W H O DRUG

INFORMATION V O L U M E 5 • N U M B E R 3 • 1 9 9 1

R E C O M M E N D E D I N N L I S T 3 1 I N T E R N A T I O N A L N O N P R O P R I E T A R Y N A M E S F O R P H A R M A C E U T I C A L S U B S T A N C E S

W O R L D H E A L T H O R G A N I Z A T I O N • G E N E V A

WHO Drug Information

WHO Drug Information provides an overview of topics relating to drug development and regulation that are of current relevance and im­portance, and will include the lists of proposed and recommended In­ternational Nonproprietary Names for Pharmaceutical Substances (INN). Its contents reflect, but do not present, WHO policies and ac­tivities and they embrace socio­economic as well as technical mat­ters.

The objective is to bring issues that are of primary concern to drug regulators and pharmaceutical manufacturers to the attention of a wide audience of health profes­sionals and policy-makers con­

cerned with the rational use of drugs. In effect, the journal seeks to relate regulatory activity to therapeutic practice. It also aims to provide an open forum for debate. Invited contributions will portray a variety of viewpoints on matters of general policy with the aim of stimulating discussion not only in these columns but wherever rel­evant decisions on this subject have to be taken.

WHO Drug Information is pub­lished 4 times a year in English and French.

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© World Health Organizat ion 1991

Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. For rights of reproduc­tion or translation, in part or in toto, applica­tion should be made to: Chief, Office of Publications, World Health Organization, 1211 Geneva 27, Switzerland. The World Health Organization welcomes such applica­tions.

The designations employed and the presen­tation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concern­ing the delimitation of its frontiers or boun­daries.

Authors alone are responsible for views expressed in signed contributions.

The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar na­ture which are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

ISSN 1010-9609

Volume 5, Number 3, 1991 World Health Organization

WHO Drug Information Contents

General Policy Topics Drug promotion and education: an uncertain

interface Cost-effectiveness studies: the bias of

sponsorship

Reports on Individual Drugs First-line treatment of asthma: inhaled

corticosteroids or bronchodilators? Permethrin, bed nets and malaria Penicillin prophylaxis and rheumatic

heart disease Cancer chemotherapy in childhood: no

evidence of second generation sequelae Folate supplements and neural tube defects Encephalitis following treatment of loiasis Oral ribavirin: promising results in hepatitis C Rifampicin: more concerns about bioavailability

General Information Terminal cancer care: unorthodox treatment

put to the test Antiseptics for vascular catheters HIV infection and health-care costs Oral rehydration therapy: its place in the

developed world

Regulatory Matters Isotretinoin: further labelling changes "Activated" cyclophosphamide: a bone marrow

purging agent Second anti-HIV drug receives tentative

approval Fenoterol: reduced dosage recommendations Fludarabine: second-line therapy for chronic

lymphatic leukaemia Alglucerase for Gaucher's disease Interferon alfa: also effective in hepatitis C

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Noscapine: polyploidy in vitro Conjugated estrogens: withdrawal of

generic versions Sargramostim (granulocyte macrophage

colony-stimulating factor) Terfenadine and ketoconazole: ventricular

arrhythmias Triazolam: safety under review

Advisory Notices Cloxacillin: interaction with anticoagulants Clozapine: dose-related convulsive episodes Flecainide: long-term use adverse effects Health claims on food labels Latex sensitivity: evidence of increasing

prevalence Ivermectin: possible neurotoxicity Breast implants: more safety queries Omeprazole: diarrhoea and skin reactions

Essential Drugs Systemic mycoses Amphotericin B Fluconazole Flucytosine Ketoconazole Corrigenda concerning dosage of

amphotericin B

Recent Publications Local, small-scale preparation of eye drops WHO Model Prescribing Information: Drugs

used in mycobacterial diseases Basic tests for pharmaceutical dosage forms Medications that increase sensitivity to light

Recommended International Nonproprietary Names: List 31

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General Policy Topics

Drug promotion and education: an uncertain interface Pharmaceutical companies, it is increasingly claimed, have cultivated a pervasive influence on the prescribing practices of doctors. No longer are companies simply involved in advertising their products through manufacturers' representatives, direct mailings and, more widely, through publicity in journals. They have also become influential sponsors of medical education and scientific exchange. In 1988, within the United States alone, it is estimated that 16 selected pharmaceutical companies sponsored a total of 34 688 symposia at a cost exceeding $US 85 million (1). The increase in this type of activity over the past decade has been described as dramatic. Undoubtedly, many of these commercially-sponsored meetings provide excellent opportunities for scientific debate and are of uncontested importance in informing and educating the medical professions. Inevitably, however, both the participants and the sponsoring companies need constantly to question the extent to which these gatherings are truly educational and the extent to which they constitute a veiled promo­tional gambit.

It is vital, both for the image of the medical profes­sions and the reputation of the industry, that promotional and educational activities remain distinct and demonstrably segregated, and that independent professionals are never employed, knowingly or naively, to lend their names to commercial objectives. At issue are more than commercially-sponsored symposia. Programmes of post-graduate medical education, press releases and press conferences, videotaped news releases, subsidized journals, special supplements and other materials that escape peer review in established medical journals are all targets for sponsorship that are potential prey to commercial abuse.

These are concerns that have been voiced by Dr David Kessler at the outset of his tenure as Commissioner of the US Food and Drug Adminis­tration (2). He has lost no time in affirming the FDA's commitment to regulatory action when it finds such activities "to be misleading, unbalanced, or otherwise promotional with regard to the sponsor's product". He is plain in his castigation of

receptive professionals as well as unprincipled companies in wilfully blurring the line between science and commerce. Nor has he left any doubt that regulatory action can be applied as readily and as effectively to individuals as to institutions. He concludes that "an aggressive alliance between the FDA and the medical community is vital if scientific and educational activities are to retain their rigour and intellectual credibility. The FDA is determined to ensure that the promotional activities of pharma­ceutical firms are identifiable as such and that they conform to the laws. To succeed in this demanding task, the agency needs the cooperation of the country's physicians".

As a consequence of its mandate and its powers of enforcement the US FDA is uniquely placed to react with determination to abuse of commercial privilege wherever it is found. In less developed countries, because of lack of resources, authority is less commanding. Yet, because these countries are of small significance within the world market for pharmaceutical products, they might be expected to offer scant incentive for questionable promotional activity. Here, more than anywhere, international companies possess the opportunity and the challenge to demonstrate their capacity for effective self-regulation. Altruism, of course, is perennially compromised by local managers mindful of their balance sheets. Yet exemplary commitment to principle does exist within globally-represented companies. Some have already instituted rigorous yet practicable codes of conduct for both clinical research and marketing that are backed by meaningful central monitoring activities intended to assure the respect and compliance of all subsidi­aries and affiliates.

A basic demand, among many others, is that drug advertising should be clearly recognizable to everyone for what it is. Education and research fit uneasily into the ambit of a marketing department. Not so many years ago companies themselves sensed the need for clear segregation of these activities. Some created independently managed foundations and trusts. Several of these became prestigious centres of free scientific expression and academic excellence. Some paid particular attention to problems specific to the developing world. They have lost none of their relevance today.

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Companies would be performing a service to themselves, to the health professions and to the patient if they were to set back the clock and re­establish themselves, through these bodies, as patrons of education unfettered by commercial considerations.

References

1. Senate Labor and Human Resources Committee, Congressional Research Service. Survey of selected pharmaceutical firms. Government Printing Office, Washington, D.C., 1991.

2. Kessler, D.A. Drug promotion and scientific exchange: the role of the clinical investigator. New England Journal of Medicine, 325: 201-203 (1991).

Cost-effectiveness studies: the bias of sponsorship The costs of health care delivery are of constant and crucial concern both to the public and private institutions that pay the bills and to the manufac­turers and contractors that supply the services. The former are committed to cost containment, the latter to competitive edge. Both have need for economic intelligence for effective strategic planning. The required analyses are commonly undertaken by independent academic researchers. But the funding is nearly always provided by an interested party, more commonly the supplier rather than the payer. Pharmaceutical companies them­selves sponsor most academic research into the cost-effectiveness of pharmaceuticals. To what extent can this generate bias sufficient to influence the results?

A potential conflict of interest must exist whenever the sponsor of a study stands to benefit from a favourable analysis. The same concern applies to clinical research undertaken in the course of pharmaceutical product development. Indeed, the responsibilities of independent clinical investigators have long been an evergreen topic for debate (1-4). No one would claim that the relationship between researcher and sponsor is without problems or that abuse cannot occur (5, 6). But many critics have long conceded that the relationship is both neces­sary and inevitable, and that, on balance, the independence of the parties enhances objectivity and operates to the public interest.

Can the sponsorship of cost-effectiveness studies be viewed in the same light? Or do a different set of

circumstances apply? The case for developing specific guidelines for the conduct of such research has recently been reviewed in the columns of the New England Journal of Medicine (7). It is pro­posed, from the vantage point of experience, by staff of the Institute of Health Economics within the University of Pennsylvania, a group that has performed 33 economic analyses for 15 pharma­ceutical companies since 1978. While, in many instances, they consider their partnership with companies to have been exemplary, they do not underplay the problems: "flagrant, intentional attempts by researchers or companies to manipu­late results are rare, but other practices are not. For example, review of manuscripts before publication is usual, attempts to fund only positive studies are the rule, and incentives for investigators to make favourable assumptions are ever present".

Seen from the company's perspective, economic analyses are potential marketing devices (3). They are typically funded and overseen, not by medical or scientific divisions, but by marketing departments that are concerned with the exigencies of the marketplace and the potential effect of the findings on sales volume. Moreover, the analytical methods that are applied to these studies are as yet still evolving and unstandardized; many editors and reviewers are unfamiliar with the principles on which they are based; and neither the research protocols nor the results are supervised by any external agency. Bias is evidently less readily detected and prevented than in other forms of research.

In these circumstances, the Pennsylvania group offers a series of eight recommendations, that address the following principles, to sponsors and investigators that are intended to provide a stan­dard for work that may be used in a marketing context in "an increasingly sceptical and competi­tive market place":

1. Funding for such studies should be in the form of research grants to individuals rather than contracts that are payable to institutions. Agreements should stipulate that the findings may be published regardless of the outcome of the study and that the investigator shall retain sufficient access to propri­etary data to allow completion of the research even if funding is withdrawn.

2. Study designs should be based on comparators that are selected for their clinical relevance and not on commercial grounds. Whenever possible, those used for controlled clinical studies required for

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registration purposes should be included. The published report of the research should be explicit about the comparators used and those that were excluded. Data from all relevant studies, rather than a selected subset, should be made available to the investigator.

3. Investigators should be permitted to extend the study design to include additional types of costs, economic perspectives, and comparators. Any constraints in this regard should be clearly de­scribed in the published report.

4. When funding is provided in instalments, results should not be provided to the sponsor until publica­tion is guaranteed and funded.

5. The hypotheses inherent in the design should be clearly identified; they should in no manner be biased toward the results sought by the funding company (8-9); the design should enable them to be examined with acceptable statistical power, and all relevant details should be included in the published report.

6. Valid results should be published regardless of their promotional significance to the sponsoring company. Editors of journals should try to avoid bias against publishing negative results (10-12).

7. Investigators conducting sponsored research should not act as consultants, during the active period of their grants, in relation to the products on which they are working. Journal editors should require that all financial relationships between authors, sponsoring companies and their direct commercial competitors should be disclosed, including equity interests other than ownership of shares in mutual funds.

8. Investigators should ensure that the conditions of sponsorship enable methodologically sound studies with adequate statistical power to be completed.

To what extent could regulation help to enforce such standards? The Pennsylvania group remarks that the relatively few economic analyses spon­sored by federal agencies in the United States are already subjected to peer review before funding. If privately-sponsored economic research were submitted to similar independent review, standard­ization of approach and of experimental method would be fostered and companies could be required to provide explicit funding from scientific depart­ments, rather than including it on a discretionary basis in marketing budgets. Its conclusion, none the

less, is that regulation introduced before the scientific and administrative ground rules are better defined would certainly invite controversy and could well operate in a way that is counter-productive to the immediate objectives.

References

1. American Federation for Clinical Research National Council. Guidelines for avoiding conflict of interest. Clinical Research, 38: 239-240 (1990).

2. Ad Hoc Committee on Medical Ethics. American College of Physicians. Ethics manual: Part II. Research, other ethical issues: recommended reading. Annals of Internal Medicine, 101: 263-274 (1984).

3. Council on Scientific Affairs and Council on Ethical and Judicial Affairs. Conflicts of interest in medical center/ industry research relationships. Journal of the American Medical Association, 263: 2790-2793 (1990).

4. The Royal College of Physicians: the relationship between physicians and the pharmaceutical industry. Journal of the Royal College of Physicians, 20: 235-242 (1986).

5. Engler, R., Covell, J., Friedman, P. et al. Misrepresen­tation and responsibility in medical research. New England Journal of Medicine, 317: 1383-1389 (1987).

6. Angell, M., Relman, A. Fraud in biomedical research: a time for Congressional Restraint. New England Journal of Medicine, 318: 1462-1463 (1988).

7. Hillman, A., Eisenberg, J., Pauly, M. et al. Avoiding bias in the conduct and reporting of cost-effectiveness research sponsored by pharmaceutical companies. New England Journal of Medicine, 324: 1362-1365 (1991).

8. Relman, A. Dealing with conflicts of interest. New England Journal of Medicine, 310: 1182-1183 (1984).

9. Petsonk, E. Conflicts of interest in drug research. New England Journal of Medicine, 301: 335 (1975).

10. Chalmers, I. Underreporting research is scientific misconduct. Journal of the American Medical Association, 263: 1405-1408 (1990).

11. Chalmers, T., Frank, C, Reitman, D. Minimizing the three stages of publication bias. Journal of the American Medical Association, 263: 1392-1395 (1990).

12. Dickersin, K. The existence of publication bias and risk factors for its occurrence. Journal of the American Medical Association, 263: 1385-1389 (1990).

13. Sharp, D. What can and should be done to reduce publication bias? The perspective of an editor. Journal of the American Medical Association, 263: 1390-1391 (1990).

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Reports on Individual Drugs

First-line treatment of asthma: inhaled corticosteroids or bronchodilators? The diagnostic hallmark of asthma is the prompt symptomatic improvement that is typically obtained from the use of a sympathomimetic bronchodilator drug (or beta-adrenoreceptor agonist) during an exacerbation. For as long as effective synthetic bronchodilators have been available they have been used in the first-line management of asthma. Anti-inflammatory agents (either corticosteroids or cromoglicic acid) have been added only when symptoms are not adequately controlled. A reap­praisal of this approach has recently been forced by mounting evidence that regular inhalation of beta agonists may sooner or later result in a rebound increase in bronchial hyperresponsiveness and clinical deterioration (1-5).

At the same time it has become accepted that asthma is not simply an expression of reversible bronchospasm, but that it is also characterized, from the earliest stages, by inflammatory changes in the mucosa of the airways (6, 7). It is the progression of this inflammatory process that is presumed to result in bronchial hyperresponsive­ness and ultimately in persistent and worsening airways obstruction (8, 9). This hypothesis is supported by evidence that the hyper-responsive state can be attenuated by inhaled corticosteroids (1 , 2, 10-13), but not by theophylline or beta-adrenoreceptor agonists (1 , 2, 10). The implications of these findings for the long-term management of asthma have recently been confirmed in a two-year clinical trial involving 103 patients with newly detected asthma, who were treated with either an inhaled steroid, budesonide, or an inhaled beta¬ adrenoreceptor agonist, terbutaline (14). Through­out this period no serious adverse reactions to treatment were detected and budesonide proved to be significantly superior in reducing the symptoms of asthma and in improving peak respiratory flow. Exacerbations also tended to be less severe among the budesonide-treated patients: only one of these, compared with 10 who received terbutaline, was withdrawn from the trial because of an inadequate response.

In these terms the results appear unequivocal, and the conclusion that patients with daily asthmatic episodes are best treated with one of the anti­inflammatory aerosols supplemented by bronchodilators for symptomatic relief, is consonant with the recent recommendations of an expert panel convened by the United States National Institutes of Health (15). At the same time, how­ever, warnings have been sounded about the possible hazards of re-espousing long-term steroid therapy for asthma too enthusiastically (16). Potent esterified steroids are more effective in asthma when administered by aerosol rather than systemi¬ cally and this reduces the risk of systemic toxicity. None the less, even when patients have been carefully trained in the technique of inhalation, a large fraction of the dose is deposited in the pharynx where it may induce dysphonia and predispose to candidiasis (17). Nor can the possibility of adverse effects from systemic absorp­tion be entirely discounted. It seems unlikely that the doses required to treat mild asthma could result in dangerous suppression of the pituitary-adrenal axis. But too little is known at present to exclude the possibility, over the long term, of compromising growth in young children or disturbing bone metabolism in elderly patients with osteoporosis. Too many misjudgements have been made in the past over the management of asthma to allow any such eventuality to remain unexplored.

References

1. Kraan, J., Koeter, G., Mark, T. et al. Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. Journal of Allergy and Clinical Immunology, 76: 628- 636 (1985).

2. Kerrebijn, K., van Essen-Zandvliet, E., Neijens, J. Effect of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma. Journal of Allergy and Clinical Immunology, 79: 653-659 (1987).

3. Vathenen, A., Knox, A., Higgins, B. et al. Rebound increase in brachial responsiveness after treatment with inhaled terbutaline. Lancet, 1: 554-558 (1988).

4. Sears, M., Taylor, D., Print, C. et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet, 336: 1391-1396 (1990).

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5. van Schayck, C, Graafma, S., Visch, M. et al. Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by subsensitization to salbutamol. Journal of Allergy and Clinical Immunology, 86:793-800 (1990).

6. Laitinen, L, Heino, M., Laitinen, A. et al. Damage of airway epithelium and bronchial reactivity in patients with asthma. American Reviews of Respiratory Disease, 131: 599-606 (1985).

7. Bousquet, J., Chanez, P., Lacoste, J. Eosinophilic inflammation in asthma. New England Journal of Medicine, 323: 1033-1039 (1990).

8. Brown, J., Greville, W., Finucane, K. Asthma and irreversible airflow obstruction. Thorax, 39: 131-136 (1984).

9. Peat, J., Woolcock, A., Cullen, K. Rate of decline of lung function in subjects with asthma. European Journal of Respiratory Disease, 70: 171- 179 (1987).

10. Dutoit, J., Salome, C, Woolcock, A. Inhaled cortico­steroids reduce the severity of bronchial hyperrespon­siveness in asthma but oral theopylline does not. American Reviews of Respiratory Disease, 136: 1174-1178 (1987).

11. Ryan, G., Latimer, K., Juniper, E. et al. Effect of beclomethasone dipropionate on bronchial responsive­ness to histamine in controlled non-steroid dependent asthma. Journal of Allergy and Clinical Immunology, 75: 25-30 (1985).

12. Jenkins, C, Woolcock, A. Effect of prednisone and beclomethasone dipropionate on airway responsiveness in asthma: a comparative study. Thorax, 43: 378-384 (1988).

13. Juniper, E., Kline, P., Vanzeileghem, M. et al. Effect of long-term treatment with inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid dependent asthmatics. American Reviews of Respiratory Disease, 142: 832-836 (1990).

14. Haahtela, T., Järvinen, M., Kava, T. et al. Comparison of a B2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. New England Journal of Medicine, 325: 388-392 (1991).

15. Expert panel report on guidelines for diagnosis and management of asthma. National Heart and Blood institute Information Center, Bethesda, Maryland, 1991.

16. Reed, C.E. Aerosol steroids as primary treatment of mild asthma. New England Journal of Medicine, 325: 425-426 (1991).

