WHO DRUG

INFORMATION

VOLUME 8 - N U M B E R 3 1994

RECOMMENDED INN LIST 34 INTERNATIONAL NONPROPRIETARY N A M E S F O R P H A R M A C E U T I C A L SUBSTANCES

WORLD HEALTH ORGANIZATION • GENEVA Volume 8, Number 3, 1994 World Health Organization, Geneva

WHO Drug Information

Contents

General Policy Topics Regulatory Matters Ethics and drug promotion: the CIOMS Large-scale HIV vaccine trials deferred 152 consensus 123 Antidepressants and hyponatraemia 152 Azapropazone and photosensitivity 153 Personal Perspectives Blood: safeguards to prevent Revision of the IFPMA code of pharmaceutical transmission of pathogens 153 Bromocriptine: no longer recommended to marketing practices 125 suppress lactation 153 Counterfeit medicines: a growing concern 154 Update on AIDS Felbamate and aplastic anaemia 154 HIV vaccines: advances and setbacks 128 Neuroleptic sensitivity in dementia 155 Zidovudine: redressment of early expectations 130 Nonsteroidal anti-inflammatory drugs: Zidovudine: renewed encouragement 131 relative safety 155 China to work with the European Reports on Individual Drugs Pharmacopoeia Commission 156 Antiarrhythmic agents: more concerns over Move to ban distribution of drug samples 156 risks and benefits 134 Theophylline potentiated by fluvoxamine 156 Oral contraceptives: no apparent association Tiaprofenic acid and severe cystitis 156 with diabetic complications 135 Zidovudine approved to prevent HIV Oral contraceptive use and protection against transmission in pregnancy 157 ovarian cancer 136 Ethical criteria for medicinal drug promotion 157 Postmenopausal use of estrogens: a risk factor for breast cancer 137 Essential Drugs Nicotine substitution therapy 140 Psoriasis 161 Dithranol 162 General Information Salicylic acid 162 Management of acute lymphoblastic leukaemia: Tar products 162 a need for compromise between extended survival and long-term toxicity? 143 Recent Publications Drug toxicity and P-glycoproteins 145 Bioethics: a professional responsibility 164 Drug-resistant pneumococal infections: a fast deteriorating situation 148 Osteoporosis in chronic inflammatory disease: Recommended International a need to reevaluate corticosteroid therapy? 149 Nonproprietary Names: List 34 165

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WHO Drug Information Vol. 8, No. 3, 1994

General Policy Topics

There was recognition throughout the consultation Ethics and drug promotion: that progress will be dependent upon the leadership the CIOMS consensus provided by WHO, since the Organization is particularly well placed to develop dialogue on how In 1988, the World Health Organization issued control of advertising can best be integrated into the ethical criteria for medicinal drug promotion in process of drug registration without limiting the response to a request by the World Health capacity to meet other vital objectives of the Assembly. The objective was to ensure that all regulatory process. Indeed, several relevant parties involved with the promotion of medicines activities are already in hand: would seek to support and encourage the improvement of health care through the rational use • WHO is promulgating its Guiding principles for of medicinal drugs. This message was directed not small national drug regulatory authorities, and only to pharmaceutical manufacturers and distri­ preparing complementary model legislation; butors but also to health personnel involved in supplying, dispensing and prescribing drugs; • it has created a model software package to patient and consumer groups; and the media support drug registration, which centres around (including publishers and editors of medical the establishment of an approved scientific data journals). sheet; • it is maintaining its system of information exhange Sensing a need to promote more effective use of on national regulatory decisions, and is producing the criteria, the Assembly subsequently requested Model Prescribing Information; and that a meeting of representatives of the various interested parties be convened "to discuss possible • it is negotiating a more searching factual basis for approaches to further advancing the principles the WHO Certification Scheme on the quality of embodied in [the criteria]". This meeting, jointly pharmaceutical products moving in international organized by WHO and the Council for International commerce. Organizations of Medical Sciences (CIOMS), was held in April 1993. Its report* reflects the spirit of the The criteria serve as a reminder that information meeting. It focuses primarily on the application of needed to assure safe and effective use is an the criteria in developing countries. It does not dwell integral component of every drug product. WHO on the deficiencies of the past. It sets out a remains acutely aware that in the majority of its commitment as agreed between the parties and Member States far too little "independent" factual outlines tasks for the future. It also defines an information about the properties and use of overriding ethical precept: the right to be informed. medicines is available to prescribers, patients and other users of these products. Nor do the resources The nineteen recommendations of the consultation exist in these countries to provide comprehensive are broad in scope. They relate to education and oversight of promotional activities. Much thus communication; the interface between promotion depends upon the observance of voluntary codes of and regulation; the development of national practice and two events have occurred in the wake policies; and international collaboration. It appears of the CIOMS meeting that strike a tone of that all the interested parties accept the validity of encouragement: the criteria and that they are prepared to work collaboratively to further their implementation. The International Federation of Pharmaceutical However, it was generally appreciated that Manufacturers Associations (IFPMA) has challenging problems will continue to emerge, and extensively revised its code of pharmaceutical that the criteria themselves may need to be marketing practices (see also page 125), while the adapted from time to time. International Committee of Medical Journal Editors has emphasized that editors must have full * Forty-seventh World Health Assembly. WHO ethical responsibility for advertising policy, and that criteria for medicinal drug promotion. Report by the advertising must be separate from, and not be Director-General, A47/7, 1994. (See also page 157.) allowed to influence, editorial decisons.

