 weeks (87 of 228 patients, 38 percent) than among patients who received interferon alone for either 24 weeks (13 of 231 patients, 6 percent) or 48 weeks (29 of 225 patients, 13 percent)(P<0.001 for the comparison of interferon alone with both 24 weeks and 48 weeks of combination treatment). Among patients with HCV genotype 1 infection, the best response occurred in those who were treated for 48 weeks with interferon and ribavirin. Histologic improvement was more common in patients who were treated with combination therapy for either 24 weeks (57 percent) or 48 weeks (61 percent) than in those who where treated with interferon alone for either 24 weeks (44 percent) or 48 weeks (41 percent). The drug doses had to be reduced and treatment discontinued more often in patients who were treated with combination therapy. Conclusions: In patients with chronic hepatitis C, initial therapy with interferon and ribavirin was more effective than treatment with interferon alone.
Comment: Results of these studies are promising and are clearly a step forward in the treatment of hepatitis C, although further studies are necessary before final approval can be made. In developing countries such as Iran, the option of ribavirin augmentation to interferon treatment of HCV is limited. Primarily the cost of combination therapy is so high that most patients and health services cannot afford. Second and probably more importantly, is the fact that approximately 90% of patients with chronic HCV infection in Iran are high risk individuals (e.g. patients with hemophilia, thalassemia major, chronic renal failure patients undergoing dialysis) who already suffer from anemia and are therefore, more vulnerable to ribavirin's hemolytic side effects.
Meanwhile, the experience with HIV and HBV infections has clearly shown that combination therapy comprised of two or more antiviral agents is much more effective than monotherapy.
Many other antiviral agents will be available for the treatment of viral hepatitis in the future. We should carefully select the most effective, safe and less costly regimens for the majority of our HCV patients, most of whom belong to the high risk groups.
Reza Malekzadeh, M.D., Tehran, Iran.
Source: McHutchison JG, Gordon SC, Schiff ER, et al. N Engl J Med 1998; 339:1485-92.
TYPHOID FEVER VACCINES: A META-ANALYSIS OF STUDIES ON EFFICACY AND TOXICITY
Summary: Objective: To estimate the efficacy and toxicity of typhoid fever vaccines. Design: Meta-analysis of randomized efficacy trials and both randomized and non-randomized toxicity studies of the parenteral whole cell, oral Ty21a, and parenteral Vi vaccines. Subjects: 1866951 subjects in 17 efficacy trials; 11204 subjects in 20 toxicity studies. Main outcome measures: pooled estimates of three year cumulative-efficacy, year specific efficacy, and incidence of adverse events. Results: Three year cumulative efficacy was 73% (95% confidence interval 65% to 80%) for two doses of whole cell vaccines (based on seven trials); 51% (35% to 63%) for three doses of Ty21a vaccine (four trials); and 55% (30% to 71%) for one dose of Vi vaccine (one trial), for whole cell and Ty21a vaccines, regimens of fewer doses were less effective. Efficacy was shown to be significant for five years for whole cell vaccines, four years for Ty21a vaccine, and two years for Vi vaccine. Neither the age of vaccine recipient nor the incidence of typhoid fever in the control group (varying from 6 to 810 cases per 100000 person years) affected the efficacy of the whole cell or Ty21a vaccines. After vaccination, fever occurred in 15.7% (11.5% to 21.2%) of whole cell vaccine recipients, 2.0% (0.7% to 5.3%) of Ty21a vaccine recipients, and 1.1% (0.1% to 12.3%) of Vi vaccine recipients. conclusions: Whole cell vaccines are more effective than the Ty21a and Vi vaccines but are more frequently associated with adverse events. Whether the added efficacy of the whole cell vaccines outweighs their toxicity will depend on the setting in which vaccination is used.
Comment: Typhoid infection or enteric fever remains a substantial medical problem in developing countries. An annual incidence of more than 33 million and 500,000 deaths are recorded. Currently, three types of preventive vaccines are available. The first one is a killed anti-salmonella typhi vaccine. The two other vaccines developed more recently comprise Ty21a which is a live attenuated strain of S. typhi administered orally and Vi vaccine which is purified bacterial capsule given parenterally. Administration of one of these vaccines is recommended to everyone who travels to the endemic countries. In order to assess efficacy and toxicity of these vaccines about 2 million subjects were enrolled in 17 efficacy trials and about 11000 subjects have been studied in toxicity trials.
According to these studies, two parenteral doses of killed vaccine, three oral doses of Ty21a vaccine and one parenteral dose of Vi vaccine produced immunity of 5,4 and 2 year duration respectively. Although the killed vaccine is more effective but the other two vaccines are preferred generally due to their less adverse effects. Decision as to the selection of type of vaccine in the third world countries including Iran depends not only on their adverse effects but also on settings like availability of the vaccine, manufacturing expenses and provision or purchase expenditure, existence or absence of natural immunity etc.
It must be considered that none of the three aforementioned vaccines against typhoid fever is suggested by WHO in the Expanded Program of Immunization in children under the age of one year. In our opinion, with good environmental hygiene and public education, there should be no need for mass vaccination in our country.
H. Mirchamcy, D.V.M., Tehran, Iran.
Source: Engels EA, Falagas ME, Lau J, Bennish ML. Br Med J 1998; 316: 110-6.