17. Toogood, J., Jennings, B., Greenway, R., Chuang, L. Candidiasis and dysphonia complicating beclomethasone treatment of asthma. Journal of Allergy and Clinical Immunology, 65: 143-153 (1980).

Permethrin, bed nets and malaria In parts of west Africa, falciparum malaria remains one of the major causes of childhood deaths (1). Its control is increasingly compromised as effective chemoprophylaxis becomes more costly with the continued progression of drug resistance. In this situation it has become important to reevaluate simple means of reducing contact with the malaria-transmitting Anopheles mosquito (2) either by eliminating its breeding sites in collections of stagnant water or by using protective clothing, mosquito nets and screens. Some inconsistent findings in field studies suggest that sleeping under netting is not always acceptable to restless children (3-8). Overall, none the less, the results leave no doubt that permethrin-impregnated bed nets or curtains, when they are reliably used, can consider­ably reduce both infection and mortality rates.

The most recent of the studies, which was under­taken in rural villages within the Gambia, is particu­larly noteworthy. In villages where permethrin-treated bed nets were used (at a target dose of 500 mg/m2), the overall reduction in mortality was greater than that previously attributed in the locality directly to malaria. Moreover, the addition of chemoprophylaxis — 2 5 mg dapsone and 3.13 mg pyrimethamine once weekly— produced no further reduction in mortality, although it did significantly reduce morbidity. The results imply that malaria is an important indirect cause of death in the Gambia, as has previously been reported in Guyana (9) and that provided the necessary household discipline can be maintained, the impact of simple primary-care technology on malaria prevention could be profound. The proof will be provided, not by more primary intervention studies, but by prolonged monitoring to assess how long these spectacular results can be sustained under routine conditions of use.

References

1. Greenwood, B., Bradley, A., Greenwood, A. et al. Mortality and morbidity from malaria in a rural area of the Gambia, West Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene, 81: 478-486 (1991).

2. Editorial. Drawing the curtain on malaria. Lancet, 337: 1515-1516 (1991).

3. Graves, P., Brabin, P., Charlwood, J. et al. Reduction in incidence and prevalence of Plasmodium falciparum in under 5-year-old children by permethrin impregnation of mosquito nets. Bulletin of the World Health Organization, 65:869-877 (1987).

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4. Snow, R., Rowan, K., Greenwood, B. A trial of permethrin-treated bed nets in the prevention of malaria in Gambian children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 81: 563-567 (1987).

5. Snow, R., Unsay, S., Hayes, R., Greenwood, B. Permethrin-treated bed nets (mosquito nets) prevent malaria in Gambian children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 82: 838-842 (1988).

6. Leake, D., Hii, J., Giving bed nets "fair" tests in field trials against malaria. Southeast Asian Journal of Tropical Medicine and Public Health, 20: 379-384 (1989).

7. Sexton, J., Rueburgh, T, Brandling-Bennett, A. et al. Permethrin-impregnated curtains and bed nets prevent malaria in western Kenya. American Journal of Tropical Medicine and Hygiene, 443: 11-18 (1990).

8. Procacci, P., Lamizana, L, Kumlien, S. et al. Permethrin-impregnated curtains in malaria control. Transactions of the Royal Society of Tropical Medicine and Hygiene, 85: 181-185 (1991).

9. Alonso, P., Linsay, S., Armstrong, J. et al. The effect of insecticide-treated bed nets on mortality of Gambian children. Lancet, 337: 1499-1502 (1991).

10. Giglioni, G. Changes in the pattern of mortality following the eradication of hyperendemic malaria from a highly susceptible community. Bulletin of the World Health Organization, 46: 181-202 (1972).

Penicillin prophylaxis and rheumatic heart disease

Use of antibiotic prophylaxis has strikingly reduced disability and death from rheumatic heart disease over the past 50 years in industrialized countries (1-3). In developing countries, however, recurrent attacks of rheumatic fever remain a dominant cause of cardiovascular disease (4-6). Single monthly intramuscular injections of benzathine benzyl-penicillin are widely recommended for routine prophylaxis (7). Very few cases of serious allergy have been ascribed to this practice (8, 9). None the less, it is claimed that anecdotal accounts of fatal allergic reactions have prejudiced the acceptance of prophylaxis in some countries, among both physicians and patients (10).

Because of these concerns, a prospective inter­national study has been undertaken to estimate the incidence of such reactions (11). A total of 1790 patients with rheumatic fever and no history of allergy to penicillin were enrolled from centres in

11 widely dispersed countries, each with a high prevalence of rheumatic fever, and followed for periods ranging from 6 to 24 months. During this period 57 (or 3.2 %) of the patients experienced an allergic reaction. Of these, 4 had anaphylaxis and 1 died.

These risks are similar in magnitude to those described for patients who receive short-term treatment with parenteral penicillin (12-14), but severe reactions tended to occur more frequently among patients with pre-existing heart disease. The authors emphasize that resuscitation facilities must be immediately available whenever penicillin is injected, but they also emphasize that the benefits of prophylaxis decisively outweigh risks. Rheumatic fever recurred during the course of the study in some 0.5 per cent of the patients who received penicillin. It recurred with 20-fold greater frequency among a group of some 100 patients who met the criteria for enrollment but who refused prophylaxis.

References

1. Stollerman, G., Rusoff, J., Hirschfeld, I. Prophylaxis against group A streptococci in rheumatic fever. New England Journal of Medicine, 252: 787-792 (1955).

2. Wood, H., Feinstein, A., Taranta, A. et al. Rheumatic fever in children and adolescents, III, Comparative effectiveness of three prophylactic regimens in preventing streptococcal infections and rheumatic recurrences. Annals of Internal Medicine, 60 (suppl. 5): 31-46 (1964).

3. Tompkins, D., Boxerbaum, B., Leibman, J. Long-term prognosis of rheumatic fever patients receiving intramus­cular benzathine penicillin. Circulation, 45: 543-551 (1972).

4. Sanyal, S., Barry, A., Duggal, S. Sequelae of the initial attack of rheumatic fever in children in north India. Circulation, 65: 375-379 (1982).

5. Lue, H., Tseng, W., Lin, G. et al. Clinical and epidemio­logical features of rheumatic fever and rheumatic heart disease in Taiwan and the Far East. Indian Heart Journal, 35: 139-146 (1983).

6. Majeed, H., Yousof, A., Khuffash, F. The natural history of acute rheumatic fever in Kuwait: a prospective six year follow-up report. Journal of Chronic Diseases, 39: 361 (1986).

7. Strasser, T., Dondog, N., El Kholy, A., Gharagozloo, R. Report of a WHO international cooperative project. Bulletin of the World Health Organization, 59: 285-294 (1981).

8. Hsu, I., Evans, J. Untoward reactions to benzathine penicillin G in a study of rheumatic fever prophylaxis in

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adults. New England Journal of Medicine, 259: 581-583 (1958).

9. Steigmann, F., Suker, J. Fatal reactions to benzathine penicillin G. Journal of the American Medical Association, 179:288-290 (1962).

10. Lue, H., Chen, H., Wei, H. Some problems in long-term prevention of streptococcal infections among children with rheumatic heart disease in Taiwan. Japanese Heart Journal, 17: 550-559 (1976).

11. International Rheumatic Fever Study Group. Allergic reactions to long-term benzathine penicillin prophylaxis for rheumatic fever. Lancet, 337: 1308-1310 (1991).

12. Idsoe, O., Guthe, T., Willcox, R„ deWeck, A. Nature and extent of penicillin side-reactions, with particular relevance to fatalities from anaphylactic shock. Bulletin of the World Health Organization, 38: 159-188 (1968).

13. Enffmeyer, J. Penicillin allergy. Clinical Reviews of Allergy, 4: 171-186 (1986).

14. Weiss, M., Adkinson, N. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clinical Allergy, 18:515-540 (1988).

Cancer chemotherapy in childhood: no evidence of second generation sequelae

The proportion of children with cancer who survive into adulthood has been rising progressively for the past two decades (1). However, many of the chemotherapeutic agents on which their lives once depended are mutagenic and, should these substances have damaged their germ-cell chromo­somes, the incidence of genetic diseases and congenital anomalies could be raised in the next generation. Early attempts to detect such sequelae have consistently yielded negative results (2-4). Further, largely reassuring data have recently been obtained from a review of 100 live and 2 stillborn children, born to a total of 60 couples, of which one partner had received chemotherapy earlier in life (5).

The only questionable finding of note was that structural cardiac defects were reported in 2 of 20 children born to women who had been treated with dactinomycin (a potential carcinogen that has not been identified as mutagenic in the Ames salmo¬ nella-microsome assay test (6, 7)). However, the authors were unable to identify any published reference to such a lesion in a child of a parent

previously treated with dactinomycin either for childhood cancer or for gestational trophoblastic disease (8-10).

In every other respect the results were unremark­able. The overall frequencies of congenital abnor­malities among the children of both treated women and treated men were within expected limits. Moreover, these anomalies were distributed without demonstrable relationship to the number of mutagens used in the treatment regimens or to the cumulative dose of any individual drug.

The authors acknowledge that none of the studies as yet undertaken can exclude the existence of positive associations with reasonable certainty. Considered as a whole, however, the data clearly favour the conclusion that previous treatment with chemotherapeutic agents has little, if any, deleteri­ous effect on the outcome of subsequent preg­nancy. If so, it must follow, as the authors point out, that DNA damage is repaired — through mecha­nisms that are as yet obscure — more efficiently in germ cells than in somatic cells.

References

1. Young, J., Ries, L, Silverberg, E. et al. Cancer incidence, survival, and mortality for children younger than 15 years. Cancer, 58: 598-602 (1986).

2. Li, F., Jaffe, N., Holmes, G., Holmes, F. Offspring of patients treated for cancer in childhood. Journal of the National Cancer Institute, 62: 1193-1197 (1979).

3. Mulvihill, J., Byrne, J., Steinhom, S. et al. Genetic disease in offspring of survivors of cancer in the young. Clinical Genetics, 39: 72 (abstract) (1986).

4. Hawkins, M., Smith, R., Curtice, L. Childhood cancer survivors and their offspring studied through a postal survey of general practitioners: preliminary results. Journal of the Royal College of General Practitioners, 38: 102-105 (1988).

5. Green, D., Zevon, M., Lowrie, G. et al. Congenital anomalies in children of patients who received chemo­therapy for cancer in childhood and adolescence. New England Journal of Medicine, 325: 141-146 (1991).

6. Benedict, W., Baker, M., Haroun, L. et al. Mutagenicity of cancer chemotherapeutic agents in the salmonella/ microsome test. Cancer Research, 37: 2209-2213 (1977).

7. Prejean, J., Montgomery, J. Structure-activity relation­ships in the carcinogenicity of anticancer agents. Drug Metabolism Reviews, 15: 619-646 (1984).

8. Pastorfide, G., Goldstein, D. Pregnancy after hydatidiform mole. Obstetrics and Gynecology, 42: 67-70 (1973).

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9. Li, F., Jaffe, N. Progeny of childhood cancer survivors. Lancet, 2: 707-709 (1974).

10. Rustin, G., Booth, M., Dent, J. et al. Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. British Medical Journal, 288: 103-106 (1984).

Folate supplements and neural tube defects The publication of the long-awaited results of a large multicentre, double-blind prevention trial to determine whether supplementation with folic acid can prevent neural tube defects (1) has largely resolved much sharply-contested uncertainty (2-12). A total of 1817 women who were planning a pregnancy were enrolled in the trial from 33 centres in 7 countries. All had previously had a conceptus with anencephaly, encephalocoele or spina bifida. Each was allocated at random either folic acid (4 mg daily), other vitamins, both or neither until the 12th week of pregnancy. In all, 27 of 1195 pregnan­cies resulted in a fetus with a neural tube defect. Only 7 of these occurred in women who had been allocated folic acid supplements. Overall, the incidence of these defects was 1.0 per cent among fetuses or infants born to mothers receiving added folic acid and 3.5 per cent among those born to other mothers.

The results were regarded as conclusive enough to warrant foreclosure of the trial before data on a planned 2000 pregnancies had been collected. It is assumed that folic acid supplements will also prevent first occurrences of neural tube defects — which account for some 95 per cent of such incidents — and not only recurrences, although direct proof of this is contingent upon completion of an ongoing study in Budapest (13).

Since no evidence has ever been adduced to show that such doses of folic acid are in any way hazardous, an expert advisory committee has now been set up in the United Kingdom to consider how best to ensure that all women likely to become pregnant receive supplementary folic acid (14). Unfortunately, the available data provide no indication of how long supplementation needs to be continued to obtain the maximum effect, or of whether the same protective effect can be obtained with lower doses. These are matters of some importance since it may be impracticable to supply a supplement of 4 mg daily from dietary sources alone (14). Some empiricism will be required to arrive at a recommendation. Short of conducting a

further trial with different dosage regimens, formal demonstration of a dose-effect relationship will remain outstanding.

References

1. Medical Research Council Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet, 338: 131-137 (1991).

2. Smithells, R., Sheppard, S., Schorah, C. et al. Possible prevention of neural tube defects by preconceptional vitamin supplementation. Lancet, 1: 339-340 (1980).

3. Laurence, K., James, N., Miller, M. et al. Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural tube defects. British Medical Journal, 282: 1509-1511 (1981).

4. Wald, N., Polani, P. Neural tube defects and vitamins: the need for a randomized clinical trial. British Journal of Obstetrics and Gynaecology, 91: 516-523 (1984).

5. Smithells, R., Sheppard, S., Wild, J. et al. Prevention of neural tube defect recurrences in Yorkshire: final report. Lancet, 2:498-499 (1989).

6. Bower, C, Stanley, F. Dietary folate as a risk factor for neural-tube defects: evidence from a case-control study in Western Australia. Medical Journal of Australia, 150: 613-619 (1989).

7. Mann, J. Dietary folate and neural tube defects. Medical Journal of Australia, 150: 609 (1989).

8. Mulinare, J., Cordero, J., Erikson, J. et al. Periconcep¬ tional use of multivitamins and the occurrence of neural tube defects. Journal of the American Medical Associa­tion, 260: 3141-3145 (1988).

9. Editorial. Vitamins and the neural tube. Lancet, 2: 486 (1989).

10. Milunski, A., Jick, H., Jick, S. et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. Journal of the American Medical Association, 262: 2847-2852 (1989).

11. Mills, J., Rhoades, G., Simpson, J. et al. The absence of a relation between the periconceptional use of vitamins and neural tube defects. New England Journal of Medicine, 321: 430-435 (1989).

12. Halsted, C. Periconceptional use of multivitamins and the prevalence of neural-tube defects. New England Journal of Medicine, 322: 1082 (1990).

13. Czeizel, A., Fritz, G. Trial to prevent first occurrence of neural tube defects by periconceptional vitamin supple­mentation. Journal of the American Medical Association, 262: 1634 (1989).

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14. Reece, D. Folic acid protects against neural tube defects. British Medical Journal, 303: 209 (1991).

Encephalitis following treatment of loiasis Loiasis, a filarial disease which is focally endemic in the rain forest belt of western and central Africa, is transmitted to man through the bite of infected Chrysops vectors. The distinctive characteristics of the condition are transient oedematous Calabar swellings on the ankles and wrists and, less commonly, fleeting ocular disturbances caused by migration of adult worms across the conjunctivae. However, in patients with intense microfilaaremia, generalized pruritus is the most debilitating con­sequence of infection. This can be suppressed for prolonged periods by administration of diethyl¬ carbamazine (DEC), which has a potent micro¬ filaricidal action, but there has long been concern that this may occasionally induce acute encephalitis in heavily microfilaraemic patients (1-4), a compli­cation which is also occasionally seen in untreated cases (4).

Encephalitis has not been reported following use of DEC in other forms of filariasis. It has been ascribed to sudden mobilization of microfilariae, but this is questionable on several grounds. Micro­filariae are not consistently demonstrable in the cerebrospinal fluid. Indeed, many patients have few, if any, microfilariae in the skin. This may be an indication of acquired immunity (5). However, even when patients with large numbers of microfilariae are treated (6), the severe cutaneous Mazzoti reactions commonly encountered in patients with onchocerciasis do not occur (7).

At least 1 % of patients with moderate to heavy microfilaraemia may develop encephalitis during treatment (3). Deaths have occurred even among patients treated in hospital (3) and, contrary to earlier speculation (8), the risk cannot be eliminated — although it may well be reduced — by adminis­tering very low doses of DEC for several days before the full therapeutic doses are given under antihistamine or corticosteroid cover. Ivermectin, a microfilaricide that is highly effective in onchocer­ciasis (9 - 12), has been evaluated as of little therapeutic value when used alone in loiasis (13, 14), although there is evidence that it significantly reduces the microfilarial load (15). Its slower time-course of action results in a less intense microfilari¬ cidal response and it has been suggested that treatment with ivermectin prior to DEC therapy

might reduce the incidence of encephalitic reactions (3,15).

This is a proposition that needs to be viewed with caution since ivermectin is inherently neurotoxic. Its safe use in onchocerciasis is dependent upon an effective blood-brain barrier which excludes it from the cerebrospinal space. In animals that lack this protective mechanism, it has lethal neurotoxicity (16-18). If susceptibility to encephalitis among patients with loiasis is an expression of an impaired blood-brain barrier, administration of ivermectin could conceivably increase rather than reduce the risk of encephalitis. Thus far, clinical experience has been strongly reassuring. It is estimated that as many as 2000 patients with concomitant loiasis have received ivermectin in therapeutic dosage without incident to suppress onchocerciasis. However, a single case (described on page 127) is now on record of a previously active man, con­firmed parasitically to have had both onchocerciasis and loiasis, who developed a cerebellar deficit before dying in coma 3 weeks after receiving an oral dose of 150 mg ivermectin (19). Other factors may well have contributed to this patient's death. None the less, the findings underscore the need for particularly rigorous surveillance of patients treated with ivermectin in those areas of Africa where onchocerciasis and loiasis coexist.

References

1. Van Bogaert, L, Dubois, A., Jannsens, P.G. et al. Encephalitis in Loa loa filariasis. Journal of Neurology, Neurosurgery and Psychiatry, 18: 103-119 (1955).

2. Fain, A. Les problèmes actuels de la loase. Bulletin of the World Health Organization, 56: 155-167 (1978).

3. Carme, B., Boulesteix, J., Boutes, H., Puruehnce, M.F. Five cases of encephalitis during treatment of loiasis with diethylcarbamazine, American Journal of Tropical Medicine and Hygiene, 44: 684-690 (1991).

4. Downie, C.G. Encephalitis during treatment of loiasis with diethylcarbamazine. Journal of the Royal Army Medical Corps, 112: 46-49 (1966).

5. Pinder, M. Loa loa — a neglected filaria. Parasitology Today, 4: 279-283 (1988).

6. Negesse, Y., Lanoie, L.O., Neafie, R.C., Connor, D.H. Loiasis: "Calabar" swellings and involvement of deep organs. American Journal of Tropical Medicine and Hygiene, 34: 537-546 (1985).

7. Bryceson, A.A., Warrell, D.A., Pope, H.M. Dangerous reactions to treatment of onchocerciasis with diethyl­carbamazine. British Medical Journal, 1: 742-744 (1977).

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8. Gentilini, M., Carme, B. Traitement des filarioses en pratique hospitalière. Annales de la Société Beige de Médicine Tropicale, 61: 319-326 (1981).

9. Ivermectin in onchocerciasis, WHO Drug Information, 1: 43-45 (1987).

10. De Sole, G., Dadsie, K.Y., Giese, J. et al. Lack of adverse reactions in ivermectin treatment of oncho­cerciasis. Lancet, 335: 12106-1107 (1990).

11. Pacqué, M., Muños, B., Greene, B.M. et al. Safety and compliance with community-based ivermectin therapy. Lancet, 335: 1377-1380 (1990).