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On the other side of the coin, Health Action promotional practice; and consumer groups at International has undertaken a review of the international, national and local levels should promotion of over-the-counter drugs within continue to work with governments and industry to countries acknowledged to maintain the highest promote constructive actions, to monitor com­ standards of regulation*, and it has concluded that pliance with the criteria, and to create a critical existing practices still fail to provide the safeguards awareness of their provisions among consumers. that society might reasonably expect. WHO and CIOMS, it is suggested, should bring these and other parties, including donor organiza­ Meanwhile there is much for WHO to attend to. It tions, into more effective interaction, and consider was agreed at the meeting that — in consultation convening regional meetings as occasion arises. with interested parties — the Organization should periodically review the ethical criteria; monitor their Education of interest groups and the public at large implementation and develop performance indicators on the principles embodied in the criteria is for this purpose; consider what remedial measures recognized to be of critical importance in their should be taken in the event of non-compliance; acceptance and implementation. Reliance is vested and assess the current and potential capacity within in WHO, universities and other interested parties to governments in countries at various levels of develop and issue relevant materials. WHO is also development to implement appropriate drug urged to extend the scope of its Model Prescribing regulation and to control promotional activities. Information and to assume the lead in promoting the provision of therapeutic guidelines for All interested parties, it was proposed, should prescribers in a form that is independent and underscore the importance of incorporating the comparative, and propounds the concepts of the criteria into national drug policies. Similarly, it was ethical criteria. All interested parties are urged to agreed that national industry associations should explore how they might act as clearing-houses for be set up in each country with a view to maintaining specific types of information relevant to appropriate standards on a voluntary basis, and implementation of the criteria. that the international associations should assist in their establishment. More specifically, it was agreed At the conclusion of the meeting it was acknow­ that WHO, together with associations representa­ ledged by consensus that the spirit that had tive of consumers, industry and national medical characterized the proceedings reflected "a common associations should develop and adopt standards commitment to enhance the positive contributions of training and responsibilities of medical of medicinal drugs to the well-being of people in all representatives, and rules for conducting countries, with special concern for those of the sponsored medical symposia, in ways consistent developing world, and to ensure that this contribu­ with the criteria. tion is not impeded by inappropriate drug pro­ motion." The test now is whether this commitment Vital contributions are expected from specific can be effectively sustained. An impressive start interest groups. Editors of scientific journals, it is has been made: it is now for each interest group to proposed, should develop advertising guidelines in review the recommendations as a whole and to compliance with the criteria; international industry ensure that they are contributing effectively to the associations should assure consistency with the full range of recommendations that constitutes the criteria in further developing their own codes of package that all parties were persuaded to adopt.

* Kardewy, H., Wieringa, N., Herxheimer, A., Vos, R. A searching look at advertising: a content analysis of magazine and newspaper advertisements for OTC medicines and health products in 11 countries. International Organization of Consumers Unions and University of Groningen, 1994. Available from IOCU Programme, 24 Highbury Crescent, London N5 1RX, United Kingdom.

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Personal Perspectives

Revision of the IFPMA code Revision of the code The 1994 edition of the IFPMA code, like the of pharmaceutical marketing original version, defines not only globally-applicable practices baseline standards of marketing practices but also provides an operational code for dealing with Margaret C. Cone complaints concerning the promotion of medicines. In order to make the complaints procedure more Vice-President for Scientific Affairs transparent: International Federation of • there is now a clearer separation of the "operative Pharmaceutical Manufacturers paragraphs" of the code from the preambular Associations (IFPMA) paragraphs; • information is provided on the procedure for At its seventeenth Assembly in Sweden in making a complaint under the IFPMA code; September 1994, the International Federation of Pharmaceutical Manufacturers Associations • there is a more detailed description of the way in (IFPMA) presented a revised and updated version which the IFPMA processes and evaluates of its self-regulatory code of pharmaceutical complaints. marketing practices, which was first adopted in 1981. The main changes which have been made to the "operative" sections of the code include the The coexistance of self-regulation and government following: regulation of pharmaceutical marketing and adver­ tising has been the subject of discussion and • The section on medical representatives has been debate for many years. Some countries such as the considerably enlarged and covers training, USA, have a long history of regulatory control and company responsibilities and remuneration. in others — the United Kingdom for example — the pharmaceutical industry association has operated a • The section on symposia, congresses and other self-regulatory code of practice for more than thirty means of verbal communication has also been years. However, many developing countries cannot expanded significantly and gives detailed afford to implement comprehensive regulatory guidance on sponsorship of conferences, control over the marketing of medicines. Neither do hospitality and the payment of travel, accommo­ they have strong local industry associations to help dation and honoraria. with the task. Recognition of this situation led to the adoption of the internationally-applicable IFPMA • Other conditions relating to hospitality and gifts code more than a decade ago, and this has have been set out in a separate section on remained an important factor in the recent decision hospitality and promotional items which bans for its revision. inappropriately lavish hospitality and gifts, while still allowing health care providers to receive text In 1993, the members of the IFPMA agreed that the books or reference books/information, and other time had come for the text of the IFPMA code to be educational material if they serve a genuine updated to set out in more detail the concepts and educational function principles of good marketing practices for prescrip­ tion medicines. At that time, IFPMA was actively • The section on printed promotional material has involved with the WHO/CIOMS consultation on the been rewritten to make a clearer distinction implementation of WHO's ethical criteria and the between the information which must appear in all recommendations from that consultation were, of advertisements and the special requirements for course, one of the important factors taken into full advertisements and "reminder" advertise­ consideration in the review process. ments.

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• In recognition of the trend towards greater The distribution of periodic reports will continue availability of information on medicines, a section under the revised code but, in addition, information on communications to the public has been on cases where a breach of the code is determined included which refers to the conditions under will be made public immediately, identifying the which information on prescription medicines may company concerned and the complainant, and be provided directly to the public. information will also be disclosed in cases where the company fails to respond within the agreed time Compliance with the code limit. The code puts emphasis on the management responsibility of individual companies for monitoring An important factor in the effectiveness of the their own promotional activities worldwide. It IFPMA code is that complaints are not only dealt specifies that "Companies should establish and with through the company subsidiary in the country maintain appropriate procedures to ensure full where they occur, but are also sent directly to top compliance with appropriate national and management at the headquarters of the company. international codes and to review and monitor ail of The deterrent impact of adverse publicity and action their promotional activities and materials. " at senior company level should not be under­ All companies are encouraged to follow the estimated as a preventive measure against code example of the many which have already violations. established internal codes and rules that must be observed by their own employees in conducting The code and the WHO ethical criteria promotional activities. In a letter addressed to the In revising the IFPMA Code, account was taken of chief executive officers of companies within the the corresponding and relevant sections of the Federation's membership, the President of IFPMA WHO ethical criteria and the introductory section. has stressed that "the first essential is for heads of The revised code states: companies to ensure that respect for the IFPMA code is an integral part of company policy." "The Federation recognizes the value of the defin­ ition by the World Health Organization in 1988 of The role of national regulatory authorities is also Ethical criteria for medicinal drug promotion. The stressed in the IFPMA code. Throughout the text present version of the IFPMA code is consonant there is emphasis on the need to comply not only with these criteria, to the extent that they are with the code but also with legal and regulatory applicable to our constituents." requirements, which must have precedence over any action taken by the IFPMA on complaints. In Some sections of the WHO ethical criteria — for the absence of local regulatory controls, reference example, those dealing with the advertising of is made to the way in which a medicine is products for self medication — are outside the authorized in countries with highly evolved scope of the IFPMA code. The inclusion of authorities and the text points out that "It is the requirements for product labels and data sheets sovereign right of any country, in which were also considered to be out of place in a self- pharmaceuticals are marketed, to decide which regulatory code. These are covered by regulations products should be available. " in so many countries that it would not be useful to include details in the international code, other than While the code operates primarily through en­ to say, as now, that national rules and regulations couraging self-audit to prevent misconduct, the must be followed and take precedence. complaint procedure for dealing with breaches after they have occurred must have "teeth" in order to be As already explained, the revision process also effective, and the main sanction remains that of took into account the discussions and adverse publicity. IFPMA has, since 1983, recommendations from the WHO/CIOMS published periodic status reports on the complaints Consultation on WHO's ethical criteria for medicinal received under the code, giving the names of drug promotion, which took place in April 1993. In companies which are found to be in breach and the particular, it reflects concerns about the need to remedial action that has been taken. These reports "formulate approaches to problems associated with are sent to Health Ministries, WHO's Director- medical representatives and symposia". General and staff, and the medical press. IFPMA Member Associations are asked to circulate code The report of the consultation recognized the status reports to member companies, government "complementarity of self regulation and national contacts and the media.

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regulation" and recommended that "the IFPMA, the • encourage the establishment and membership of WFPMM (World Federation of Proprietary Medicine new industry associations in countries where none Manufacturers), national associations and local exists. companies continue to develop their own codes relating to the promotion of medicinal drugs in ways Conclusion which are consistent with the ethical criteria". Pharmaceutical products are of little value without information. Prescribers must be informed of the In response to this, the Annex to the code includes availability and use of established medicines, and a section entitled encouragement of adherence to new and improved medicines can only find their the code which mandates the IFPMA Secretariat to: place in therapeutics if their existence and properties are brought to the attention of the health care professions. If prescribers are unaware of new • collect and disseminate information on activities of developments, the enormous cost and effort of national associations related to marketing innovation and discovery may be wasted. In practices, including the establishment, democratic societies, advertising and promotion of strengthening and implementation of national self- pharmaceuticals are the main ways in which this regulatory codes of practice, and steps taken to dissemination of information is achieved and thus, encourage companies to adhere to the IFPMA in some respects, these activities can be code; considered as an extension of the process of research and development. • provide advice and make recommendations to member associations on the establishment and It follows, therefore, that the manufacturer has a strengthening of national codes and procedures responsibility to ensure that as much attention is for their implementation, based on experience paid to the quality of product information as is paid gained in operating the IFPMA code; to the quality of the product itself, and this includes the information conveyed through all advertising, • develop contacts and arrange meetings with other marketing and other promotional activities. interested parties in order to provide a forum for the discussion of issues related to promotion and The 1994 edition of the IFPMA code is being widely marketing practices; distributed — to WHO, government, industry and other interested parties, as well as publicized in the • encourage industry associations, in countries technical press and media. Copies can be obtained where the IFPMA does not have a member, to join from: IFPMA, 30, rue de St-Jean, P.O. Box 9, 1211 the Federation, which entails commitment to the Geneva 18, Switzerland. Tel: +41 (22) 340 12 00, IFPMA code; Fax:+41 (22) 340 13 80