12. Community-based ivermectin therapy, WHO Drug Information, 4: 48-49 (1990).

13. Richard-Lenoble, D., Kombila, N., Chandenier, J., Gaxotte, P. Efficacité et tolerance de I'ivermectine (Mectizan) prescrit chez les sujets multifilariens (Loa loa, Onchocercoese et/ou M. perstans). Bulletin de la Societé de Pathologie Exotique et ses Filiales, 82: 65-71 (1989).

14. Carme, B., Ebikili, B., Mbitsi, A., Copin, N. Essai therapeutique de I'ivermectine au cours de la loase a moyenne et forte microfilarémie. Annales de la Societe Beige de Medicine Tropicale, 71 : 47-50 (1991).

15. Richard-Lenoble, D., Kombila, M., Rupp, E. et al. Ivermectin in loiasis associated with or without concomi­tant O. volvulus and M. perstans infections. American Journal of Tropical Medicine and Hygiene, 39: 480-483 (1988).

16. Pulliam, J.D., Seward, R.L., Henry, R.T., Steinberg, S.A. Investigating ivermectin toxicity in collies, Veterinary Medicine, 80: 33-40 (1985).

17. Paul, A.J., Tranquilli, W.J., Seward, R.L. et al. Clinical observations in collies given ivermectin orally. American Journal of Veterinary Research, 48: 684-685 (1987).

18. Seaman, J.T., Eagleson, J.S., Carrigan, M.J., Webb, R.F. Avermectin B, toxicity in a herd of Murray Grey cattle, Australian Veterinary Journal, 64: 284-285 (1987).

19. Boussinesq, M., Louis, F.J., Sam-Abbenyi, A., Maubert, B. Description d'un cas d'encéphalopathie après prise oral d'ivermectine. Rapport commun ORSTOM/ OCEAC, Yaoundé, Cameroun, 26 August 1991.

Oral ribavirin: promising results in hepatitis C

Since it was first discovered two years ago, the RNA hepatitis C virus has been identified as the cause of most cases of chronic non-A, non-B hepatitis (1, 2), an infection which is estimated to

supervene, in developed countries, in as many as 5 per cent of recipients of multiple transfusions (3, 4). Although it is typically subclinical in the acute phase, chronic hepatitis subsequently develops in a high proportion of patients. Some 20 per cent ultimately become cirrhotic and, among these, there is a presumptive risk of hepatocellular carcinoma (5).

Long-term treatment with subcutaneous interferon alfa is estimated to restore serum alanine amino­transferase concentrations to normal in about 50 per cent of infected patients (see page 124), but many subsequently relapse on withdrawal of therapy (6, 7). There is now a possibility, however, that oral therapy with ribavirin — a nucleotide analogue with a broad spectrum of action against both DNA and RNA viruses (8, 9), first described almost 20 years ago — may open the way to a more practicable and more effective approach to treatment. Results reported from a pilot study involving 10 adult patients with histologically and serologically confirmed hepatitis C who received a daily oral dose of ribavirin 1000-1200 mg for 12 weeks, indicate that serum enzyme concentrations were reduced during treatment by an average of more than 60 per cent, although they rapidly rose to pretreatment concentrations after withdrawal of therapy (10). A tendency for serum uric acid concentrations to rise slightly during therapy was noted and, in one patient the haemoglobin concen­tration fell significantly but transiently during treatment. Otherwise, no adverse biochemical or clinical effects of any consequence were detected.

The exploratory use of ribavirin in human viral disease has been approached with some caution because it has been reported to have teratogenic potential in rodents and rabbits (11). In other respects, however, clinical experience indicates that it is well tolerated (12-14). The mechanism of action of ribavirin remains uncertain. Since it does not induce endogenous production of interferons, it presumably acts independently of exogenous interferon alfa. The next step, as the authors of this trial propose, is to evaluate the therapeutic effect of both agents in combination.

References

1. Choo, Q., Kuo, G., Weiner, A. et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science, 244: 359-362 (1989).

2. Kuo, G., Choo, Q., Alter, H. et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science, 244: 362-364 (1989).

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3. Mattson, L, Aberg, B., Weiland, O. et al. Non-A, non-B hepatitis after open-heart surgery in Stockholm: declining incidence after introduction of restrictions for blood donations due to the human immunodeficiency virus. Scandinavian Journal of Infectious Diseases, 20: 371 -376 (1988).

4. Van der Poel, C , Reesink, H., Lelie, P. et al. Anti-hepatitis C antibodies and non-A, non-B post transfusion hepatitis in the Netherlands. Lancet, 2: 297-298 (1989).

5. Mattsson, L, Weiland, O., Glaumann, H. Long-term follow-up of chronic post-transfusion non-A, non-B hepatitis: clinical and histological outcome. Liver, 8: 184-188 (1988).

6. Davis, G., Balart, L, Schiff, E. et al. Treatment of chronic hepatitis C with recombinant interferon alpha. A multicenter randomized controlled trial. New England Journal of Medicine, 321: 1501-1506 (1989).

7. Di Biscegli, A., Martin, P., Kassiandes, C. et al. Recombinant interferon alpha therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. New England Journal of Medicine, 321: 1506-1510 (1989).

8. Sidwell, R., Hoffman, J., Kharp, L. et al. Broad-spectrum activity of virazole: 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science, 117: 705-706 (1972).

9. Patterson, J., Fernandez-Larson, R. Molecular action of ribavirin. Reviews of Infectious Diseases, 12:1132-1146 (1990).

10. Reichard, O., Andersson, J., Schvarcz, R. et al. Ribavirin treatment for chronic hepatitis C. Lancet, 337: 1058-1061 (1991).

11. Johnson, E. The effects of ribavirin on development and reproduction — a critical review of published and unpublished studies in experimental animals. Journal of the American College of Toxicologists, 9: 114-119 (1990).

12. Patki, S., Gupta, P. Evaluation of ribavirin in the treatment of acute hepatitis. Chemotherapy, 28: 298-303 (1982).

13. McCormiac, J., King, I., Webb, P. et al. Lassa fever: effective therapy with ribavirin. New England Journal of Medicine, 314: 20-26 (1986).

14. Roberts, R., Jurica, K., Meyer, W. et al. A phase-1 study of ribavirin in human immunodeficiency virus infected patients. Journal of Infectious Diseases, 162: 638-642 (1990).

Rifampicin: more concerns about bioavailability

All highly-effective short-course antituberculosis chemotherapy regimens include the administration of rifampicin, isoniazid and pyrazinamide at the

outset of treatment together, most commonly, with streptomycin or ethambutol. Over 90 % of infections can now be cured within 6 months but, because these treatment regimens are costly and cumber­some, possibilities of simplifying them without losing therapeutic efficacy are still being explored. One such study recently completed by the Govern­ment Chest Service in Hong Kong suggests that, when streptomycin is dropped from the regimen, the failure rate is marginally but demonstrably increased (1). Another trial, undertaken in Singapore (2), intensifies previously-expressed concerns about the bioavailability of rifampicin when it is administered in triple combination preparations with isoniazid and pyrazinamide (3).

The use of combination preparations has been recommended by the International Union against Tuberculosis on the grounds that prescribing is simpler, self-administration becomes more reliable, and compliance is increased (4). More recently, however, tests of bioavailability in patients have shown that some two- and three-drug combination preparations provide unacceptably low plasma rifampicin concentrations. In the recent trial undertaken in Hong Kong, the bioavailability of the various preparations used was shown to be satisfactory within the context of the trial. Bioequivalence was not established in the Singapore study in which isoniazid, rifampicin and pyrazinamide were allocated at random to be given either in separate dosage forms or in a combined preparation that had been shown, in tests under­taken on an earlier batch, to have satisfactory bioavailability (5).

Such results, coupled with evidence that dissolution characteristics are comparable from batch to batch, are generally accepted as sufficient assurance of bioavailability. However, the outcome of this trial, in which the 18-month relapse rate was significantly raised among the 130 patients who received the combination formulation (6.3 % compared with 1.5 %), casts doubt on the adequacy of routine assurances regarding bioavailability in these circumstances. This doubt needs to be resolved as rapidly as possible. As the authors point out, even a small deficiency in a widely-recommended and widely-used antituberculosis regimen could have important consequences in terms both of treatment failures and the the emergence of drug-resistant strains of tubercle bacilli.

References

1. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 2, 4, and 6 months of

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pyrazinamide in 6-month, three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampicin, and pyrazinamide: results at 30 months. American Reviews of Respiratory Disease, 143: 700-706 (1991).

2. Singapore Tuberculosis Service/British Medical Research Council. Assessment of a daily combined preparation of isoniazid, rifampicin, and pyrazinamide in a controlled trial of three 6-month regimens for smear-positive tuberculosis. American Reviews of Respiratory Disease, 143: 707-712 (1991).

3. The resurgence of tuberculosis: a call for commitment. WHO Drug Information, 5: 39-40 (1991).

4. Antituberculosis regimens of chemotherapy: recom­mendations from the Committee on Treatment. Bulletin of the International Union against Tuberculosis and Lung Disease, 63:60-64 (1988).

5. Ellard, G.A., Ellard, D.R., Allen, B.W. et al. The bioavailability of isoniazid, rifampicin, and pyrazinamide in two commercially-available combined formulations designed for use in the short-term treatment of tuberculo­sis. American Reviews of Respiratory Disease, 133: 1076-1080 (1986).

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General Information

Terminal cancer care: unorthodox treatment put to the test

As patients and the public at large become more sophisticated about health care, so their scepticism grows about the value of conventional terminal cancer care. The toxic effects of chemotherapy; the static survival statistics; and the lack, after decades of endeavour, of any decisive breakthrough in the treatment of the major cancers of adulthood bear witness to disappointment and frustration. Increas­ing numbers of patients — and even their doctors — eschew conventional care and turn, instead, to unproven systems of unorthodox medicine in the hope of enhancing the quality of the ebb of life ( 1 - 3 ) .

Given the increasing importance of alternative systems of therapy it is vital to obtain objective information on their attributes. Not all the interven­tions are safe (4-6), and others have been evalu­ated as worthless or harmful on objective criteria (7-12) but little has been recorded of the holistic response to unorthodox therapy in terms of well-being and quality of life. A rare opportunity to measure these effects arose recently when a Californian cancer clinic — which treats its patients with autogenous immune-enhancing vaccine, bacille Calmette-Guérin, vegetarian diets, and coffee enemas — agreed to collaborate with an academic cancer centre that provides only conven­tional treatment in comparing the length of survival and the quality of life of their patients (13).

All the patients had extensive malignant disease and a predicted median survival time of less than 1 year. The study sample consisted of 78 pairs of patients matched according to sex, age, race, diagnosis, and time from diagnosis of metastatic or recurrent disease. Median survival time for both groups was 15 months, and quality of life scores were consistently better among conventionally treated patients from the time of enrolment.

This result refutes the assumption that unproven therapies necessarily enhance the quality of life but, since patients were self-selected in their use of conventional or unorthodox treatment, the potential for bias is manifest. It is evident that the quality of

life is influenced by the care received in a particular setting. More subtly, the authors speculate either that poorer quality of life contributes to the decision to seek unproved therapy, or that patients who are so inclined have higher expectations of improve­ment and therefore greater disillusionment if it fails to achieve anticipated benefits. Whatever the explanation, the authors suggest that those who argue and lobby for the acceptance of unproven methods of therapy should be prepared to submit them to similar investigation. Rejection of this challenge inevitably invites speculation about the sincerity with which such services are offered.

References

1. Cassileth, B., Lusk, E., Strouse, T., Bodenheimer, B. Contemporary unorthodox treatments in cancer medicine: a study of patients, treatments, and practitioners. Annals of Internal Medicine, 101: 105-112 (1984).

2. House Select Commitee on Aging. Quackery: a $10 billion scandal. 98th Congress, second session, May 1984. Government Printing Office, Washington, D.C. (SUDOC no. 98-435).

3. Office of Technology Assessment. Unconventional cancer treatments, 1990. Government Printing Office, Washington, D.C. (OTA publication no. OTA-H-405).

4. Eisele, J., Reay, D. Deaths related to coffee enemas. Journal of the American Medical Association, 244: 1608-1609 (1980).

5. Istre, G., Kreiss, K., Hopkins, R. et al. An outbreak of amebiasis spread by colonic irrigation at a chiropractic clinic. New England Journal of Medicine, 307: 339-342 (1982).

6. Schaumberg, H., Kaplan, J., Windebank, A. et al. Sensory neuropathy from pyridoxine abuse: a new megavitamin syndrome. New England Journal of Medicine, 309: 445-448 (1983).

7. Hindmarsh, W. LeGatt, D. Mexican drug therapy. Clinical Toxicology, 17: 85-99 (1980).

8. DiPalma, J., McMichael, R. Assessing the value of meganutrients in disease. Bulletin of the New York Academy of Medicine, 58: 254-262 (1982).

9. Moertel, C, Fleming, T., Rubin, J. et al. A clinical trial of amygdalin (Laetrile) in the treatment of human cancer. New England Journal of Medicine, 306: 201-206 (1982).

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10. Bowman, B., Kushner, R., Dawson, S., Levin, B. Macrobiotic diets for cancer treatment and prevention. Journal of Clinical Oncology, 2: 702-711 (1984).

11. Moertel, C, Fleming, T., Creagan, E. et al. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy: a randomized double-blind comparison. New England Journal of Medicine, 312: 137-141 (1985).

12. Curt, G., Katterhagen, G., Mahaney, F. Immuno-augmentative therapy: a primer on the perils of unproved treatments. Journal of the American Medical Association, 255: 505-507 (1986).

13. Cassileth, B., Lusk, E., Guerry, D. et al. Survival and quality of life among patients receiving unproven as compared with conventional cancer therapy. New England Journal of Medicine, 324: 1180-1185 (1991).

Antiseptics for vascular catheters Septicaemia is an ever-present risk in patients with indwelling vascular catheters. It has been estimated that, within the United States of America, bacter¬ aemia or fungaemia supervenes in some 3-7 per cent of patients with central venous catheters and about 1 per cent of those with arterial catheters (1 -3). Most of these infections are due to transcutane­ous infection at the insertion site (4) and many might presumably be avoided by more efficient disinfection of the surrounding skin. Until now, the choice of antiseptic for this purpose has been largely arbitrary, since very few prospective comparative trials have been reported (5-7) and, with one exception (7), these have focused on skin colonization patterns rather than rates of catheter-related infections.

The results of a recent randomized comparison of the use of three widely used antiseptics — povidone-iodine 10 per cent, alcohol 70 per cent and aqueous chlorhexidine gluconate 2 per cent — in the management of 668 catheters in a surgical intensive care facility should provide a more objective basis for selection (8). In each instance the infusion site was disinfected with one of these agents before insertion of the catheter and every other day thereafter. Only 1 of a total of 14 infusion-related bacteremias , occurred at sites disinfected with chlorhexidine. These results may well reflect the relatively prolonged residual antibacterial activity of chlorhexidine (9) and its unattenuated action in protein-rich fluids (10). Chlorhexidine holds advantage in several other respects: it is not demonstrably absorbed (11), sensitization appears to be very uncommon (12), and colonization by

resistant bacteria or yeasts seems not to have been recorded (13, 14).

The study convincingly demonstrates the value of randomized comparison in the simplest of thera­peutic interventions. Indeed, it is puzzling that such little attention has been paid in the past to objective assessment of the management of a complication of therapy that, each year, threatens the lives of some 50 000 patients in North America alone. Unfortunately, however, the study also underscores the need to adopt strict and precise criteria for the selection of patients. It has been pointed out that between one-third and one-half of the catheter­izations were reinsertions at a previously used site (15). No information has been provided on the antiseptics previously used at these sites, on the flora that existed at these locations at the time of reinsertion, or on the techniques by which reinser­tion was accomplished. Yet it is known, for in­stance, that use of guidewires during reinsertion can be associated with an increased risk of catheter infection (16). The conclusions of the study are of prime importance to clinical practice and, as they stand, they are decisive in their message. It is vital that any possibility of the existence of confounding bias be examined and discussed.

References

1. Nyström, B., Olesen Larsen, S., Dankert, J. et al. Bacteraemia in surgical patients with intravenous devices: a European multicentre incidence study. Journal of Hospital Infections, 4: 338-349 (1983).

2. Maki, D. Pathogenesis, prevention, and management of infections due to intravascular devices used for infusion therapy. In: Bisno, A., Waldvogel, F. Eds. Infections associated with indwelling medical devices, pp 161-177. American Society for Microbiology, Washington, D.C. 1989.

3. Maki, D., Cob, I., Garman, J. et al. An attachable silver-impregnated cuff for prevention of infection with central venous catheters. A prospective randomized multi-center trial. American Journal of Medicine, 85: 307-314 (1988).

4. Snydman, D., Pober, B., Murray, S. et al. Predictive value of surveillance skin cultures in total-parenteral nutrition-related infection. Lancet, 2:1385-1388 (1982).

5. Champagne, S., Fussell, S., Scheifele, D. Evaluation of skin antisepsis prior to blood culture in neonates. Infection Control, 5: 489-491 (1984).

6. Goldblum, S., Goldman, R., Ulrich, J. et al. Compara­tive effectiveness of Hibiclens and Betadine in the skin preparation for hemodialysis patients and personnel. American Journal of Kidney Disease, 11: 548-552 (1983).

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7. Smallman, L, Burdon, D., Alexander-Williams, J. The effect of skin preparation and care on the incidence of superficial thrombophlebitis. British Journal of Surgery, 67:861-862 (1980).

8. Maki, D., Ringer, M., Alvarado, C. Prospective randomized trial of povidone-iodine, alcohol, and chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet, 338: 339-343 (1991)

9. Lilly, H., Lowbury, E., Wilkins, M. Detergents compared with each other and with antiseptics as skin "degerming" agents. Journal of Hygiene, 82: 89-93 (1979).

10. Lowbury, E., Lilly, H. The effect of blood on disinfec­tion of surgeons' hands. British Journal of Surgery, 61: 19-21 (1974).

11. Case, D., McAinsh, J., Rushton, A., Window, M. Chlorhexidine: attempts to detect percutaneous absorp­tion in man. Chemotherapy, 3: 367-374 (1976).

12. Okano, M., Nomura, M., Hata, S., et al. Anaphylactic symptoms due to chlorhexidine gluconate. Archives of Dermatology, 125: 50-52 (1989).

13. Aly, R., Maibach, H. Effect of antimicrobial soap containing chlorhexidine on the microbial flora of the skin. Applied Environmental Microbiology, 31: 931 -935 (1976).

14. Freney, J., Husson, M., Gavini, F. et al. Susceptibili­ties to antibiotics and antiseptics of new species of the family Enterobacteriaceae. Antimicrobial Agents and Chemotherapy, 32: 873-876 (1988).

15. Wilcox, M., Spencer, R. Antiseptic catheter care. Lancet, 338:635 (1991).

16. High, K.P., Cobb, D.J., Sable, C.A. et al. A random­ized controlled trial of scheduled central venous catheter replacement. In: Program and Abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 1990, Atlanta, Georgia, p. 714. American Society for Microbiology, 1990.

HIV infection and health-care costs The comprehensive annual cost of treating patients infected with the human immunodeficiency virus within the United States was estimated in 1988 to be about US$ 2.2 billion (1). It is predicted that these costs will rise to US$ 4.5 billion in 1991. This implies, because of the fast-rising target population, that the costs per patient have decreased perhaps ten fold as a result of the extension of community-based services. Early estimates of lifetime costs per patient ranged to more than US$ 350 000 (2-4),

but a more recent survey suggests that, with less reliance placed upon inpatient hospital care (5), they had fallen within the range of US$ 20 000 to 40 000 (6).

Whether this amelioration in costs can be main­tained is uncertain. The median survival of patients who receive zidovudine has been estimated, on the basis of data collected between 1983 and 1989, to be 770 days — approximately four fold longer than that of patients who never received the drug (7). Throughout this period, the population of patients taking zidovudine is vulnerable to a variety of opportunistic and pathogenic infections. Moreover, the projected use of zidovudine in asymptomatic infections could well alter the characteristic course of the disease from a fulminant illness to a chronic condition requiring prolonged outpatient monitoring and frequent therapeutic intervention. This, it has been anticipated, will generate a significant diagnostic challenge, greater reliance upon microbiological services, and a sustained need for a wide variety of antimicrobial and other drugs (8).

Recent experience suggests, however, that these misgivings may not be borne out in practice. A study recently undertaken in California has shown that, over a period of 12 months, the total cost of treating patients receiving zidovudine was approxi­mately half, per capita, of that expended on AIDS patients not taking the drug. On average, it is claimed, life was extended for one year for no more than the annual cost of the drug — approximately US$ 16 000 (9). These results have now been confirmed independently in two other studies which indicate that, whether zidovudine is administered alone (10) or in combination with prophylaxis against Pneumocystis carinii pneumonia (11), the annual per capita cost of treatment per year of extended life will be of the same order and possibly somewhat less.

These estimates, it is claimed, are comparable in terms of cost-benefit to the expense of treating moderate hypertension and some thirteen fold less than treating patients in an intensive coronary-care unit. With the target population for treatment expanding inexorably, and with recommended routine doses of zidovudine likely to fall further on the basis of currently accumulating evidence, there may well be scope for further reducing these costs.

References

1. Hellinger, F.J. Forecasting the personal costs of AIDS from 1988 through 1991. Public Health Reports, 103: 309-319 (1988).

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2. Hardy, A.M., Rauch, K., Echenberg, D. et al. The economic impact of the first 10 000 cases of acquired immunodeficiency syndrome in the United States. Journal of the American Medical Association, 255: 209-211 (1986).

3. Scitovski, A., Cline, M., Lee, P. Medical care costs of patients with AIDS in San Francisco. Journal of the American Medical Association, 256: 3103-3106 (1986).

4. Report of the Presidential Commission on the Human Immunodeficiency Virus Epidemic. Pp. xvii. Washington, D.C., 1988.

5. Scitovski, A., Rioce, D. Estimates of the direct and indirect economic costs of acquired immunodeficiency syndrome. Public Health Reports, 102: 1-17 (1987).

6. Andrulkis, D., Beers, V., Bentley, J. et al. The provision and financing of medical care for AIDS patients in the US public and private teaching hospitals. Journal of the American Medical Association, 258: 1343-1346 (1987).

7. Moor, R.D., Hidalgo, J., Sugland, B. et al. Zidovudine and the natural history of the acquired immunodeficiency syndrome. New England Journal of Medicine, 324: 1412-1416 (1991).

8. Bjornson, D., Meyer, D., Hiner, W. Impact of human immunodeficiency virus infection on pharmaceutical services at the Walter Reed Army Medical Center. American Journal of Hospital Pharmacy, 46: 1170-1175 (1989).

9. Williams, I.G., Gabriel, G., Kelly, G. et al. Response of serum p24 antigen and antibody to p24 antigen in patients with AIDS and AIDS-related complex treated with zidovudine. AIDS, 4 : 909-912 (1990).

10. Schulman, K.A., Lynn, L.A., Glick, M.A. et al. Cost-effectiveness of low-dose zidovudine therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection. Annals of Internal Medicine, 114: 798-802 (1991).

11. Poster FD 832 presented at the Sixth International Conference on AIDS as reported in SCRIP, No 1619, 24 May 1991, p.26.

Oral rehydration therapy: its place in the developed world

Few controlled trials have been conducted in developed countries to assess the relative efficacy of oral and intravenous rehydration in children with acute diarrhoea. Those that have been undertaken (1-4) reinforce, in general, the considerable evidence from developing countries that oral

rehydration is both safe and effective, provided the child has no signs of shock, even when dehydration is severe. None the less, many doctors still give preference to intravenous therapy, despite its expense and the trauma it imposes on the child. In part, this may reflect a tendency to overestimate the degree of dehydration (5) and a belief that oral rehydration is a labour-intensive procedure (6, 7). Clearly, the potential of oral rehydration in highly developed settings deserves further exploration, and a randomized controlled trial recently con­ducted within the Royal Children's Hospital, Victoria, Australia, provides some persuasive data (8). The objectives were to assess the effectiveness of oral rehydration and to compare the complica­tions associated with oral and intravenous treat­ment. Because of the detrimental effects of admitting children to hospital and the shortage of hospital beds, one specific aim was to determine whether dehydration could be corrected orally over 6 hours so that children could be managed on an outpatient or short-stay basis. In all, 104 children aged between 3 and 36 months with acute gastroenteritis and moderate dehydration were admitted to the study. In half the subjects the aim was to replace the fluid deficit orally over 6 hours using a glucose-electrolyte solution containing sodium 50 mmol/l, potassium 20 mmol/l, chloride 40 mmol/l, citrate 10 mmol/l, and glucose 111 mmol/l. In the remainder, intravenous rehydration was planned over 24 hours using an infusion of 4 % dextrose in physiological saline to which potassium chloride 20 mmol/l was added.

Oral rehydration failed as a result of persistent vomiting in only two children. Although vomiting was twice as common among those treated orally, possibly as a result of the speed with which fluid replacement was attempted, this was not consid­ered to have clinical significance. Within 6 hours half the children treated orally and three-quarters of those treated intravenously were largely rehydrated. All but 2 children in each of the treatment groups were fully rehydrated within 48 hours. Acidosis was corrected at the same rate in both treatment groups and no other biochemical differences of importance were noted.

The authors calculated that at least 85% of children who would previously have received intravenous therapy were treated effectively with the oral solution. As reflected by biochemical tests, the responses were fully equivalent to those obtained with intravenous fluid replacement. It was con­cluded that there is no call for routine electrolyte or acid-base measurements during oral therapy and

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the suggestion was made that the small failure rate associated with oral treatment in the trial might have been even lower had the two children with persistent vomiting received the solution through a naso-gastric tube.

In a broader context, the authors appeal to the readership of the British Medical Journal in the following terms:

"Entrenched attitudes to management are not easy to overcome. The turning point in this study occurred when a doctor personally supervised the rehydration of a moderately dehydrated infant over the first six hours. The staff were so impressed with the success of oral rehydration in this one child that their attitude to treatment changed, and it became necessary to put a good case for using an intrave­nous line. Education of staff is crucial if developed countries are to catch up with advances in the developing world.

"It is time for staff in the teaching hospitals in developed countries to become familiar with oral rehydration therapy, which includes early feeding (9), and to use it in all but the most severe cases of dehydration. In the long term, oral rehydration solutions would become more widely used in the community, and this would greatly reduce the incidence of dehydration and decrease the need for children to be admitted to hospital."

References

1. Santosham, M., Daums, R., Dillman, L. et al. Oral rehydration therapy of infantile diarrhea. New England Journal of Medicine, 306: 1070-1076 (1982).

2. Tamer, A., Friedman, L, Maxwell, S. et al. Oral rehydration of infants in a large urban US medical center. Journal of Pediatrics, 107: 14-19 (1985).

3. Listemick, R., Zieserl, E., Davis A. Outpatient oral rehydration in the United states. American Journal of Diseases of Childhood, 140: 211-215 (1986).

4. Vesikari, T., Isolauri, E., Baer, M. A comparative trial of rapid oral and intravenous rehydration in acute diarrhoea. Acta Pediatrica Scandinavica, 76: 300-305 (1987).

5. Mackenzie, A., Barnes, G., Shann, F. Clinical signs of dehydration in children. Lancet, 2: 605-607 (1989).

6. Avery, M., Snyder, J. Oral therapy for acute diarrhea: the underused simple solution. New England Journal of Medicine, 323: 891-894 (1990).

7. Candy, C. Recent advances in the care of children with acute diarrhoea: giving responsibility to the nurse and parents. Journal of Advances in Nursing, 12: 95-99 (1987).

8. Mackenzie, A., Barnes, G. Randomised controlled trial comparing oral and intravenous rehydration therapy in children with diarrhoea. British Medical Journal, 303: 393-396 (1991).

9. Santosham, M., Brown, K., Sack, B. Oral rehydration therapy and dietary therapy for acute childhood diarrhea. Pediatric Reviews, 8: 273-278 (1987).

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Regulatory Matters

Isotretinoin: further labelling changes United States of America — Two advisory panels to the US Food and Drug Administration have concluded that restrictions previously imposed on the distribution of the vitamin-A derivative, isotretinoin have greatly reduced the number of birth defects attributed to its use. No additional restrictions are considered to be warranted.

Use of the drug by women of childbearing age and reports of birth defects attributed to its use have both decreased markedly over the past 5 years as a result of an extensive educational campaign implemented by the manufacturer of the drug, Hoffmann-La Roche. However, both panels recommend that consideration be given to addi­tional labelling changes to advise doctors that:

• the indication for use of the drug should be revised from "severe, recalcitrant cystic acne" to "severe, recalcitrant nodular and inflammatory acne";

• a urine test for pregnancy could be used instead of a blood test provided that it is sensitive enough to detect beta-chorionic gonadotrophin at a concentration of 50 µU/ml;

• the drug should not be dispensed until the pregnancy test has been reported negative, and the patient has been instructed to defer treatment until the second day of the next menstrual period.

The FDA is now working with Hoffman-La Roche to plan the implementation of these changes.

Source: FDA Medical Bulletin, 21 (2), 1991.

"Activated" cyclophosphamide: a bone marrow purging agent United States of America — The US Food and Drug Administration has provisionally authorized the use of an activated form of cyclophosphamide, which is commonly used to treat patients with leukaemia, lymphomas and other forms of cancer, as a bone marrow purging agent for selected

patients with acute myelogenous leukaemia who are in a second or subsequent remission following conventional drug therapy and who require autolo­gous bone marrow transplants. This treatment involves removing a portion of the patient's bone marrow prior to treatment with high doses of chemotherapy and radiation, and subsequent reinfusion of the aspirated marrow after it has been purged of leukaemic cells.

The purging agent, 4-hydroperoxycyclophos-phamide, which kills leukaemic cells at doses that spare normal stem cells, has already been em­ployed in the treatment of more than 1 000 patients with acute myeloid leukaemia. These studies have indicated that it is only after a second or later remission following conventional therapy that bone marrow purging offers an increased expectation of survival.

Source: US Food and Drug Administration. Talk Paper, T91-30 (1991).

Second anti-HIV drug receives tentative approval United States of America — The Food and Drug Administration has arranged for the antiretroviral drug, dideoxycytidine (DDC) to be made available to patients with AIDS and advanced AIDS-related complex who fail to benefit from or who are unable to tolerate treatment with zidovudine.

DDC, which is chemically related to zidovudine, has now been administered to more than 3500 patients. As yet, the FDA considers that its efficacy has not been fully established. All patients who are treated will consequently be monitored monthly for 6 months and bimonthly thereafter. The available data indicate that, unlike zidovudine, DDC does not cause anaemia, but its use is associated with other adverse effects which are sometimes severe. Cutaneous rashes and ulceration of the oropharynx are common and, occasionally, either peripheral neuropathy involving the hands and feet or acute pancreatitis forces discontinuation of treatment.

Source: United States Food and Drug Administration. Talk Paper, T91 -29 (1991).

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Fenoterol: reduced dosage recommendations United Kingdom — Having regard to evidence that the beta-adrenoreceptor agonist, fenoterol, is effective in asthmatic patients at doses lower than those previously recommended, doctors have been advised to review the dosage regimens of all patients currently receiving fenoterol in the light of the following changes:

• a new low-strength 100 microgram metered dose inhaler has been introduced which doctors are urged to prescribe for all newly-treated patients. The maximum recommended daily dose is 800 micrograms.

• the existing 200 microgram metered dose inhaler is intended to be reserved for patients with persistent bronchospasm that is not effectively relieved by the lower-dose product. The maximum recommended dose is 1600 micrograms daily.

• recommended dosages of the nebulizer solution have been revised to provide 500 to 1250 micrograms no more than 4 times daily.

Source: Committee on Safety of Medicines. Current Problems, 31: June 1991.

Fludarabine: second-line therapy for chronic lymphatic leukaemia United States of America — Fludarabine phos­phate has been approved by the US Food and Drug Administration for parenteral treatment of beta-cell chronic lymphatic leukaemia unresponsive to therapy with alkylating agents such as chlorambucil administered in combination with corticosteroids. In clinical studies involving patients refractory to con­ventional therapy, one-third to one-half responded positively to intravenous infusions of fludarabine and full remission was reported in more than one in ten.

Unwanted effects, which were more common with relatively high doses used earlier in the drug's development, include myelosuppression, fever, chills, infection, nausea, vomiting and fatigue. Less frequently, patients have developed pneumonitis, peripheral neuropathy and tumour lysis syndrome. Rarely (in less than 0.2 per cent of patients), severe reactions to currently recommended doses have involved the central nervous system, resulting in

blindness, coma and death. However, most patients consider that their quality of life is improved and treatment has frequently been conducted success­fully in an outpatient setting.

The currently recommended dose of 25 mg/m2 is infused intravenously on 5 consecutive days in 28-day cycles. Close haematological monitoring to detect infection or risk of spontaneous bleeding is necessary and, in the event of toxicity, dosage may need to be reduced or delayed. Optimal duration of treatment has not been clearly established. Three additional cycles of therapy are at present recom­mended after the full response has been obtained.

Source: FDA Medical Bulletin, 21 (2), 1991.

Alglucerase for Gaucher's disease

United States of America — Type 1 Gaucher's disease, which predominantly affects people of eastern European Jewish descent, is an hereditary metabolic disorder that results from lack of alglucerase, an enzyme vital to the catabolism of glycolipids. In its absence, these fats accumulate in the spleen, liver and bone marrow. Patients develop anaemia and thrombocytopenia; hepatosplenomegaly results in gross abdominal distension; and fragile bones fracture readily. In some instances abnormal lipid storage also results in progressive and ultimately fatal brain damage. Severe cases could previously be treated only by splenectomy and bone marrow transplantation.

Effective long-term, enzyme replacement therapy has now become possible as a result of extraction of alglucerase from large pools of human placental tissue derived from selected donors. Each batch is tested for hepatitis B surface antigen and antigens of the human immunodeficiency virus, but it is emphasized that negative tests cannot completely exclude the possibility of viral contamination. Intravenous infusion of alglucerase at 14-day intervals over 10 months at varying dosage has decreased splenic and hepatic enlargement, reversed anaemia and boosted platelet counts in several treated patients. Adverse reactions, which in no instance required medical intervention, included slight fever, chills, abdominal discomfort, nausea and vomiting. Alglucerase has also been designated an "orphan" drug by the Food and Drug Administration, a status that provides incentives to develop products for rare diseases.

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Sources

1. US Department of Health and Human Services. HHS News, 8 April 1991.

2. FDA Medical Bulletin, 21 (2), 1991.

Interferon alfa: also effective in hepatitis C United States of America — The US Food and Drug Administration has extended the approved indications for the use of recombinant interferon alfa-2b to the treatment of chronic non-A, non-B hepatitis (also more recently described as hepatitis C) and of patients exposed to infected blood or blood-derived products who develop antibodies to this virus. The product has previously been approved as a treatment for hairy-cell leukaemia, AIDS-related Kaposi's sarcoma, and genital warts.

Although no other effective treatment currently exists for hepatitis C, interferon alfa should not be administered to patients with evidence of hepatic failure or more than minimal disturbance of hepatic function. In clinical studies, a fall in serum alanine aminotransferase concentration occurred in slightly over half the patients who received 3 million IU three times weekly for approximately 6 months. In half of these, remission has been sustained and, among the patients who relapsed, over 80 per cent have responded favourably to further treatment.

Influenza-like symptoms, including fever, headache, fatigue, anorexia, nausea, or vomiting are common at the outset, but they usually decrease in severity as treatment continues. About 1 per cent of patients have developed abnormalities of thyroid function that have responded satisfactorily to conventional therapy.

Source: FDA Medical Bulletin, 21 (2), 1991.

Noscapine: polyploidy in vitro

United Kingdom — Following evidence that noscapine, which is contained in many cough syrups and is one of the constituents of the compound papaveretum, can induce polyploidy (an increase in chromosome number) in mammalian cell lines in vitro, the Committee on Safety of Medicines has recommended that all products containing papaveretum or noscapine be placed under prescription control and be contraindicated in

pregnancy and in women of childbearing age. As a result of this recommendation, all cough mixtures containing noscapine have been withdrawn voluntarily from the British market by the companies concerned. One manufacturer has also withdrawn preparations containing anhydrous morphine.

Source: Committee on Safety of Medicines. Current Problems, Number 31 (1991).

Conjugated estrogens: withdrawal of generic versions United States of America — On the basis of data relating dosage to safety and efficacy and on new evidence demonstrating significant differences in plasma concentration profiles, the US Food and Drug Administration has withdrawn marketing approval for all generic versions of conjugated estrogen tablets on the grounds that they had not been established as bioequivalent to the innovator product, Premarin®, manufactured by Wyeth Ayerst Laboratories (1).

All new generic drug applications for conjugated estrogen tablets are required to include an accept­able in vivo plasma study demonstrating bioequivalence with the innovator product. Because of the complexity of the pharmacokinetics of oral estrogens, previously accepted methods of detecting bioequivalence by urinary excretion are now considered insufficient (2).

References

1. FDA Medical Bulletin, 21 (2), July 1991.

2. Burlington, B. Conjugated oestrogens: FDA's position. American Pharmacy, 30: 28-29 (1990).

Sargramostim (granulocyte macro­phage colony-stimulating factor) United States of America — A genetically engineered version of human granulocyte macro­phage colony-stimulating factor (sargramostim) has been approved by the US Food and Drug Adminis­tration to accelerate the growth of transplanted bone marrow in patients with Hodgkin's disease, non-Hodgkin's lymphoma, and acute lymphoblastic anaemia in whom neutropenia is associated with impaired immunity.

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Clinical studies have indicated that administration of this cytokine to patients who have received trans­plantations of autologous bone marrow expedites the recovery of the blood count and reduces the immediate risk of infection (1, 2). Thus far, no serious adverse effects have been reported, but the FDA advises that careful consideration should be given before this drug is administered to a patient with a myeloid malignancy, since it could well act as a growth factor for tumours of this type.

References

1. Nemunaitis, J., Singer, J., Buckner, C. et al. Use of recombinant human granulocyte-macrophage colony-stimulating factor in autologous bone marrow transplanta­tion for lymphoid malignancies. Blood, 72: 834-836 (1988).

2. Appelbaum, F. The clinical use of hematopoietic growth factors. Seminars in Hematology, 26 (Suppl. 3): 7-14 (1989).

3. FDA Medical Bulletin, 21 (2), 1991.

Terfenadine and ketoconazole: ventricular arrhythmias United States of America — Terfenadine, an antihistamine commonly used to obtain symptom­atic relief in allergic rhinitis, has occasionally been reported to induce cardiac abnormalities, particu­larly ventricular tachyarrhythmias associated with a prolonged QT interval. Most reported cases have occurred following overdosage, but it has recently been shown that this adverse effect is potentiated in volunteers taking the antifungal agent, keto­conazole, which interferes with the metabolism of terfenadine in the liver (1). Subsequently, cases have been reported to indicate that both severe liver disease and concurrent use of the macrolide antibiotic, troleandomycin, similarly potentiate terfenadine toxicity (2).