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Update on AIDS

HIV vaccines: cell-mediated cytotoxic T-cell response. Given this hypothesis, a candidate vaccine should conse­ advances and setbacks quently induce both antibody and cell-mediated immunity. Breakdown of the immune system is the hallmark of infection by the human immunodeficiency virus Notwithstanding their marked genetic variability (9- (HIV). This effect results from selective infection 11), the envelope glycoproteins of HIV, gp120 and and loss of CD4 T lymphocytes, a subset of gp160, have long been the primary foci for vaccine immunocompetent cells that determine protective development (12-15). This is because neutralizing responses against environmental pathogens. Early antibodies to these proteins, and vaccines in the course of HIV infection immune mechanisms developed from these proteins — more consistently remain well preserved. During this period both cell- gp120 — have been shown to protect primates mediated responses and neutralizing antibodies are from infection with either homologous virus or virus- directed against the virus. infected cells (16-19). However, the degree to which the vaccines might confer protection against Whereas antibody may protect against initial infec­ heterologous strains of HIV-1, or induce demon­ tion by free virus, the high levels of neutralizing strable cell-mediated cytotoxicity, has remained antibody produced by most HIV-positive patients do uncertain. In all, seven subtypes of HIV-1 have not eradicate an established infection, nor do they been identified by sequencing the genes express­ prevent progression to AIDS (1). In the early stage ing gp120 (20). It is from the B-subtype, which is of infection, it seems that a cytotoxic cell-mediated dominant within the United States and Europe, that response may be of greater importance. the strains commonly used in production of candidate vaccines — MN, SF-2, and IIIB — have The early phase of HIV infection is typically charac­ been selected. terized by a short-lasting febrile illness accom­ panied by an initial intense viraemia (2). Within a day or two of the onset of symptoms cytotoxic Preliminary study of such preparations in sero­ T lymphocytes proliferate (3, 4) and levels of negative volunteers at low risk of infection has circulating viral antigen rapidly decline. The aroused optimism that safe and immunogenic available evidence indicates that immunogenic vaccines can be developed, although it is too early epitopes in the outer envelope of the virus stimulate to venture any prediction regarding their prospec­ proliferation of antigen-specific clones of cytotoxic T tive clinical efficacy. A subunit vaccine containing lymphocytes which, by a lytic action, provide the IIIB strain of gp120 has been shown to produce protective immunity (5). neutralizing antibodies, not only to the homologous IIIB glycoprotein but also, in some subjects, to MN This type of immune response is probably an and SF-2 (15). More recently, a double-blind, important defence mechanism against the gener­ randomized, placebo-controlled study of a vaccine ality of acute viral infections (5), but in HIV infection derived from recombinant gp120 from the MN strain it tends to wane rapidly as the disease progresses (21) has indicated that multiple injections broaden (4, 5). However, there is inferential evidence that, and increase the neutralizing antibody response. exceptionally, this response may abort an early infection: some individuals at risk of HIV who In the latter study, groups of 12 volunteers received remain healthy and who do not produce HIV anti­ 4 successive doses of either 100, 300 or 600 µg of bodies have positive cellular immune responses to recombinant gp120 at 0, 4, 24, and 48 weeks. Two HIV peptides (6-8). doses were sufficient to induce neutralizing anti­ bodies in most volunteers. Administration of two These observations hold relevance to the develop­ further doses substantially increased the antibody ment of protective vaccines. It seems that at the titres, and the fourth dose induced antibody- time of initial infection, HIV may be neutralized by dependent, cell-mediated cytotoxic T-cell circulating antibody. If the virus evades this protec­ responses in slightly more than one-third of the tive mechanism, however, it may still succumb to a subjects. In all, three doses of the vaccine induced