In response to these findings the US Food and Drug Administration has approved changes in the product information provided for these drugs which emphasize that use of terfenadine in patients receiving ketoconazole or troleandomycin is not recommended, and that the same risk may apply to patients receiving other macrolide antibiotics including erythromycin.

References

1. Monanan, B. Journal of the American Medical Associa­tion, 264: 2788-2790 (1990).

2. FDA Medical Bulletin, 21 (2) 1991.

Triazolam: safety under review European Communities — The Committee for Proprietary Medicinal Products (CPMP) is reviewing the safety of the benzodiazepine sedative/hypnotic, triazolam, following the decision taken in the United Kingdom on 2 October 1991 to suspend all dosage forms of this product initially for a period of 3 months on grounds of safety. At a subsequent hearing, to which representatives of the manufac­turer were invited, the CPMP was apprised of the factual basis on which the suspension had been ordered in the United Kingdom.

The CPMP has deferred formulating its opinion on the matter pending the report of a working group. In a preliminary position statement it has commented that "evidence of new risks at recommended doses does not seem to be available". It has, none the less, urged the manufacturer to introduce smaller pack sizes, of not more than 7 tablets, immediately and to present a protocol for an extensive pan-European controlled comparative safety and efficacy study within a 3-month time frame. It has also called for the approved product information to be revised in the following particulars:

Indications: A sentence should be added to stress that triazolam is indicated in sleeping disorders only when the condition is severe, disabling or causing extreme distress.

Duration of use: Triazolam should not be used for more than 2—3 weeks. Thereafter a complete re-evaluation of therapy is required.

Dosage: The lowest effective dose should be used. For many patients a dose of 0.125 mg immediately before bedtime may be sufficient. A dose of 0.25 mg should not be exceeded.

Warning: Triazolam should not be used in patients with any major psychiatric disorder.

At present, the only regulatory agencies that have indicated an intention to follow the British decision are Bermuda, Finland and Norway. Several others, including those of Canada and the United States, are awaiting further information on adverse experiences with triazolam in the United Kingdom.

Source: Committee for Proprietary Medicinal Products, Position statement on triazolam, 16 October 1991.

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Advisory Notices

Cloxacillin: interaction with anticoagulants Sweden — Over a period of several years the National Centre on Adverse Drug Reaction Monitor­ing has received reports of 13 patients on long-term treatment with coumarin anticoagulants whose prothrombin time rose rapidly by 50 to 60 % when they additionally received a course of oral cloxacillin. No haemorrhagic sequelae were associated with these changes and, in each instance, the prothrombin time rapidly returned to normal as soon as cloxacillin was discontinued. All doctors have been requested to report any such interactions involving either cloxacillin or flucloxacillin to their competent national authority.

Source: Information från Läkemedelsverket, 2: 143 (1991).

Clozapine: dose-related convulsive episodes United Kingdom —The Committee on Safety of Medicines has received 8 reports of convulsions occurring in patients receiving the antipsychotic agent, clozapine, for the treatment of schizophre­nia. Only one of these patients had a previous history of epileptiform attacks.

The dosages taken by these patients varied from 25 to 800 mg daily and the interval between starting treatment and the onset of convulsions ranged from 5 days to 6 months. Notwithstanding these differ­ences, the Committee has concluded that the convulsions may have resulted from relatively high plasma concentrations in susceptible patients. It recommends that the total dose of clozapine should not exceed 30 mg on the first day of treatment and that it should then be incremented, having regard to the clinical response, by no more than 25—30 mg daily. After full therapeutic benefit has been obtained in this way, it is suggested that an attempt should be made to establish whether the patient can be successfully maintained on lower doses by careful downward titration.

Source: Committee on Safety of Medicines. Current Problems, Number 31 (1991).

Flecainide: long-term use adverse effects United Kingdom — A variety of pathological lesions, including neuropathy, ataxia, corneal deposits and pulmonary fibrosis have been reported in a small number of patients who have been treated for prolonged periods with the anti-dysrhythmic agent, flecainide. These changes became apparent when treatment had been continued for periods ranging from 3 to 28 months. A causal relationship has not been definitely established and doctors have been asked to notify the Committee on Safety of Medicines of any patient under treatment with flecainide in whom such changes occur.

Source: Committee on Safety of Medicines. Current Problems, Number 31 (1991).

Health claims on food labels United States of America — A law recently enacted in the United States permits health claims on the labels of packaged foods and dietary supplements only if there is substantial scientific agreement that the claims are supported by publicly-available evidence. To assist in the determination of a number of decisions to be announced before 8 November 1991, the Food and Drug Administration has already requested data from interested parties on claims relating to calcium and osteoporosis; sodium and hypertension; lipids and cardiovascular disease; lipids and cancer; dietary fibre and cancer; dietary fibre and cardio­vascular disease; folic acid and neural tube defects; antioxidant vitamins and cancer; zinc and immune function in the elderly; and omega-3 fatty acids and heart disease.

Source: United States Federal Register, 28 March 1991.

Latex sensitivity: evidence of increasing prevalence United States of America — In recent years many cases of systemic anaphylaxis associated with drug delivery have been attributed, not to the active

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agent, but to sensitivity to latex (natural rubber) contained in the delivery system. One brand of latex-cuffed enema tips was recently recalled by the FDA after several patients had died as a result of their use. Latex is a component of many medical devices including catheters, intubation tubing, anaesthesia masks and dental dams. Various reports of latex sensitivity to such devices have been published and the prevalence of latex sensitivity seems to be increasing. Current esti­mates suggest that, within the United States, some 7 per cent of surgeons and 20 to 40 per cent of patients with spina bifida are already sensitized. In contrast, no evidence has been forthcoming to suggest that use of condoms is a cause of serious latex reactions.

The responsible allergens are assumed to be among the protein components of latex and the FDA is working with manufacturers on ways of reducing the protein content of their products to the lowest possible levels. In the meantime doctors are advised:

• to include questions about latex sensitivity when taking the general histories of all patients. This is particularly important for patients about to undergo surgery or radiology, those who are health-care workers, and those with spina bifida. Questions about itching, rash or wheezing after wearing latex gloves or inflating a toy balloon are particularly useful. Patients with positive histories should have their chart flagged and those with severe sensitiv­ity should be advised to wear a medical identifica­tion bracelet.

• whenever latex-containing medical devices are used, and especially when latex comes in contact with mucous membranes, to consider the possibil­ity of an allergic reaction.

• when latex sensitivity is suspected, to consider using devices made with plastic or other alterna­tive materials.

• when an allergic reaction does occur, to consider the need for immunological investigation and, when appropriate, advise the patient to inform health-care personnel of their sensitivity to latex before undergoing surgery or other medical intervention.

Copies of a comprehensive reference list on latex sensitivity may be obtained by writing to LATEX, FDA, HFZ-220, Rockville, MD 20857, USA.

Source: FDA Medical Bulletin, 21 (2), July 1991.

Ivermectin: possible neurotoxicity Cameroon — A previously active man of 37 who received a single oral dose of 150 micrograms/kg ivermectin during a mass chemotherapy campaign directed against onchocerciasis is reported to have died in coma 23 days later. He was initially discov­ered alone in his home, incapable of walking or speaking, 4 days after treatment. On transfer to hospital he was found to have a cerebellar deficit. No meningism or other focal neurological signs were recorded. Blood pressure and retinal fundi were normal.

Microfilariae of O. volvulus were identified in skin biopsies and a sample of cerebrospinal fluid, that was not significantly contaminated with blood, was found to contain live microfilariae of Loa loa (100-200/ml). The latter finding, which was confirmed in 2 subsequent CSF samples, was exceptional in that infiltration of this intensity has not apparently been recorded when encephalopathy has occurred in patients with loiasis following treatment with diethylcarbamazine (see page 113). Culture of these samples has thus far provided no evidence of viral, bacterial, treponemal, mycobacterial, crypto-coccal or trypanosomal infection. No soluble antigens were detected to support the possibility of bacterial meningitis — even though a few extracel­lular Gram-negative diplococci were identified in a second sample — and the patient failed to respond to treatment with chloramphenicol.

The blood sedimentation rate increased progres­sively to more than 100mm in 1 hour. Corticosteroid therapy was started when tuberculosis had been excluded. This was stopped 10 days later, despite some improvement in the patient's condition, following an episode of gastrointestinal bleeding which heralded a period of terminal decline.

The evidence that ivermectin might be responsible for the patient's terminal illness is entirely circum­stantial. Moreover, ivermectin has already been given in mass treatment campaigns, and without known untoward reactions, to over 2000 inhabitants of this area of the Cameroon in which up to 35% of the population are estimated to have loiasis. This patient was also exceptional in that, although he was apparently well at the time he received ivermectin, he was said to have complained for some 3 years, and without apparent cause, of intermittent headaches and impairment of visual acuity. For these various reasons, no call is proposed on the basis of this case to change the

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criteria on which ivermectin is administered in areas where loiasis and onchocerciasis coexist. This experience underscores the importance of the routine post-treatment monitoring of all patients receiving ivermectin that is currently in place throughout those areas of equatorial Africa in which onchocerciasis remains endemic. The implications of this case for the monitoring process are being carefully examined.

Source: Boussinesq, M., Louis, F.J., Sam-Abbenyi, A., Maubert, B. Description d'un cas d'encephalopathie après prise orale d'ivermectine. Rapport commun ORSTOM/ OCEAC, Yaoundé, Cameroun, 26 August 1991.

Breast implants: more safety queries United States of America — A study undertaken by the Food and Drug Administration showing that polyurethane foam can degrade in simulated in vivo conditions into a potential carcinogen, 2-toluene diamine, has prompted the manufacturer of a foam-coated breast implant to voluntarily withdraw its product from the market pending publication of the definitive risk assessment.

The Agency is urging doctors to inform women considering reconstructive surgery about the potential adverse effects of all types of silicone implant as well as their benefits. However, it does not consider that removal of prostheses already implanted — including those coated with poly­urethane foam — is warranted on the present evidence since the risks of surgical removal could be greater than those of retention.

Many of these devices were in use before 1976 when manufacturers were first required by law to obtain premarketing approval. Over 2 years ago, however, the FDA expressed concern about possible carcinogenic and immunogenic risks associated with silicone breast implants as well as other hazards, including infection, pain, fibrotic

induration of surrounding tissues, silicone leakage, implant failure and the difficulty of detecting mammary lesions in radiographs. Manufacturers of all such devices marketed in the USA were consequently required to submit to the FDA by 9 July 1991 the data on which they have evaluated the safety and acceptability of their products. Within 6 months of this date the FDA has to evaluate whether the devices can remain on the market.

Sources

1. US Food and Drug Administration. Talk Paper T91-18, 10 April 1991.

2. FDA Medical Bulletin, 21 (2), 1991.

Omeprazole: diarrhoea and skin reactions United Kingdom — Omeprazole, a proton-pump inhibitor indicated for short-term treatment of gastric and duodenal ulcers unresponsive to conventional therapy and for erosive reflux oesophagitis, was introduced onto the market in the United Kingdom in June 1989. Since then, 521 suspected adverse reactions associated with its use have been reported to the Committee on Safety of Medicines. Prominent among these are gastrointestinal reactions (159 cases, including 70 cases of diarrhoea) and skin rashes (104 cases).

In 14 of these cases diarrhoea was severe enough to warrant discontinuation of treatment. Among the reports of skin reactions were 4 cases of photo­sensitivity, 3 of exfoliative disease and single cases of bullous eruption and erythema multiforme. To obtain a more precise indication of the incidence of such reactions the Committee has requested doctors to report all adverse effects associated with the use of omeprazole.

Source: Committee on the Safety of Medicines. Current Problems, Number 31 (1991).

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Essential Drugs

Systemic mycoses Systemic fungal infections are sometimes caused by inhalation, ingestion or inoculation of primary pathogens, and sometimes by opportunistic invasion of commensals in patients with lowered host resistance. They are increasing in prevalence not only because of the pandemic of human immunodeficiency virus infections, but because of the rise in illicit intravenous drug use in many countries, and greater use of broad spectrum antibiotics and invasive medical procedures.

Until the mid 1970s the only drugs of value in treating life-threatening fungal infections were amphotericin B, which has to be administered parenterally and is liable to cause myelosuppression and hepatotoxicity, and flucytosine, which has a narrow spectrum of activity. Since then, the development of several new imidazole and triazole derivatives with a broad spectrum of antifungal activity — of which ketoconazole, fluconazole, and itraconazole have been most widely used — has greatly improved therapeutic prospects.

Ketoconazole is an imidazole that is effective orally against many systemic fungal infections including blastomycosis, systemic candidosis, coccidio¬ mycosis, histoplasmosis and paracoccidiomycosis. However, it can cause severe hepatitis, which is sometimes fatal. It is unsuitable for patients with pre-existing hepatic disease, and hepatic function needs to be monitored regularly throughout long-term treatment.

Fluconazole, a less toxic triazole derivative that can be administered either orally or intravenously, diffuses readily into the cerebrospinal fluid. It, too, has a wide range of activity and is currently considered to be the most effective available treatment for cryptococcal meningitis and dissemi­nated candidosis.

Another triazole, itraconazole, which is at present available only in oral formulation, has a similarly broad spectrum of activity. Limited evidence suggests that it may be particularly effective in aspergillosis which until now has been largely refractory to treatment.

There is still much uncertainty about how these agents are best used and which should be selected in specific circumstances. Before some of these questions are securely answered, a variety of additional antifungal preparations currently under­going early clinical evaluation, including cilofungin, saperconazole, genaconazole, and liposomal amphotericin B, are likely to become more widely available.

Diseases caused by pathogenic fungi Infection by these organisms, which exist sapro-phytically in soil and are sometimes contained in the faeces of birds and bats, is rare outside endemic areas. Inhalation of airborne spores produces a primary focus of infection in the lungs. This usually calcifies without giving rise to symp­toms. In a few cases, however, breakdown of local phagocytic defences results either in progressive pulmonary disease that must be differentiated from tuberculosis or, rarely, in disseminated infection characterized by generalized febrile reactions and the development of other foci of infection. Meta­static lesions are particularly common in bones and in the skin.

Histoplasmosis Histoplasma capsulatum (var. capsulation) is widely distributed and is most highly endemic in North America where it has been isolated from soil, particularly that enriched by excreta of certain birds and bats. Pulmonary infection, which results from inhalation of the microconidia, is usually mild or asymptomatic. However, occasional patients develop either chronic fibrocavitatory pneumonia or, less commonly, an acute disseminated infection similar to acute miliary tuberculosis in which hepatosplenomegaly is often prominent.

Histoplasma capsulatum (var. duboisii) is confined to Africa. Although the primary focus of infection is probably in the lungs, skin lesions are predominant. These are pleomorphic: papules, pustules, nodules, erythema nodosum, granulomata, ulcers and eczema have been described. Bone involvement resulting in osteomyelitis, abscess formation and

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spontaneous fractures is a serious and frequent complication. Diagnosis is dependent upon culture of the organism in the sputum, urine, bone marrow or the blood.

In endemic areas workers who cultivate and move soil should wear protective masks wherever this is practicable. All patients with disseminated disease or chronic fibrocavitary pneumonia should receive chemotherapy. Oral ketoconazole is usually effec­tive in patients with competent immune systems. However, patients with progressive disease — and particularly those with AIDS — should be treated with amphotericin B intravenously.

Coccidiomycosis Coccidioides immitis occurs in the southern states of the USA, Central and South America, where it is prevalent in soil samples and can become airborne during dust storms. The initial pulmonary lesions usually resolve spontaneously, but destructive pulmonary lesions and disseminated disease can occur. Arthralgia and skin eruptions, which may be erythematous, exanthematous, macular or urticarial, are the most frequent signs of haemato¬ genous spread. Meningitis and osteomyelitis are rare, but potentially fatal complications.

Diagnosis is established definitively when the organism is cultured from urine, sputum or pus. These specimens are highly contagious and special precautions must be taken when they are handled.

Grassing or paving the ground reduces the risk of inhalation of spores in endemic areas. In its mild forms infection is usually responsive to prolonged oral administration of ketoconazole. Progressive disease requires treatment with amphotericin B, either intravenously or — if there is meningeal involvement — intrathecally. Preliminary results indicate that oral administration of fluconazole may be similarly effective.

Paracoccidiomycosis Paracoccidioides brasiliensis, which occurs in South America, predominantly in Brazil, exists saprophytically in plants as well as in the soil. Infection most commonly simulates tuberculosis, but metastatic mucocutaneous disease is also characteristic. Visceral involvement is less frequent, but the liver, spleen and intestines are sometimes infected as a result of lymphatic or haematogenous spread. Slow-growing ulcerative, nodular or vegetative lesions can develop in the nose and

mouth, ultimately destroying the palate and nasal septum.

Mild cases are usually responsive to prolonged treatment with oral ketoconazole. Itraconazole appears to be comparably effective. More serious disease requires intravenous administration of amphotericin B.

Blastomycosis Blastomyces dermatitidis is responsible for sporadic cases of blastomycosis in North America and, more recently, in eastern and southern Africa. The primary pulmonary lesions resolve slowly and haematogenous dissemination to the skin and bone occurs in most cases. The cutaneous lesions, which are particularly frequent among African patients, occur as raised plaques or ulcers, usually on the face and arms. Osteolytic lesions, which can occur in most bones, present with pain and abscess formation. The diagnosis is established by the identification of B. dermatitidis in scrapings from skin lesions or in pus or urine.

Since the course of blastomycosis is generally slowly progressive, therapy is necessary for all patients with active disease. Oral ketoconazole is often effective in mild to moderate cases, but severe cases require treatment with intravenous amphotericin B.

Diseases caused by opportunistic fungi These infections occur almost exclusively in patients with serious immune deficiency or meta­bolic disease. They are becoming more prevalent with the emergence of acquired immunodeficiency syndrome.

Aspergillosis Moulds of the Aspergillus group are found through­out the world in soil dust and vegetable matter. The major pathogenic species is A. fumigatus, but others, including A. flavus and A. niger, also cause disease. Infection resulting from inhalation of airborne spores by immunosuppressed individuals, and particularly those with neutropenia, can have various clinical consequences. Proliferation of the organism within the airways can result in local formation of either a solid fungal ball (or asper¬ gilloma) or a more diffuse infiltrative lesion. More

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widespread involvement of the lungs or invasion of the central nervous system following haemato¬ genous dissemination can also occur. Aspergilloma is a cause of cough, malaise and weight loss. Haemoptysis, which can be severe and even fatal, is likely to occur as the lesion develops. Small quantities of the fungal mycelium may be expecto­rated but the diagnosis is usually established radiographically.

Aspergillomas need to be resected surgically. If there is evidence of disseminated infection, intravenous administration of amphotericin B should be started without delay. Preliminary reports that require further confirmation suggest that the less toxic triazole, itraconazole, may be similarly beneficial.

Systemic candidosis Species of Candida, and particularly Candida albicans, are the most prevalent cause of systemic fungal infections among immunocompromised patients. The clinical consequences of infection are varied and range from superficial mucocutaneous involvement to deep infiltrative lesions and dissemi­nated disease. Invasive spread of superficial infection can involve the kidneys, heart and brain and virtually any other organ of the body. Haematogenous dissemination results in fever and toxicity, often with no localizing signs. The diagno­sis is established by culture of Candida from cerebrospinal fluid or blood.

Intravenous administration of amphotericin B should be started without delay and, if the disease progresses further, flucytosine should be added. A small number of patients with deep candidosis, including some who either could not tolerate or did not respond to amphotericin B, have responded favourably to fluconazole.

Cryptococcosis The yeast, Cryptococcus neoformans, occurs widely in soil, dust and pigeon droppings. The primary focus of infection is in the lungs. However, metastatic spread is common, particularly to the skin and meninges. Skin involvement, which occurs in some 10 to 15 per cent of cases, is characterized by nodules, ulcers and subcutaneous abscesses which invade underlying bone. Cryptococcal meningitis usually presents with headache, fever, drowsiness and mental impairment. Diagnosis is confirmed by demonstrating the organisms in a smear of cerebrospinal fluid.

The need for treatment is urgent since meningitis is likely to develop at any stage and to progress rapidly. Current experience suggests that either oral or intravenous fluconazole is as effective and much less toxic than intravenous therapy with amphotericin B. Treatment should be continued for at least 6 weeks and, when the meninges are involved, until the cerebrospinal fluid is clear of cells and protein.

Mucormycosis Mucor and the related genera of fungi, Absidia and Rhizopus, are ubiquitous in soil and decaying vegetation. Airborne spores rarely induce an opportunistic infection in immunosuppressed or diabetic patients. The paranasal sinuses and lungs are most frequently the initial focus of infection. Systemic dissemination can result in extensive necrosis and infarction of large blood vessels. Intravenous therapy with amphotericin B should be started immediately, but most cases are rapidly fatal.

Diseases caused by Actinomyces

Actinomycosis Actinomyces are free-living soil bacteria, but they resemble fungi in their branching, filamentous vegetative structure. Infection results either from inhalation or inoculation of Actinomyces israelii, an anaerobe present in the normal buccal flora. The clinical presentation is determined by the primary focus of infection.

Cervicofacial disease is most distinctive. Chronic granulomatous lesions in lymphatics draining the area break down to form indurated nodules, scars and sinuses that discharge characteristic "sulphur granules". Ultimately the underlying bone of the maxilla, orbit and skull is invaded. Similar lesions develop locally as a result of dermal inoculation.

Primary involvement of the lung must be differenti­ated from tuberculosis, while intestinal involvement may simulate appendicitis or a slowly growing tumour. Other organs, particularly the liver, kidneys and bladder, are less frequently involved.

Poor mouth hygiene and dental care increase the risk of infection. Prolonged treatment with penicillin is often effective in the early phases of the disease. This should be administered intravenously for the first 4 weeks and oral therapy should subsequently

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be maintained for a further 18 months. In more advanced cases surgical resection or drainage of diseased tissue may also be required.

AMPHOTERICIN B powder for injection: 50 mg vial

A lipophilic polyene antibiotic active against Leishmania spp and fungistatic to many yeasts and yeast-like fungi. It is presumed to alter membrane permeability by binding with sterols in the fungal cell wall. It is insoluble in water and is administered systemically by intravenous infusion as a colloidal dispersion. Although extensively bound to plasma lipoproteins, it enters serous cavities and crosses the placental barrier. The plasma half-life is about 24 hours. It is excreted very slowly by the kidneys and remains detectable in blood and urine for several weeks after discontinuation of treatment.

Uses All life-threatening fungal infections including progressive histoplasmosis, coccidiomycosis, advanced paracoccidiomycosis, severe blastomycosis, disseminated aspergillosis, deep candidosis, cryptococcosis and mucormycosis.

Dosage and administration Treatment is usually started with a dose of 250 micrograms/kg daily by slow intravenous infusion. This is increased gradually to 0.4 to 0.6 mg/kg daily. If the response remains unsatisfactory dosage can be increased further to a maximum of 1 mg/kg daily or, in severe infection, to 1.5 mg/kg either daily or on alternate days.

When administered together with flucytosine to patients with severe candidosis or cryptococcal meningitis, the daily dose of amphotericin B should not be raised above 0.3 mg/kg daily. (See p. 134.)

Duration of therapy varies with the initial severity of the infection and the clinical response of the patient. A satisfactory response is usually obtained only after several months of sustained treatment. The total dose administered is generally of the order of 2 g, but some immunosuppressed patients and those with aspergillosis commonly require 3.5 g or more.

Intrathecal infusion has been used successfully in patients with meningeal coccidiomycosis. Intravenous fluids should be freshly prepared by dissolving 50 mg in 10 ml of sterile water and

making up to 500 ml with 5% commercial glucose injection (pH > 4.2) to give a final concentration of 10 mg per 100 ml. Solutions containing electrolytes or preservatives are incompatible since they promote precipitation. Infusions should always be administered slowly over a period of at least 6 hours using strict aseptic technique. No other substances, except a small amount of heparin to decrease the risk of thrombophlebitis, should be added either to the solution or to the infusion line.

Intolerance can often be attenuated by giving acetylsalicylic acid, antihistamines or antiemetics. Small amounts of corticosteroids given shortly before infusion may reduce febrile reactions.

Contraindications Known hypersensitivity to amphotericin B.

Precautions Close medical supervision in a hospital setting is required throughout systemic treatment.

Renal function and serum potassium should be closely monitored at all times. Impairment of renal function, which may not be reversible, is virtually inevitable when prolonged high dosages are administered, and marked deterioration can force reduction of dosage.

A high fluid intake should be maintained and potassium supplements may be required. Sodium supplements may be of value.

The blood count should be monitored at weekly intervals since a normochromic, normocytic anaemia is frequently induced. Occasionally, blood transfusion becomes necessary.

Use in pregnancy Safe use in pregnancy has not been established. Amphotericin B should be used only when the needs of the mother outweigh the risk to the fetus.

Adverse effects Anaphylaxis, flushing, muscle and joint pains, headache and anorexia can occur during infusion. Chills, fever and vomiting are frequent. Maculo¬ papular rash, pruritus and haemorrhagic gastro­enteritis are less common.

Deterioration of renal function, which may be only partially reversible, must be anticipated. Bone marrow depression may result in normo-

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chromic anaemia. Leukopenia, thrombocytopenia and coagulation defects are less common.

Nerve palsies, impaired vision, tinnitus, hearing loss, convulsions, and difficulty in micturition have been reported.

Cardiac toxicity, including dysrhythmias, cardiac arrest, and changes in blood pressure occur rarely.

Drug interactions Concomitant administration of other nephrotoxic drugs should be avoided.

Overdosage Treatment is symptomatic. Large doses can result in anuria, dysrhythmias, cardiac arrest, hypo­tension, visual disturbances and convulsions. Amphotericin B cannot be removed by haemodialysis.

Storage Keep powder for injections in tightly closed contain­ers, below 4 °C, protected from light.

FLUCONAZOLE tablet: 50 mg, 100 mg, 200 mg intravenous infusion: 2 mg/ml in sodium

chloride infusion 0.9 %

Fluconazole is a triazole derivative with a broad spectrum of fungistatic activity. It is effective against Cryptococcus neoformans infections, particularly in patients with human immunodeficiency virus infection. Early experience indicates that it may also be of use in severe candidosis and meningeal coccidiomycosis. It is well absorbed and passes readily across the blood-brain barrier into the cerebrospinal fluid. It is slowly eliminated un­changed in the urine.

Uses Treatment and secondary prevention of cryptococ-cal meningitis.

Its place is currently being evaluated in the treat­ment of both meningeal coccidiomycosis and serious systemic candidal infections, particularly of the urinary tract and the lungs.

Dosage and administration Cryptococcal meningitis: 400 mg either orally or intravenously daily for at least 12 weeks after cultures from the cerebrospinal fluid are negative. This should be followed by a suppressive dose of 200 mg daily.

Meningeal coccidiomycosis and severe candidal infections: Optimum dosage has yet to be estab­lished.

Contraindications Hypersensitivity to imidazole and triazole deriva­tives.

Precautions Dosage should be reduced having regard to the creatinine clearance rates in patients with renal dysfunction.

It is prudent to monitor hepatic function in all patients on longer-term therapy. Hepatic impair­ment has been reported in patients seriously ill with human immunodeficiency virus infection or cancer.

Use in pregnancy Fluconazole has been shown to have teratogenic potential in experimental animals. The need for treatment during pregnancy must be determined having regard to the safety of the mother. Women of childbearing age should take effective contracep­tive precautions during treatment and for several weeks thereafter. Treatment should be suspended during lactation.

Adverse effects Fluconazole is generally well tolerated. Nausea is the most frequently reported adverse effect. Vomiting, abdominal distension and discomfort have also been reported.

Elevation of hepatic enzyme levels, which occurs in a small percentage of individuals, is readily reversible in the early stages. Treatment should be discontinued if signs develop that are suggestive of hepatic disease.

Fluconazole should be withdrawn if skin rashes appear during treatment. Exfoliative skin disorders have been reported, but a causal association has not been established.

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Drug interactions The hepatic metabolism of other lipid-soluble drugs, including ciclosporin, phenytoin and warfarin is inhibited.

Rifampicin accelerates the clearance of fluconazole.

Overdosage No experience has been gained with overdosage of fluconazole. Emesis and gastric lavage may be of use in the case of accidental overdosage.

Storage Tablets should be kept in well-closed containers protected from light.

FLUCYTOSINE capsules: 250 mg infusion: 2.5 g in 250 ml

A synthetic fluorinated pyrimidine with selective antifungal activity, particularly against Cryptococcus and Candida spp. It acts by penetrating into vulner­able fungi where it is deaminated to fluouracil, a competitive inhibitor of uracil metabolism. It is readily absorbed from the gastrointestinal tract and is widely distributed in body tissues and fluids. Peak serum concentrations occur within 2 hours after oral administration. The plasma half-life is approxi­mately 2.5-5.0 hours and the compound is ex­creted largely unchanged in the urine.

Uses It is used in combination with amphotericin B in treating systemic infections due to Cryptococcus neoformans, Candida albicans and certain other Candida species.

Dosage and administration Severely infected adults and children should receive a total of 200 mg/kg daily in 4 divided doses, administered either orally or by intravenous infusion over a total of 20 to 40 minutes. Somewhat lower doses have been used successfully against highly-sensitive organisms. Blood concentrations of 25 - 50 micrograms/ml are usually effective. Flucytosine can be added to infusions of normal saline, dextrose or dextrose/saline. No other drugs should be added to the solution or to the infusion line.

Patients should be transferred to oral therapy at the earliest opportunity and, whenever possible, within one week. Duration of therapy should be deter­mined primarily on clinical grounds. However, patients with cryptococcal meningitis should be treated for at least 4 months.

Dosage must be reduced having regard to creati­nine clearance rates in patients with renal impair­ment. The maximum daily dose recommended for a patient with a creatinine clearance of 10 to 20 ml/ min is 50 mg/kg.

Contraindications Known hypersensitivity to flucytosine. Severe renal or hepatic insufficiency. Thrombocytopenia and other blood dyscrasias.

Precautions Dosage must be reduced in patients with renal insufficiency. Particular care is needed in treating patients additionally receiving amphotericin B since both drugs are nephrotoxic (See p.133). Any necessary adjustment should be based on the serum creatinine concentration and on blood concentrations of flucytosine, which should be estimated twice weekly. The latter samples should be withdrawn shortly before the subsequent dose is scheduled.

Blood counts and hepatic function tests should be performed at regular intervals in all patients and with greatest frequency in patients with bone marrow depression or hepatic impairment.

Use in pregnancy Teratogenic effects have been demonstrated in rats. The implication of these changes for patients is uncertain, but flucytosine should be administered to pregnant women only when the needs of the mother outweigh any possible risk to the fetus.

Adverse effects Rashes, nausea, vomiting and diarrhoea some­times occur and are usually transient. However, diarrhoea can become protracted if treatment is sustained. Mild disturbances in liver function tests occur in some 10 per cent of treated patients.

The most important serious adverse effects are blood dyscrasias, including leukopenia and potentially fatal thrombocytopenia.

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Overdosage Gastric lavage and forced diuresis are of value. Haemodialysis results in a rapid fall in serum flucytosine concentrations.

Storage Capsules and infusion should be stored in tightly closed containers protected from light.

KETOCONAZOLE tablet: 200 mg

A synthetic imidazole derivative, active after oral administration, with fungistatic activity against dermatophytes, yeasts and other pathogenic fungi. It disrupts the function of membrane-bound enzymes by inhibiting the synthesis of ergosterol, an essential component of the surface membrane of fungal cells. It is widely used in the treatment of serious gastrointestinal and systemic mycosis as well as in the management of superficial infections. It is rapidly absorbed from the gastrointestinal tract, partially metabolized in the liver, and largely excreted in the faeces via the bile.

Uses Ketoconazole is used in the treatment of non-life-threatening systemic mycoses including histo­plasmosis, coccidiomycosis without meningeal involvement, paracoccidiomycosis and blasto­mycosis.

Severe infections should be treated without delay by intravenous administration of amphotericin B.

Dosage The initial adult dose for the treatment of systemic mycoses is normally 200 mg daily taken with food and, for children, 3 mg/kg daily. Daily administra­tion should be maintained for a minimum of at least 6 months.

Contraindications Known hypersensitivity to imidazole and triazole derivatives. Significantly impaired hepatic function. Chronic alcohol dependence.

Precautions The risk of hepatitis increases when treatment is sustained for more than 2 weeks. The potential

benefit must consequently be weighed against the perceived risk. Serial estimations of serum transaminases should be made before treatment is started, at 2 weeks, 4 weeks and monthly intervals thereafter. If progressive and significant elevation occurs, or if signs of hepatitis develop, treatment should be withdrawn immediately.

Use in pregnancy Ketoconazole has been shown to be fetotoxic in rats. It should be administered during pregnancy only when the need of the mother outweighs the risk to the fetus.

Adverse effects Nausea, vomiting, abdominal pain, constipation and diarrhoea are frequent adverse effects.

Transient rises in plasma concentrations of hepatic enzymes are common. Severe hepatocellular damage is rare but potentially fatal if treatment is continued in the face of progressive deterioration of hepatic function.

In rare instances, an anaphylactic reaction has occurred following administration of the first dose. Hypersensitivity may also present as pruritus, purpura, urticaria and angio-oedema. Occasional cases of thrombocytopenia have also been reported.

Drug interactions Absorption of ketoconazole from the gastrointesti­nal tract is pH dependent. Concomitant administra­tion of antacids and other drugs that reduce gastric secretion should be avoided whenever possible.

Ketoconazole is extensively bound to plasma proteins and induces hepatic enzymes. Both effects give rise to potential drug interactions. Serum concentrations of theophylline are reduced. The anticoagulant effect of coumarin compounds may be enhanced. Concomitant use of ketoconazole with rifampicin, phenytoin and ciclosporin may alter the metabolism of one or both drugs.

Overdosage Emesis or gastic lavage should be undertaken in the event of overdose.

Storage Ketoconazole tablets should be kept in well-closed containers.

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Corrigenda concerning dosage of amphotericin B:

WHO Drug Information, Volume 5, Number 1 "Update on AIDS", page 27. Dosage of amphotericin B in: oesophageal candidosis: 0.3 mg/kg daily.

WHO Drug Information, Volume 5, Number 2 "Fungal infections of the skin and mucous mem­branes", page 67.

Dosage of amphotericin B in: oral and intestinal candidosis: 1-2 ml viscous suspension retained in the mouth for as long as possible, 4 times daily. sporotrichosis and oesophageal candidosis: 0.25 -1.0 mg/kg daily to a maximum of 11.5 mg/kg may be required in disseminated candidosis.

The information in this section is subject to consultation prior to definitive publication in the WHO Model Prescribing

Information series. Comments, which are invited at this stage, should be referred to:

Division of Drug Management and Policies, World Health Organization, 1211 Geneva 27, Switzerland

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Recent Publications

Local, small-scale preparation of eye drops

It is becoming increasingly difficult to obtain even basic eye medications in many developing coun­tries. The price of commercially prepared eye drops is rising, and deteriorating infrastructures make their distribution more problematical. In an attempt to overcome these constraints the WHO Programme for the Prevention of Blindness, working in collaboration with the Christoffel Blinden-mission, has developed a simple scheme for the local, small-scale, non-commercial production of a range of aqueous eye drops at low cost using simple, appropriate technology. "Local" within this context refers to production in a setting as close to the patient as possible, and always within the country in which the products are to be used.

The scheme is described in detail in a booklet that is not issued to the general public but that is intended for limited distribution to pharmacists in regional or district hospitals in developing countries where the necessary facilities are available. It is recognized that in rural areas of many of these countries, the preparation of medicines is often of necessity left to personnel who may not have had full formal pharmaceutical training. It is forcefully stressed, however, that on no account should persons become engaged in such manufacture without undergoing a period of training in a depart­ment where eye drops are already being prepared under the supervision of a pharmacist with experi­ence in this field.

The local small-scale production of eye drops. Programme for the Prevention of Blindness, WHO document WHO/ PBL/90.20 World Health Organization, Geneva, 1990.

WHO Model Prescribing Information: Drugs used in mycobacterial diseases

This book provides model prescribing information for some thirteen essential drugs used for the prevention and treatment of tuberculosis, for the treatment of leprosy, and for the treatment of

diseases caused by nontuberculous mycobacteria, including localized cutaneous lesions, pulmonary disease, lymphadenitis, and disseminated disease. Model prescribing information is produced by WHO to assist national authorities, particularly in develop­ing countries, when preparing drug formularies, data sheets, and teaching materials.

The information is presented in three main chap­ters. The first, devoted to tuberculosis, opens with a detailed overview of the disease, its clinical features, and the main principles of prevention, tuberculin testing, and chemotherapy. The special problems of diagnosis and treatment in HIV-infected patients are briefly discussed. Readers are also given detailed information on the properties of antituberculosis drugs, preferred treatment regi­mens, monitoring of patient compliance and therapeutic response, and the treatment of relaps­ing and unresponsive disease. Against this back­ground, model prescribing information is presented for ten drugs used in vaccination, chemoprophy-laxis, and chemotherapy. Each drug is profiled in terms of its clinical uses, dosage and mode of administration, contraindications and precautions, use in pregnancy, adverse effects, and possible interactions with other drugs.

Drugs used in the treatment of leprosy are covered in the second chapter, which also features back­ground information on the disease and the main principles of multidrug therapy. The final chapter provides prescribing information for drugs used to treat non-specific mycobacterial infections.

Drugs Used in Mycobacterial diseases. World Health Organization, Geneva, 1991, 40 pages (available in English; French and Spanish editions in preparation). ISBN 92 3 140103 6. Order No. 1150363 Sw.fr. 9-/US$8.10. In developing countries: Sw. fr. 6.30.

Basic tests for pharmaceutical dosage forms This book sets out rapid screening tests required to verify the identity of some 150 pharmaceutical dosage forms in common use. The tests, which are simple and readily applicable, make it possible to

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confirm the identity of pharmaceutical substances in tablet, capsule, solution, lotion and other forms in those cases where quality is in doubt. The basic tests detailed in this book may also be applied to determine whether gross degradation has occurred despite high standards of packaging.

The book opens with an outline of the essential equipment and laboratory services needed to carry out basic tests. Readers are also advised on what to look for during visual inspection for physical defects, and given detailed information on the procedures required for the determination of melting characteristics.

The core of the book provides step-by-step instructions in the test procedures required to verify the identity of each formulation. The methods describe the use of a limited number of easily available reagents and equipment, and do not require a fully-equipped laboratory. These are predominantly test-tube reactions which can be undertaken away from a laboratory - at a customs post or in a warehouse - by anyone with some understanding of analytical chemistry.

The book concludes with an extensive list of reagents, test solutions, and volumetric solutions needed for testing dosage forms. Preparation

procedures are also provided, in full detail, for those test solutions requiring special attention.

Basic tests for pharmaceutical dosage forms. World Health Organization, 1991, v + 129 pages (available in English; French and Spanish in preparation). ISBN 92 4 154418 x. Order No. 11500359. Sw. fr. 24,-/US$ 21.60. In developing countries: Sw. fr. 16.80.