128 WHO Drug Information Vol. 8, No. 3, 1994 Update on AIDS

neutralizing antibodies against MN, SF-2, and IIIB considerably higher rates of incident HIV infection. in 96%, 94%, and 63% of subjects respectively. It is recognized that, in the last analysis, such a trial offers the only assured means of establishing the The investigators emphasize that immunogenicity efficacy of a candidate vaccine with the precision may not be indicative of a protective effect and that necessary to assess its potential value in field if, indeed, neutralizing antibodies are protective, conditions. they may fail to provide the breadth of immunity needed to protect against all prevalent HIV-1 References variants. Much concern was generated when sera 1. Mossman, T. Cytokine patterns during the progression from these vaccinees failed in vitro, to neutralize to AIDS. Science, 265: 193-194 (1994). closely-related strains of HIV freshly isolated from 2. Daar, E., Moudgil, T., Meyer, R., Ho, D. Transient high other subjects (21, 22). However, the relevance of levels of viremia in patients with primary human immuno­ this test has been thrown into doubt by the finding deficiency virus type 1 infection. New England Journal of that sera from chimpanzees, protected against HIV Medicine, 324: 961-964 (1991). infection, did not neutralize the same virus grown in cell lines (21, 22). 3. Safrit, J., Andrews, C, Zhu, T. et al. Characterization of human immunodeficiency virus type-1 specific cytotoxic L lymphocyte clones isolated during acute seroconversion: Since no laboratory test is yet available to predict recognition of autologous virus sequences within a con­ vaccine-induced protection of human subjects from served immunodominant epitope. Journal of Experimental HIV infection, definitive assessments can be made Medicine, 179: 463-472 (1994). only in prospective clinical studies of candidate vaccines. Since 1988, more than 1400 volunteers in 4. Pantaleo, G., Demarest, J., Soudeyns, H. et al. Major whom HIV infection was initially excluded have expansion of CD8+ T cells with a predominant Vb usage enrolled in 17 clinical studies involving 12 vaccines during the primary immune response to HIV. Nature, 370: organized under the aegis of the US National 463-467(1994). Institute of Allergy and Infectious Diseases (22, 23). 5. Koup, R., Ho, D. Shutting down HIV. Nature, 370: 416 These studies, which embrace those described (1994). above, are too small to provide information on efficacy. They are designed to assess both 6. Clerici, M., Giorgi, J., Chou, C. et al. Cell-mediated immunogenicity and safety. Much publicity has immune response to human immunodeficiency virus (HIV) recently been accorded to information that some 13 type 1 in seronegative homosexual men with recent of these subjects have acquired HIV infection sexual exposure to HIV-1. Journal of Infectious Diseases, subsequent to their enrolment in the trials (23, 24). 165: 1012-1019 (1992). Because each of the tested vaccines contains only gp120 of HIV (produced either by recombinant DNA 7. Rowland-Jones, S., Nixon, D., Aldhous, M. et al. HIV- technology or chemical peptide synthesis) and not specific cytotoxic T-cell activity in an HIV-exposed but uninfected infant. Lancet, 341: 860-861 (1993). reverse transcriptase or other components necessary for viral replication, these infections 8. Langlade-Demoyen, P., Ngo-Giang-Huong, N. cannot be attributed to vaccination. Indeed, most Oksenhendler, E. Human immunodeficiency virus (HIV) were acquired before the subject had completed nef-specific cytotoxic T lymphocytes in noninfected the projected course of immunizations, and in each heterosexual contact of HIV-infected patients. Journal of case high-risk sexual behaviour was reported (25). Clinical Investigation, 93: 1293-1297 (1994).

9. Leigh Brown A. Sequence variability in human immuno­ Largely because of uncertainty about the efficacy of deficiency viruses: pattern and process in viral evolution. the currently-available vaccines, the only two AIDS, 5(suppl. 12): 35-42 (1991). products under investigation in phase 2 trials — gp120 MN, Genentech; and gp120 SF-2, Biocine — 10. Kusumi, K., Conway, B., Cunningham, S. et al. Human will not immediately be taken into large phase 3 immunodeficiency virus type I envelope gene structure trials in the USA (26). The circumstances and diversity in vivo after co-cultivation in vitro. Journal of influencing this decision are described on page 152 Virology, 66: 875-885 (1992). of this journal. They apply exclusively to the situation that prevails in the USA. Those involved 11. Mascola, J., Louwagie, J., McCutchan, F. et al. Two with the decision have emphasized that it should antigenically distinct subtypes of human immuno­ not delay or otherwise prejudice consideration of a deficiency virus type I: viral genotype predicts neutralization serotype. Journal of Infectious Diseases, phase 3 trial within any country burdened with 169: 48-54 (1994).

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12. Dolin, R., Graham, B., Greenberg, S. et al. The safety 25. Belshe, R., Bolognesi, D., Clements, M. et al. HIV and immunogenicity of a human immunodeficiency virus infection in vaccinated volunteers. Journal of the American type 1 (HIV-1) recombinant gp160 candidate vaccine in Medical Association, 272: 431 (1994). humans. Annals of Internal Medicine, 114: 119-127 (1991). 26. National Institute of Allergy and Infectious Diseases. NIAID advisors recommend continuing but not expanding 13. Fast, P., Walker, M. Human trials of experimental at this time ongoing trials of two candidate HIV vaccines. AIDS vaccines. AIDS, 7 (suppl 1): 147-159 (1993). National Institutes of Health, Bethesda, MD. June 1994.

14. Belshe, R., Clements, M., Dolin, R. et al. Safety and immunogenicity of a fully glycosylated recombinant gp160 HIV-1 vaccine in low risk volunteers. Journal of Infectious Zidovudine: redressment Diseases, 168:1387-1395 (1993). of early expectations

15. Schwartz, D., Gorse, G., Clements, M. et al. Induction In 1987, a placebo-controlled clinical trial of of HIV-1 neutralising and syncytium-inhibiting antibodies zidovudine in AIDS was terminated prematurely in seronegative recipients of HIV-1 MN rgp120 subunit vaccine. Lancet, 342: 69-73 (1993). after patients had been treated for an average period of some 20 weeks (1). More deaths and 16. Berman, P., Gregory, T., Riddle, L el al. Protection of more opportunistic infections had been recorded chimpanzees from infection by HIV-1 after vaccination among the patients allocated to placebo and, in with recombinant glycoprotein gp120 but not gp 160. vitro, zidovudine had already been shown to inhibit Nature, 345: 622-625 (1990). the replication of human immunodeficiency virus (HIV) (2). A means had been found, it seemed, of 17. Girard, M., Kieny, M., Pinter, A. et al. Immunization of suppressing the infection; further adminstration of chimpanzees confers protection against challenge with placebo was consequently regarded as unethical; human immunodeficiency virus. Proceedings of the and a resounding success was claimed for the National Academy of Sciences, USA, 88: 542-546 (1991). concept of the accelerated clinical trial. 18. Fultz, P., Nara, P., Barre-Sinoussi, F. et al. Vaccine The results of this single study had immediate protection of chimpanzees against challenge with HIV-1 impact on the routine management of AIDS. infected peripheral blood mononuclear cells. Science, 256: 1687-1690 (1992). Antiviral therapy first with zidovudine, and latterly with other nucleoside analogues, became the 19. Mannhalter, J., Pum, M., Wolf, H. et al. Immunization cornerstone of management — notwithstanding of chimpanzees with the HIV glycoprotein gp160 induces early concerns about potential toxicity and long-lasting T-cell memory. AIDS Research and Human development of resistance (3). The limitations in the Retroviruses, 7: 485-493 (1991). value of antiviral therapy took considerably longer to become recognized and accepted. It is now 20. Myers, G., Korber, B., Wain-Hobson, S. et al. Human evident, when treatment is started after the retroviruses and AIDS. National Laboratory of Theoretical diagnosis of AIDS, that use of zidovudine cannot be Biology and Biophysics, Los Alamos, NM. 1993. expected to extend survival time for more than a year or two (4-9). 21. Belshe, R., Graham, B., Keefer, M. et al. Neutralizing antibodies to HIV-1 in seronegative volunteers immunized with recombinant gp120 from the MN strain of HIV-1. There remained the possibility that starting treat­ Journal of the American Medical Association, 272: 475- ment early in the asymptomatic phase of HIV 480 (1994). infection might have greater potential, but experience has since indicated that this has little 22. Cohen, J. The HIV vaccine paradox. Science, 264: influence on overall survival time (10-12). indeed, 1072-1074 (1994). an observational study of some 750 homosexual men conducted in San Francisco between 1983 23. National Institute of Allergy and Infectious Diseases. Scientific review supports expanded clinical studies of two and 1993 indicates that prophylaxis and treatment candidate HIV vaccines. National Institutes of Health, of Pneumocystis carinii pneumonia is more Bethesda, MD. April 1994. important than antiviral therapy in extending life (13). Yet, where it can be afforded, antiviral therapy 24. National Institute of Allergy and infectious Diseases. remains entrenched in routine management of HIV infection in vaccine trial volunteers. National Institutes symptomatic HIV infection (14) on the basis that it of Health, Bethesda, MD. June 1994. confers "limited but measurable benefit" (15).