Medications that increase sensitivity to light The Center for Devices and Radiological Health of the United States Food and Drug Administration has produced a listing of drugs and other sub­stances that can increase sensitivity to natural and artificial exposure to ultraviolet light. Intended to alert both health professionals and consumers to the risk of photosensitization and the need for protective measures, it has been compiled from currently available literature and it will be updated as new information becomes available.

Medications that Increase Sensitivity to Light: A 1990 Listing. Obtainable from: FDA, Center for Devices and Radiological Health, HFZ-114, 5600 Fishers Lane, Rockville, MD 20857.

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International Nonproprietary Names for Pharmaceutical Substances Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances*, the following names are selected as Recommended International Nonproprietary Names. The inclusion of a name in the lists of Recommended International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy.

Recommended International Nonproprietary Names (Rec. INN): List 31 Lists of proposed (1-58) and recommended (1-27) international nonproprietary names can be found in Cumulative List No. 7, 1988.

Recommended International Nonproprietary Name (Latin, English)

Chemical Name or Description and Molecular Formula

abanoquilum abanoquil

4-amino-2-(3,4-dihydro-6,7-dimethoxy-2(1 H)-isoquinolyl)-6,7-dimethoxy-quinoline C 2 2 H 2 5 N 3 O 4

acadesinum acadesine

5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide C9H14N4O5

acidum gadobenicum gadobenic acid

dihydrogen [( ± )-4-carboxy-5, 8, 11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oato(5-)]gadolinate(2-) C22H28GdN3O11

acidum penteticum pentetic acid

N,N-bis[2-[bis(carboxymethyl)amino]ethyl]glycine C14H23N3O10

adaprololum adaprolol

2-(1-adamantyl)ethyl (±)-[p-[2-hydroxy-3-(isopropylamino)-propoxy]phenyl]acetate C26H39NO4

* Official Records of the World Health Organization, 1955, 60, 3 (Resolution EB15.R7); 1969,173,10 (Resolution EB43.R9).

139

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

adosopinum adosopine

N-(5,6-dihydro-5-methyl-6,11-dioxo-10-morphanthridinyl)acetamide C17H14N2O3

adozelesinum adozelesin

(7bR,8aS)-N-[2-[(4,5,8,8a-tetrahydro-7-methyl-4-oxocyclopropa[c]pyrrolo-[3,2-e]indol-2(1 H)-y l )carbonyl ] indol-5-y l ] -2-benzofurancarboxamide C30H22N4O4

afalaninum afalanine

N-acetyl-3-phenyl-DL.-alanine or N-acetyl-DL-phenylalanine C11H13NO3

aldesleukinum aldesleukin

125-L-serine-2-133-interleukin 2 (human reduced) C 6 9 0 H 1 1 1 5 N 1 7 7 O 2 0 3 S 6

alentemolum alentemol

( + )-2-(dipropylamino)-2,3-dihydrophenalen-5-ol C19H25NO

almokalantum almokalant

( ± ) -p- [3- [ethyl [3-(propylsul f iny l )propyl ]amino]-2-hydroxypropoxy]benzo-nitr i le C18H26N2O3S

amel to l idum ameltol ide

4-amino-2' ,6 ' -benzoxyl id ide C15H16N2O

angiotensinum II angiotensin II

5-L-isoleucineangiotensin II The species specif icity should be indicated in brackets after the name. C50H71N13O12

apr ika l imum apr ika l im

(-)-(R*,2 R*)-tetrahydro-N-methyl-2-(3-pyridyl)thio-2 H-thiopyran-2-carboxamide 1-oxide C12H16N2OS2

aprosulatum natr icum aprosulate sodium

N,N'- t r imethylenebis[ lactobionamide] hexadecakis (sodium sulfate) (ester) C27H34N2Na16O70S16

arbutaminum arbutamine

(R)-3,4-dihydroxy-a-[ [ [4-(p-hydroxyphenyl)buty l ]arnino]rnethyl ]benzyl alcohol C18H23NO4

asobamastum asobamast

2-ethoxyethyl [4-(3-methyl-5- isoxazolyl)-2-thiazolyl ]oxamate C13H15N3O5S

avizafonum avizafone

2 ' -benzoyl-4 ' -chloro-2- [ (S)-2,6-diaminohexanamido]-N-methylacetani l ide C22H27CIN4O3

barn id ip inum barnid ip ine

( + )-(3'S,4S)-1-benzyl-3-pyrrol idinyl methyl 1,4-dihydro-2,6-dimethyl-4-(m-ni t rophenyl)-3,5-pyr id inedicarboxylate C27H29N3O6

140

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

batelapinum batelapine

2-methyl-5-(4-methyl-1-piperazinyl)-11 H-s-triazolo[1,5-c][1,3]benzodiazepine C16H20N6

bemesetronum bemesetron

endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl 3,5-dichlorobenzoate C15H17CI2NO2

berlafenonum berlafenone

(±)-1-(2-biphenylyloxy)-3-(tert-butylamino)-2-propanol C19H25NO2

bertosamilum bertosamil

3'-isobutyl-7'-isopropylspiro[cyclohexane-1,9'-[3,7]diazabicyclo[3.3.1 ]nonane] C19H36N2

betamipronum betamipron

N-benzoyl-β-alanine C10H11NO3

bidisomidum bidisomide

(±)-α-(o-chlorophenyl)-α-[2-(N-isopropylacetamido)ethyl]-1-piperidine-butyramide C22H34CIN3O2

bimakalimum bimakalim

2,2-dimethyl-4-(2-oxo-1(2H)-pyridyl)-2H-1-benzopyran-6-carbonitrile C17H14N2O2

bindaritum bindarit

2-[(1-benzyl-1 H-indazol-3-yl)methoxy]-2-methylpropionic acid C19H20N2O3

brinazaronum brinazarone

p-[3-(/ef/-butylamino)propoxy]phenyl 2-isopropyl-3-indolizinyl ketone C25H32N2O2

butixocortum butixocort

11β,17-dihydroxy-21-mercaptopregn-4-ene-3,20-dione 17-butyrate C 2 5 H 3 6 O 5 S

caldiamidum caldiamide

hydrogen [N,N-bis[2-[(carboxymethyl)[(methylcarbamoyl)methyl]-amino]ethyl]glycinato(3-)]calciate[1-) C16H27CaN5O8

carperitidum carperitide

L-seryl-L-leucyl-L-arginyl-L-arginyl-L-seryl-L-seryl-L-cysteinyl-L-phenylalanylglycylglycyl-L-arginy!-L-methionyl-L-aspartyl-L-arginyl-L-isoleucylglycyl-L-alanyl-L-glutaminyl-L-serylglycyl-L-leucylglycyl-L-cysteinyl-L-asparaginyl-L-seryl-L-phenylalanyl-L-arginyl-L-tyrosine cyclic(7-23)-disulfide C 1 2 7 H 2 0 3 N 4 5 O 3 9 S 3

cefclidinum cefclidin

( + )-1-[[(6R,7R)-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-4-carbamoylquinuclidi-nium hydroxide, inner salt, 72-(Z)-(O-methyloxime) C21H26N8O6S2

cefdaloximum cefdaloxime

( + )-(6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 72-(Z)-oxime C14H15N6O6S2

141

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

cefetecolum cefetecol

(6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 72-(Z)-[O-[(S)-α-carboxy-3,4-dihydroxybenzyl]oxime] C20H17N5O9S2

ceronaprilum ceronapril

1-[(2S)-6-amino-2-hydroxyhexanoyl]-L-proline, hydrogen (4-phenyl-butyl)phosphonate (ester) C21H33N2O6P

cetrorelixum cetrorelix

N-acetyl-3-(2-naphthyl)-D-alanyl-p-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-L-tyrosyl-N5-carbamoyl-o-ornithyl-L-leucyl-L-arginyl-L-prolyl-D-alanin-amide C70H92CIN17O14

cilobradinum cilobradine

(±)-3-[[1-(3,4-dimethoxyphenethyl)-3-plperidyl]methyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one C28H38N2O5

colfoscerili palmitas colfosceril palmitate

choline hydroxide, dihydrogen phosphate, inner salt, ester with L-1,2-dipalmitin or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine C40H80NOSP

corticorelinum corticorelin

corticotropin-releasing factor; the species specificity should be indicated in brackets after the name e.g.:

crilvastatinum crilvastatin

5-oxo-L-proline, (±)-cis-3,3,5-trimethylcyclohexyl ester C14H23NO3

crospovidonum crospovidone

1-vinyl-2-pyrrolidinone polymer, crosslinked (C6H9NO)n

dacopafantum dacopafant

(3 R)-3-(3-pyridyl)-1 H, 3 H-pyrrolo[1,2-c]thiazole-7-carboxamide C12H1lN3OS

dalfopristinum dalfopristin

(3R,4R,5E,10E,12E,14S,26R,26aS)-26-[[2-(diethylamino)ethyl]sulfonyl)-8,9,14,15,24,25,26,26a-octahydro-14-hydroxy-3-isopropyl-4,12-dimethyl-3 H-21,18-nitrilo-1 H,22H-pyrrolo[2,1 c] [1,8,4,19]dioxadiazacyclotetracosine-1,7,16,22(4H,7H)-tetrone C34H50N4O9S

dalteparinum natricum dalteparin sodium

Sodium salt of depolymerized heparin obtained by nitrous acid degradation of heparin from pork intestinal mucosa, the majority of the components have a 2-O-sulfo-α-L-idopyranosuronic acid structure at the non-reducing end and a 6-O-sulfo-2,5-anhydro-D-mannitol structure at the reducing end of their chain; the average relative molecular mass is about 5000, 90 per cent of which ranging between 2000 and 9000; the degree of sulfatation is 2 to 2,5 per disaccharidic unit.

dalvastatinum dalvastatin

( ± )-(4R*,6S*)-6-[(E)-2-[2-(4-fluoro-m-tolyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]vinyl]tetrahydro-4-hydroxy-2H-pyran-2-one C24H31FO3

142

corticorelin (human) C 2 0 8 H 3 4 4 N 6 0 O 6 3 S 2

corticorelin (ovine) C 2 0 5 H 3 3 9 N 5 9 O 6 3 S

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

dexormaplat inum dexormaplat in

(+)- t rans- tet rachforo(1,2-cyc lohexanediamine)plat inum C6H14CI4N2Pt

d idanosinum didanosine

2' ,3 '-dideoxyinosine C1 0H1 2N40,

d iethy l to luamidum diethyl to luamide

N,N-diethyl -m-to luamide C12H17NO

dofet i l idum dofet i l ide

β- [ (p-methanesul fonamidophenethy l )methy lamino]methanesul fono-p-phenet idide C19H27N3O5S2

doramect inum doramect in

25-cyclohexyl-5-O-demethyl-25-de(1-methylpropyl)avermect in A1a or (2aE,4E,8E)-(5'S,6S,6'R,7S,11R,13S,15S,17aR,20R,20aR,20bS)-6'-cyclohexyl-5',6,6',7,10,11,14,15,17a, 20,20a, 20b-dodecahydro-20,20b-dihydroxy-5',6,8,19-tetramethy 1-17-oxospiro[ 11,15-methano-2 H, 13 H, 17 H-furo-[4,3,2-pq][2,6]benzodioxacyclooctadecin-13,2'- [2H]pyran]-7-yl 2,6-dideoxy-4-O-(2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranosyl)-3-O-methyl-α-L-

draf laz inum draf lazine

( ± )-4 ' -amino-4-[5,5-bis(p-f luorophenyl)pentyl ] -2-carbamoyl-2 ' ,6 ' -dichloro-1-piperazineacetani l ide C30H33CI2F2N5O2

eberconazolum eberconazole

(±)-1-(2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-y l ) imidazole C18H14Cl2N2

ecabetum ecabet

13-isopropyl-12-sulfopodocarpa-8,11,13-trien-15-oic acid C20H28O5S

engl i tazonum engl i tazone

(-)-5-[ [ (2R)-2-benzyl-6-chromanyl ]methyl ] -2,4-thiazol id inedione C20H19NO3S

enloplat inum enloplat in

c is-(1,1-cyclobutanedicarboxylato)[ tetrahydro-4H-pyran-4,4-bis(methyl-amine) ]p lat inum C13H22N2O5Pt

eprobemidum eprobemide

p-chloro-N-(3-morphol inopropyl )benzamide C14H19CIN2O2

143

arabino-hexopyranoside C50H74O14

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

fadrozolum fadrozole

(±)-p-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile C14H13N3

fantofaronum fantofarone

1-[[p-[3-[(3,4-dimethoxyphenethyl)methylamino]propoxy]phenyl]-sulfonyl]-2-isopropylindolizine C13H38N2O5S

fasudilum fasudil

hexahydro-1-(5-isoquinolylsulfonyl)-1 H-1,4-diazepine C14H17N3O2S

filgrastimum filgrastim

N-L-methionylcolony-stimulating factor (human clone 1034) C 8 4 5 H 1 3 3 9 N 2 2 3 O 2 4 3 S 9

flosatidilum flosatidil

isobutyl [2-(dimethylarnino)ethyl][[[o-(methylthio)phenyl]-[m-(trifluoromethyi)benzyl]carbamoyl]methyl]carbamate C26H34F3N3O3S

flosulidum flosulide

N-[6-(2,4-difluorophenoxy)-1-oxo-5-indanyl]methanesulfonamide C16H13F2NO4S

fluorodopum (18F) fluorodopa (18F)

3-(2-fluoro-18F-4,5-dihydroxyphenyl)-L-alanine C9H10

18FNO4

fomepizolum fomepizole

4-methylpyrazole C4H6N2

gadodiamidum gadodiamide

aqua[N,N-bis[2-[(carboxymethyl)[(methylcarbamoyl)methyl]amino]ethyl]-glycinato(3-)]gadolinium hydrate C16H28GdN5O9 · x H2O

gadoteridolum gadoteridol

(±)-[10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclodecane-1,4,7-triacetato[(3-)]gadolinium C17H29GdN4O7

giracodazolum giracodazole

(αS)-2-amino-α-[(1S)-2-amino-1-chloroethyl]imidazole-4-methanol C6H11CIN4O

ibutilidum ibutilide

( ± )-4'-[4-(ethylheptylamino)-1-hydroxybutyl]methanesulfonanilide C20H36N2O3S

irinotecanum irinotecan

( + )-7-ethyl-10-hydroxycamptothecine 10-[1,4'-biperidine]-1'-carboxylate or ( + )-(S)-4,11-diethyl-4,9-dihydroxy-1 H-pyrano[3',4':6,7]indolizino[1,2-P]-quinoline-3,14(4H,12H)-dione 9-[1,4'-bipiperidine]-1'-carboxylate C33H38N4O6

isalsteinum isalsteine

( ± )-N-[2-[(2-methyl-4-oxo-1,3-benzodioxan-2-yl)thio]propionyl]glycine C14H15NO6S

lactitolum lactitol

4-O-β-D-galactopyranosyl-D-glucitol C12H24O11

144

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

lanreotidum lanreotide

3-(2-naphthyl)-D-alanyl-L-cysteinyl-L-tyrosyl-o-tryptophyi-L-lysyl-i.-valyl-L-cysteinyl-L-threoninamide, cyclic (2-7)-disulfide C54H69N11O10S2

ledazerolum ledazerol

2-hydroxy-3-(imidazol-4-ylmethyl)benzyl alcohol C11H12N2O2

lenograstimum lenograstim

133-[O-[O-(N-acetyl-α-neuraminosyl)-(2-3)-[O-β-D-galactopyranosyl-(1-3)]-2-acetamido-2-deoxy-β-D-galactopyranosyl]-L-threonine)]colony-stimulating factor (human clone 1034) mixture with 133-[O-[O-(N-acetyl-α-neuraminosyl)-(2-6)-O-[O-(N-acetyl-α-neuraminosyl)-(2-3)-β-D-galacto-pyranosyl-(1-3)]-2-acetamido-2-deoxy-β-D-galactopyranosyl]-L-threonine]-colony-stimulating factor (human clone 1034)

leuciglumerum leuciglumer

L-leucine polymer with 5-methyl hydrogen L-glutamate (C6H13NO2)m · (C6H1lNO4)n

leurubicinum leurubicin

(8S,10S)-10-[[3-[(S)-2-amino-4-methylvaleramido]-2,3,6-trideoxy-a-L-/yxo-hexopyranosyl]oxy]-8-glycoloyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-napnthacenedione C33H40N2O12

levofloxacinum levofloxacin

(-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid C18H20FN3O4

levomentholum levomenthol

(-)-(1R,3R,4S)-menthol C10H20O

levosulpiridum levosulpiride

(-)-N-[[(S)-1-ethyl-2-pyrrolidinyl]methyl]-5-sulfamoyl-o-anisamide C15H23N3O4S

liarozolum liarozole

( ± )-5-(m-chloro-α-imidazol-1-ylbenzyl)benzimidazole C17H13CIN4

liranaftatum liranaftate

O-(5,6,7,8-tetrahydro-2-naphthyl) 6-methoxy-N-methylthio-2-pyridinecarbamate C18H20N2O2S

lisadimatum lisadimate

(±)-glycerol 1-(p-aminobenzoate) C10H13NO4

litoxetinum litoxetine

4-(2-naphthylmethoxy)piperidine C16H19NO

lometrexolum lometrexol

N-[p-[2-[(R)-2-amino-3,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]-L-glutamic acid C21H25N5O6

145

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

loteprednolum loteprednol

chloromethyl 11β,17-dihydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate C 2 1 H 2 7 C I O 5

loxoribinum loxoribine

7-allyl-2-amino-9-β-D-ribofuranosylpurine-6,8(1 H,9H)-dione C13H17N5O6

lufironilum lufironil

N,N-bis(2-methoxyethyl)-2,4-pyridinedicarboxamide C13H19N3O4

mabuprofenum mabuprofen

( ± )-N-(2-hydroxyethyl)-p-isobutylhydratropamide C15H23NO2

masoprocolum masoprocol

meso-4,4'-(2,3-dimethyltetramethylene)dipyrocatechol C18H2204

melarsominum melarsomine

bis(2-aminoethyl) p-[(4,6-diamino-s-triazin-2-yl)amino]dithiobenzenearsonite C13H21AsN8S2

midesteinum midesteine

2-thiophenecarbothioic acid, S-ester with ( ± )-2-mercapto-N-(tetrahydro-2-oxo-3-thienyl)propionamide C12H13NO3S3

minamestanum minamestane

4-aminoandrosta-1,4,6-triene-3,17-dione C19H23NO2

mipragosidum mipragoside

N-(ll3-N-acetylneuraminosylgangliotetraosyl)ceramide, isopropyl ester C 7 6 H 1 3 7 N 3 O 3 1

mirfentanilum mirfentanil

N-(1-phenethyl-4-piperidyl)-A/-pyrazinyl-2-furamide C 2 2 H 2 4 N 4 O 2

miripirii chloridum miripirium chloride

1-tetradecyl-4-picolinium chloride C20H36CIN

mivazerolum mivazerol

α-imidazol-4-yl-2,3-cresotamide C11H11N3O2

mizolastinum mizolastine

2-[[1-[1-(p-fluorobenzyl)-2-benzimidazolyl]-4-piperidyl]methylamino]-4(3H)-pyrimidinone C24H25FN60

modecainidum modecainide

( ± )-2'-[2-(1-methyl-2-piperidyl)ethyl}vanillanilide C 2 2 H 2 8 N 2 O 3

mofezolacum mofezolac

3,4-bis(p-methoxyphenyl)-5-isoxazoleacetic acid C19H17NO5

146

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

molgramostimum molgramostim

colony-stimulating factor 2 (human clone pHG25 protein moiety reduced) C639H1007N171O196S8 (for non-glycosylated protein)

mosapraminum mosapramine

(±)-1'-[3-(3-chloro-10,11-dihydro-5H-dibenz[b, f]azepin-5-yl)propyl]hexahydro-spiro[imidazo[1,2-a]pyridine-3(2H),4'-piperidin]-2-one C28H35CIN4O

nadifloxacinum nadifloxacin

( ± )-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidino)-5-methyl-1-oxo-1 H,5H-benzo[ij]quinolizine-2-carboxylic acid C19H21FN2O4

nadroparinum calcicum nadroparin calcium

Calcium salt of depolymerized heparin obtained by nitrous acid degradation of heparin from pork intestinal mucosa; the majority of the components have a 2-O-sulfo-α-L-idopyranosuronic acid structure at the non-reducing end and a 6-O-sulfo-2,5-anhydro-D-mannitol structure at the reducing end of their chain; the average relative molecular mass is 4000 to 5000; the degree of sulfatation is about 2,1 per disaccharidic unit.

nafagrelum nafagrel

(±)-5,6,7,8-tetrahydro-6-(imidazol-1-ylmethyl)-2-naphthoic acid C15H16N2O2

nafarelinum nafarelin

5-oxo-L-prolyl-L-histidyl-u-tryptophyl-L-seryl-L-tyrosyl-3-(2-naphthyl)-D-alanyl-L-leucyl-L-arginyl-L-prolylglycinamide C66H83N17O13

naroparcilum naroparcil

p-[p-[(5-thio-β-D-xylopyranosyl)thio]benzoyl]benzonitrile C19H17NO4S2

nemazolinum nemazoline

2-(4-amino-3,5-dichlorobenzyl)-2-imidazoline C10H11Cl2N3

nemonapridum nemonapride

(±)-cis-N-(1-benzyl-2-methyl-3-pyrrolidinyl)-5-chloro-4-(methylamino) o-anisamide C21H26CIN3O2

nestifyllinum nestifylline

7-(1,3-dithiolan-2-ylmethyl)theophylline C11H14N4O2S2

neticonazolum neticonazole

(E)-1-[2-(methylthio)-1-[o-(pentyloxy)phenyl]vinyl]imidazole C17H22N2OS

nicoracetamum nicoracetam

1-(6-methoxynicotinoyl)-2-pyrrolidinone C11H12N2O3

ocaperidonum ocaperidone

3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one C24H25FN4O2

147

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

ormaplatinum ormaplatin

( ± )-frans-tetrachloro(1,2-cyclohexanediamine)platinum C6H14CI4N2Pt

otenzepadum otenzepad

( ± )-11-[[2-[(diethylamino)methyl]piperidino]acetyl]-5,11-dihydro-6W-pyrido[2,3-b][1,4]benzodiazepin-6-one C24H31N5O2

oxiglutationum oxiglutatione

N,N'-[dithiobis[(R)-1-[(carboxymethyl)carbamoyl]ethylene]]di-L-glutamine C 2 0 H 3 2 N 6 O 1 2 S 2

palonidipinum palonidine

(± )-3-(benzylmethylamino)-2,2-dimethylpropyl methyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate C29H34FN3O6

panipenemum panipenem

( + )-(5R,6S)-3-[[(S)-1-acetimidoyl-3-pyrrolidinyl]thio]-6-[(R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid C15H21N3O4S

parnaparinum natricum parnaparin sodium

Sodium salt of depolymerized heparin obtained by hydrogen peroxide and cupric acetate degradation of heparin from bovine and pork intestinal mucosa; the majority of the components have a 2-O-sulfo-α-L-idopyrano-suronic acid structure at the non-reducing end and a 2-N,6-O-di-sulfo-D-glucosamine structure at the reducing end of their chain; the average relative molecular mass is between 4000 and 6000 (5000 ± 20 per cent); the degree of sulfatation is 2,15 (± 10 per cent) per disaccharidic unit.

pegademasum pegademase

adenosine deaminase, reaction product with succinic anhydride, esters with polyethylene glycol monomethyl ether The species specificity should be indicated in brackets after the name.

pegaspargasum pegaspargase

asparaginase, reaction product with succinic anhydride, esters with polyethylene glycol monomethyl ether

picumeterolum picumeterol

(-)-(R)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridyl)ethoxy]hexyl]amino]-methyl]benzyl alcohol C21H29CI2N3O2

pidotimodum pidotimod

(R)-3-[(S)-5-oxoprolyl]-4-thiazolidinecarboxylic acid C9H12N2O4S

pirodavirum pirodavir

ethyl p-[2-[1-(6-methyl-3-pyridazinyl)-4-piperidyl]ethoxy]benzoate C21H27N3O3

pirodomastum pirodomast

4-hydroxy-1-phenyl-3-(1-pyrrolidinyl)-1,8-naphthyridin-2(1 H)-one C18H17N3O2

porfimerum natricum imer sodium

photofrin II

148

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

prinoxodanum prinoxodan

3,4-dihydro-3-methyl-6-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2(1 H)-quinazolinone C13H14N4O2

prisotinolum prisotinol

(±)-6-[2-(isopropylamino)propyl]-3-pyridinol C11H18N2O

propagermanium propagermanium

polymer obtained from 3-(trihydroxygermyl)propionic acid (C3H5GeO3,5)n

quinotolastum quinotolast

4-oxo-1-phenoxy-N-1 H-tetrazol-5-yl-4H-quinolizine-3-carboxamide C17H12N6O3

quinupristinum quinupristin

N-[(6R,9S,10R,13S,15aS,22S,24aS)-22-[p-(dimethylamino)benzyl]-6-ethyl-docosahydro-10,23-dimethyl-5,8,12,15,17,21,24-heptaoxo-13-phenyl-18-[[(35)-quinuclidinylthio]methyl]-12H-pyrido[2,1-f]pyrrolo[2,1-/][1,4,7,10,13,16]oxa-pentaazacyclononadecin-9-yl]-3-hydroxypicolinamide C53H67N9O10S

racementholum racementhol

(±)-(1R*,3H*,4S*)-menthol C10H20O

regramostimum regramostim

colony-stimulating factor 2 (human clone pCSF-1 protein moiety reduced), glycoform GMC 89-107 C 6 3 7 H 1 0 0 3 N 1 7 1 O 1 9 7 S 8

repagermanium repagermanium

poly-trans-[(2-carboxyethyl)germasesquioxane] (C18H30Ge6O21)n

reviparinum natricum reviparin sodium

Sodium salt of depolymerized heparin obtained by nitrous acid degradation of heparin from pork intestinal mucosa; the majority of the components have a 2-O-sulfo-α-L-idopyranosuronic acid structure at the non-reducing end and a 6-O-sulfo-2,5-anhydro-D-mannitol structure at the reducing end of their chain; the average relative molecular mass is 3500 to 4500, 90 per cent of which ranging between 2000 and 8000; the degree of sulfatation is about 2,2 per disaccharidic unit.

rispenzepinum rispenzepine

( ± )-6,11-dihydro-11-(1-methylnipecotoyl)-5H-pyrido[2,3-b][1,5]berizo-diazepin-5-one C19H20N4O2

ritolukastum ritolukast

1,1,1-trifluoro-α-2-quinolylmethanesulfon-m-anisidide C17H13F3N2O3S

roxadimatum roxadimate

ethyl (± )-p-[bis(2-hydroxypropyl)amino]benzoate C15H23NO4

sagandipinum sagandipine

methyl (5-piperidinomethyl)furfuryl 4-(o-fluorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate C27H31FN2O5

149

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

sapropterinum sapropterin

(-)-(6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(3H)-pteridinone C9H15N5O3

sarpogrelatum sarpogrelate

(±)-2-(dimethylamino)-1-[[o-(m-methoxyphenethyl)phenoxy]methyl]ethyl hydrogen succinate C24H31NO6

semotiadilum semotiadil

( + )-(R)-2-[5-methoxy-2-[3-[methyl[2-[3,4-methylenedioxy)phenoxy]ethyl]-amino]propoxy]phenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one C29H32N2O6S

serazapinum serazapine

methyl ( ± )-1,3,4,16b-tetrahydro-2-rnethyl-2H,10H-indolo[2,1-c]pyrazino-[1,2-a][1,4]benzodiazepine-16-carboxylate C22H23N3O2

siltenzepinum siltenzepine

5-[N,N-bis(2-hydroxyethyl)glycyl]-8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one C19H20CIN3O4

somagrebovum somagrebove

1-[N2-(N-L-methionyl-L-α-aspartyl)-L-glutamine]growth hormone (ox reduced) C 9 8 7 H 1 5 5 4 N 2 6 8 O 2 9 1 S 9

somavubovum somavubove

127-L-leucinegrowth hormone (ox) C 9 7 6 H l 5 3 3 N 2 6 5 O 2 8 6 S 8

sorivudinum sorivudine

( + )-1-β-D-arabinofuranosyl-5-[(E)-2-bromovinyl]uracil C11H13BrN2O6

sparfloxacinum sparfloxacin

5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid C 1 9 H 2 2 F 2 N 4 O 3

spiriprostilum spiriprostil

(±)-(5R*,6S, 7R*)-7-hexyl-2,4-dioxo-1,3-diazaspiro[4,4]nonane-6-heptanoic acid C20H34N2O4

sucrosofatum sucrosofate

sucrose octakis (hydrogen sulfate) C12H22O35S8

sulazurilum sulazuril

2-[3,5-dichloro-4-[p-(methylsulfonyl)phenoxy]phenyl]dihydro-1-methyl-as-triazine-3,5(2H,4H)-dione C17H15CI2N3O5S

suleparoidum natricum suleparoid sodium

heparitin sulfate, sodium salt (C14H18NO17S2Na3)n

sulofenurum sulofenur

1-(p-chlorophenyl)-3-(5-indanylsulfonyl)urea C18H15CIN2O3S

150

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

sulukastum sulukast

3-[[(1 R,2E,4Z)-1-[(αS)-α-hydroxy-m-1 H-tetrazol-5-ylbenzyl]-2,4-tetradecadienyl]thio]propionic acid C25H36N4O3S

sumarotenum sumarotene

1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-[(5)-a-methyl-p-(methylsulfonyl)-styryljnaphthalene C 2 4 H 3 0 O 2 S

suplatastum tosilas suplatast tosilate

(±)-[2-[[p-(3-ethoxy-2-hydroxypropoxy)phenyl]carbamoyl]ethyl]-dimethylsulfonium p-toluenesulfonate C23H33NO7S2

tamsulosinum tamsulosin

(-)-(R)-5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzene-sulfonamide C20H28N2O5S

taurosteinum taurosteine

N-2-thenoyltaurine C7H9NO4S2

tebufelonum tebufelone

3',5'-di-tert-butyl-4'-hydroxy-5-hexynophenone C20H28O2

technetii (99mTc) bicisas technetium (99mTc) bicisate

[N,N'-ethylenedi-L-cysteinato(3-)]oxo[99mTc] technetium(V), diethyl ester C12H21N2O5S2

99mTc

technetium (99mTc) siboroximum technetium (99mTc) siboroxime

[bis[(2,3-butanedione dioximato) (1-)-O][(2,3-butanedione dioximato) (2-)-O]isobutylborato(2-)-N, N', N'', N''', N'''', N'''''] chloro[99mTc]technetium (lll) C16H29BClN6O6

99mTc

telmesteinum telmesteine

(-)-3-ethyl hydrogen (R)-3,4-thiazolidinedicarboxylate C7H11NO4S

teludipinum teludipine

(±)-4-[o-[(E)-2-carboxyvinyl]phenyl]-2-[(dimethylamino)rnethyl]-1,4-dihydro-6-methyi-3,5-pyridinedicarboxylic acid, 4-tert-butyl diethyl ester C28H38N2O6

tematropii metilsulfas tematropium metilsulfate

3α-hydroxy-8-methyl-1αH, 5αH-tropanium methyl sulfate (salt), (±)-ethyl hydrogen phenylmalonate C21H31NO8S

temocaprilum temocapril

( + )-(2S,6R)-6-[[(1S)-1-carboxy-3-phenylpropyl]amino]tetrahydro-5-oxo-2-(2-thienyl)-1,4-thiazepine-4(5H)-acetic acid, 6-ethyl ester C23H28N2O5S2

tenosalum tenosal

2-thiophenecarboxylic acid, ester with salicylic acid C12H8O4S

tenosiprolum tenosiprol

(R)-4-hydroxy-L-proline 2-thiophenecarboxylate (ester) C10H11NO4S

151

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

terbequinilum terbequinil

1,4-dihydro-1-(methoxymethyl)-4-oxo-N-propyl-3-quinolinecarboxamide C15H18N2O3

terikalantum terikalant

(-)-1-[2-(4-chromanyl)ethyl]-4-(3,4-dimethoxyphenyl)piperidine C24H31NO3

tiagabinum tiagabine

(-)-(R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid C 2 0 H 2 5 N O 2 S 2

tibeglisenum tibeglisene

( + )-5-(p-chlorophenyl)-2-(p-tolylsulfonyl)-4-pentynoic acid C18H15CIO4S

tirilazadum tirilazad

21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16a-methylpregna-1,4,9(11 )-triene-3,20-dione C38H52N6O2

tulopafantum tulopafant

( + )-3'-benzoyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxanilide C25H19N3O2S

utibaprilum utibapril

(S)-2-tert-butyl-4-[(S)-N-[(S)-1-carboxy-3-phenylpropyl]alanyl]-Δ2-1,3,4-thiadiazoline-5-carboxylic acid, 4-ethyl ester C22H31N3O5S

vamicamidum vamicamide

(± )-(R*)-α-[ (R*)-2-(dimethylamino)propyl]-a-phenyl-2-pyridineacetamide C18H23N3O

vanoxerinum vanoxerine

1-[2-[bis(p-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine C28H32F2N2O

vinfosiltinum vinfosiltine

[23(S)]-4-deacetyl-3-de(methoxycarbonyl)-3-[(2-methyl-1-phosphonopropyl)carbamoyl]vincaleukoblastine, diethyl ester C51H72N5O10P

vinleucinolum vinleucinol

[23(1S,2S)]-4-deacetyl-3-[(1-carboxy-2-methylbutyl)carbamoyl]-3-de(methoxycarbonyl)vincaleukoblastine, ethyl ester C51H69N5O3

vorozolum vorozole

( + )-6-(p-chloro-α-1 H-1,2,4-triazol-1-ylbenzyl)-1-methyl-1 H-benzotriazole C16H13CIN6

zabiciprilatum zabiciprilat

(S)-2-[(S)-N-[(S)-1-carboxy-3-phenylpropyl]alanyl]-2-azabicyclo[2.2.2]octane-3-carboxylic acid C21H28N2O5

zalospironum zalospirone

(1R*,2fi*,5S*,6S*,7S*,8R*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-tricyclo[4.2.2.02.5]deca-3,9-diene-7,8-dicarboximide C24H29N5O2

152

Recommended International Nonproprietary Name (Latin, English)

Chemical Name or Description and Molecular Formula

zaltoprofenum zaltoprofen

( ± )-10,11-dihydro-α-methyl-10-oxodibenzo[b,f]thiepin-2-acetic acid C17H14O3S

zatosetronum zatosetron

5-chloro-2,3-dihydro-2,2-dimethyl-N-1αH,5αH-tropan-3α-yl-7-benzofuran-carboxamide C19H25CIN2O2

zenarestatum zenarestat

3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazo-lineacetic acid C17H11BrCIFN2O4

zeniplatinum zeniplatin

cis-[2,2-bis(aminomethyl)-1,3-propanediol](1,1-cyclobutane-dicarboxylato) platinum C11H20N2O6Pt

zilascorbum (2H) zilascorb (2H)

5,6-O-[(RS)-benzylidene-α-d]-L-ascorbic acid C13H11DO6

zileutonum zileuton

( ± )-1-(1-benzo[b]thien-2-ylethyl)-1 -hydroxyurea C11H12N2O2S

zofenoprilatum zofenoprilat

(4S)-1-[(S)-3-mercapto-2-methylpropionyl]-4-(phenylthio)-L-proline C15H19NO3S2

zopolrestatum zopolrestat

3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazineacetic acid C19H12F3N3O3S

153

AMENDMENTS TO PREVIOUS LISTS

WHO Chronicle, Vol. 19, No. 4, 5 and 6, 1965

Recommended International Nonproprietary Names (Rec. INN): List 5

p. 9 galantaminum galantamine

replace the chemical name by the following: 1,2,3,4,6,7,7a,11c-octahydro-9-methoxy-2-methylbenzofuro[3a,3,2-ef][2]-benzazepin-6-ol

Supplement to WHO Chronicle, Vol. 35, No. 5, 1981

Recommended International Nonproprietary Names (Rec. INN): List 21 p. 2

p. 6

amifostinum amifostine

loprazolamum loprazolam

replace the chemical name and the molecular formula by the following: S-[2-[(3-aminopropyl)amino]ethyl] dihydrogen phosphorothioate C5H15N2O3PS

replace the chemical name by the following: (Z)-6-(o-chlorophenyl)-2,4-dihydro-2-[(4-methyl-1-piperazinyl)methylene]-8-nitro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-one

Supplement to WHO Chronicle, Vol. 39, No. 5, 1985

Recommended International Nonproprietary Names (Rec. INN): List 25 p. 5

p. 6

efrotomycinum efrotomycin

enoxapannum enoxaparin

insert enoxaparinum natricum enoxaparin sodium

replace the chemical name by the following:

insert Sodium salt of depolymerized heparin obtained by alcaline degradation of heparin benzyl ester from pork intestinal mucosa; the majority of the components present a 2-O-sulfo-4-enepyranosuronic acid structure at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine structure at the reducing end of their chain; the average relative molecular mass is about 4500, ranging between 3500 and 5500; the degree of sulfatation is about 2 per disaccharidic unit.

Supplement to WHO Chronicle, Vol. 40, No. 6, 1986

Recommended International Nonproprietary Names (Rec. INN): List 26

p. 4 epalrestatum epalrestat

replace the chmical name by the following: 5-[(Z,E)-β-methylcinnamylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid

154

an antibiotic produced by Streptomyces lactamdurans efrotomycin A1, or (αS,2R,3R,4R,6S)-4-[[6-deoxy-4-0-(6-deoxy-2,4-di-0-methyl-a-L-manno-pyranosyl)-3-0-methyl-β-D-allopyranosyl]oxy]-N-[(2E,4E,6S,7R)-7-[(2S.3S,-4R,5R)-5-[(1E,3E,5E)-6-(1,2-dihydro-4-hydroxy-1-methyl-2-oxonicotinoyl)-1,3,5-heptatrienyl]tetrahydro-3,4-dihydroxy-2-furyl]-6-methoxy-5-methyl-2,4-octadienyl]-a-ethyltetrahydro-2,3-dihydroxy-5,5-dimethyl-6-[(1E,3Z)-1,3-pentadienyl]-2H-pyran-2-acetamide

delete the whole entry

SELECTED WHO PUBLICATIONS OF RELATED INTEREST

The use of essential drugs Fourth report of the WHO Expert Committee WHO Technical Report Series, No. 796 1990 (57 pages)

WHO model prescribing information: drugs used in anaesthesia 1989 (53 pages)

WHO model prescribing information: drugs used in parasitic diseases 1990 (128 pages)

WHO model prescribing information: drugs used in mycobacterial diseases 1991 (40 pages)

Guidelines for developing national drug policies 1988 (iv + 52 pages)

The International Pharmacopoeia, third edition Volume 1: general methods of analysis. 1979 (223 pages) Volume 2: quality specifications. 1981 (342 pages) Volume 3: quality specifications. 1988 (407 pages)

Basic tests for pharmaceutical substances 1986 (vi + 204 pages)

Basic tests for pharmaceutical dosage forms 1991 (v + 129 pages)

International Nonproprietary Names (INN) for pharmaceutical substances, cumulative list no. 7 1988 (xviii + 617 pages)

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