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The Lancet, in a recent editorial (16), laments the 9. Lundgren, J., Phillips, A., Pedersen, C. et al. Com­ disillusionment and confusion that prevails among parison of long-term prognosis of patients with AIDS clinicians and patients over the value of antiviral treated and not treated with zidovudine. Journal of the therapy. At the same time, however, it emphasizes American Medical Association, 271: 1088-1092 (1994). the need to obtain more information about the use of nucleoside analogues in children. It estimates 10. Hamilton, J., Hartigan, P., Simberkoff, M. et al. A controlled trial of early versus late treatment with that more than 4000 young HIV-positive patients zidovudine in symptomatic human immunodeficiency virus have been enrolled in therapeutic trials, many of infection: results of the Veterans Affairs Cooperative which have involved use of antivirals. None the Study. New England Journal of Medicine, 326: 437-443 less, it documents continued uncertainty and wide (1992). variations in the use of these products among paediatricians. Despite the general aura of 11. Aboulker, J-P., Swart, A. Preliminary analysis of the disappointment over the suppressive action of Concorde trial. Lancet, 341: 889-890 (1993). antivirals, it argues strongly in favour of continuing an ongoing European multicentre study designed to 12. Concorde Coordinating Committee. Concorde: MRC/ compare the results of immediate and deferred ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV zidovudine therapy in paediatric practice. infection. Lancet, 343: 871-881 (1994). References 13. Osmond, D., Charlbois, E., Lang, W. et al. Changes in 1. Fischl, M., Richmann, D., Grieco, M. et al. The efficacy AIDS survival time in two San Francisco cohorts of of azidothymidine (AZT) in the treatment of patients with homosexual men, 1983 to 1993. Journal of the American AIDS and AIDS-related complex: a double-blind, placebo- Medical Association, 271: 1083-1087 (1994). controlled trial. New England Journal of Medicine, 317: 185-191 (1987). 14. Sande, M., Carpenter, C, Cobbs, G. et al. Anti¬ retroviral therapy for adult HIV-infected patients: 2. Mitsuya, H., Weinhold, K., Furman, P. et al. 3'-azido-3'- recommendations from a state-of-the-art conference. deoxythimidine (BW A509U): an antiviral agent that Journal of the American Medical Association, 270: 2583- inhibits the infectivity and cytopathic effect of human T- 2589(1993). lymphotropic virus type lll/lymphadenopathy-associated virus in vitro. Proceedings of the International Academy of 15. Phair, J. Effectiveness of zidovudine in treatment of Sciences, USA. 82: 7096-7100 (1985). advanced HIV infection, Journal of the American Medical Association, 271: 1121 -1122 (1994). 3. Erice, A., Balfour, H. Resistance of human immuno­ deficiency virus type 1 to antiretroviral agents: a review. 16. Editorial. Zidovudine for mother, fetus, and child: hope Clinically Infectious Diseases, 18: 149-156 (1994). or poison? Lancet, 344: 207-209 (1994). 4. Baccetti, P., Osmond, D., Chaisson, R. et al. Survival patterns of the first 500 patients with AIDS in San Francisco. Journal of Infectious Diseases, 157: 104-157 Zidovudine: (1988). renewed encouragement 5. Creagh-Kirk, T., Doi, P., Andrews, E. et al. Survival experience among patients with AIDS receiving Disappointment over the limitations of suppressive zidovudine. Journal of the American Medical Association, antiviral therapy in established HIV infection has 260: 3009-3015 (1988). recently been relieved by evidence that zidovudine may be effective in preventing vertical transmission 6. Lemp, G., Payne, S., Neal, D. et al. Survival trends for patients with AIDS. Journal of the American Medical of HIV-infection from mother to child. It is now clear Association, 263: 402-406 (1990). that the majority of paediatric infections result from maternal transmission which occurs with varying 7. Seage, G., Landers, S., Lamb, G., Epstein. A. Effect of intensity in different settings and has been reported changing patterns of care and duration of survival on the to attain levels approaching 50% (1-5). Clinical cost of treating the acquired immunodeficiency syndrome studies indicate that transmission is facilitated when (AIDS). American Journal of Public Health, 80: 835-839 the mother has advanced disease, a low CD4 cell (1990). count, or a high viral load (6-8). Typically, it occurs 8. Moore, R., Hidalgo, J., Sugland, B., Chaisson, R. late in pregnancy (9-12), frequently at the time of Zidovudine and the natural history of the acquired birth (13), and sometimes as a result of breast­ immunodeficiency syndrome. New England Journal of feeding (14, 15). Medicine, 324: 1412-1416 (1991).

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Zidovudine is already widely used by obstetricians Taken together, the results of these two studies to treat HIV-infected pregnant women, and the suggest that maternal zidovudine therapy may limited data available suggest that it is relatively reduce vertical transmission even in the presence well tolerated both by the mother and the fetus of advanced disease and that infants may not (16-18). Slightly reduced haemoglobin concentra­ require prolonged treatment after birth. More needs tions among treated infants have returned rapidly to to be known about the effect of maternal risk normal following withdrawal of zidovudine (17). factors, the optimum timing of treatment, and the Until recently, however, no formal studies had been minimum dosages required. Above all, to be published to assess the effect of this therapy on absolutely certain that zidovudine has prevented transmission. Firm data have now been presented and not merely suppressed the infective process, from two independent studies undertaken in the there is a need to maintain the children of USA to indicate that pre- and perinatal zidovudine zidovudine-treated mothers under extended therapy considerably reduces the risk of vertical observation. transmission (17, 18). References The first of these studies to be reported was a 1. Blanche, S., Rouzioux, C, Moscato, M. et al. A placebo-controlled randomized trial involving prospective study of infants born to women seropositive symptom-free, HIV-positive pregnant women for human immunodeficiency virus type 1. New England presenting with a CD4 count greater than 200/µL Journal of Medicine, 320: 1643-1648 (1989). (17). Oral zidovudine administered at a dose of 100 mg five times daily from the 14th to the 31st 2. Ryder, R., Nsa, W., Hassig, S. et al. Perinatal transmission of the human immunodeficiency virus type 1 week of pregnancy was supplemented (in 80% of to infants of seropositive women in Zaire. New England cases) with an intravenous infusion of zidovudine Journal of Medicine, 320: 1637-1642 (1989). during labour, and babies in the treated group continued to receive zidovudine syrup, 2mg/kg for 3. Halsey, N., Boulos, R., Holt, E. et al. Transmission of the first 6 weeks of life. The first scheduled analysis HIV-1 infections from mothers to infants in Haiti: impact on showed that only 8% of the infants who received child mortality and malnutrition. Journal of the American zidovudine, compared with some 25% of those in Medical Association, 264: 2088-2092 (1990). the placebo group, had become HIV-positive. In the face of an estimated two-thirds reduction in trans­ 4. Hutto, C, Parks, W., Lai, S. et al. A hospital-based mission rate, the trial was terminated when less prospective study of perinatal infection with human immunodeficiency virus type 1. Journal of Pediatrics, 118: than 500 of a planned intake of 750 women had 347-353 (1991). been enrolled. 5. European Collaborative Study. Risk factors for mother- The second investigation was a non-randomized to-child transmission of HIV-1. Lancet, 339: 1007-1012 prospective cohort study involving 63 HIV-positive (1992). pregnant women, most of whom were symptom- free, but many of whom had lower CD4 cell counts 6. Mayers, M., Davenny, K., Schoenbaum, E. et al. A at delivery than the women enrolled in the placebo- prospective study of infants of human immunodeficiency virus seropositive and seronegative women with a history controlled trial (18). In all, 28 women received of intravenous drug use or of intravenous drug-using sex zidovudine antepartum at a dose of 500 mg daily partners, in the Bronx, New York City. Pediatrics, 88: for a mean period of 13.6 weeks. This was sup­ 1248-1256 (1991). plemented in most cases with a slow intravenous infusion of zidovudine during labour, but none of the 7. St Louis, M., Kamenga, M., Brown, C. et al. Risk for infants received zidovudine therapy. Overall, only 1 perinatal HIV-1 transmission according to maternal of 26 women who received antepartum and/or immunologic, virologie, and placental factors. Journal of intrapartum zidovudine treatment was shown to the American Medical Association, 269: 2853-2859 have transmitted HIV-1 to her infant, compared with (1993). 12 of 42 women who did not receive zidovudine. The one mother who transmitted HIV to her infant, 8. Blanche, S., Mayaux, M., Rouzioux, C. et al. Relation of the course of HIV infection in children to the severity of the despite prenatal zidovudine therapy, had a history disease in their mothers at delivery. New England Journal of varicella-zoster infection and cocaine use during of Medicine, 330: 308-312 (1994). pregnancy. It is probable that this infant acquired infection during labour which was complicated by 9. Centers for Disease Control and Prevention. Morbidity early rupture of membranes and fetal distress. and Mortality Weekly Report: HIV/AIDS Surveillance Report. 5: 3-9 (1993).

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10. Ehrnst, A., Lindgren, S., Dictor, M., et al. HIV in 15. Lederman, S. Estimating infant mortality from human pregnant women and their offspring: evidence for late immunodeficiency virus and other causes in breast­ transmission. Lancet, 338: 203-207 (1991). feeding and bottle-feeding populations. Pediatrics, 89: 290-296 (1992). 11. Kivine, A., Firtion, G., Cao, L. et al. HIV replication during the first weeks of life. Lancet, 339: 1187-1189 16. Sperling, R., Stratton, P., O'Sullivan, M. et al. A survey (1992). of zidovudine use in pregnant women with immuno­ deficiency virus infection. New England Journal of 12. Luzuriaga, K., McQuilken, P., Alimenti, A. et al. Early Medicine, 326: 857-861 (1992). viremia and immune responses in vertical human immunodeficiency virus type 1 infection. Journal of 17. Centers for Disease Control and Prevention. Infectious Diseases, 167: 1008-1013 (1993). Zidovudine for the prevention of HIV transmission from mother to infant. Morbidity and Mortality Weekly Report, 13. Goedert, J., Duliege, A., Amos, C. et al. High risk of 43: 285-287 (1994). HIV-1 infection for first-born twins. Lancet, 338: 1471- 1475 (1991). 18. Boyer, P., Dillon, M., Navaie, M. et al. Factors predictive of maternal-fetal transmission of HIV-1 : 14. Dunn, D., Newell, M., Ades, A., Peckham, C. Risk of preliminary analysis of zidovudine given during pregnancy human immunodeficiency virus type 1 transmission and/or delivery. Journal of the American Medical through breast-feeding. Lancet, 340: 585-588 (1992). Association, 271: 1925-1930 (1994).

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Reports on Individual Drugs

Antiarrhythmic agents: more the other drug. Sotalol was effective in 69% of cases while lidocaine was effective in only 18%. concerns over risks and benefits The apparent superiority of sotalol in the emer­ In vulnerable individuals, antiarrhythmic agents can gency treatment of sustained ventricular tachy­ themselves exacerbate potentially fatal ventricular cardia is likely to reflect its effect, contrary to that of arrhythmias, including sustained ventricular lignocaine, in prolonging the intra-ventricular action tachycardia and ventricular fibrillation (1, 2). potential and increasing the effective refractory period (15). On the available evidence, sotalol Uncertainty and controversy consequently still seems to offer a reasonably safe and effective surround their use in suppressing ventricular agent for terminating both ventricular and supra­ ectopic beats in patients with recent myocardial ventricular tachycardia even in smaller hospitals infarction, and many national drug regulatory where diagnostic facilities and specialist care are authorities have restricted their indications to the limited and where it is impossible to attempt over­ treatment of life-threatening ventricular arrhythmias drive pacing, or cardioversion in patients under (3). anaesthesia. None the less, even within this small trial, the In the most comprehensive comparative clinical results underscore the dangers inherent in using study as yet undertaken in patients with ventricular any anti-arrhythmic agent in ventricular tachycardia. tachyarrythmias, the beta-adrenoreceptor anta­ Two of three deaths that occurred were considered gonist, sotalol, has been shown to hold significant to be drug related and four other episodes were advantage over six other widely-used anti-arrhyth­ recorded of severe hypotension necessitating mic agents in two vital aspects: it is associated with cardioversion. The risk of life-endangering reactions a lower rate of recurrence of the arrhythmia and can be reduced by clinical acumen: hyperkalemia with increased survival (4). It remains possible, and other electrolyte imbalances, drug overdose, however, since no comparison has been made with myxoedema and hypothermia are predisposing placebo, that sotalol might, like other anti-arrhyth­ factors to serious ventricular arrhythmias that mic agents, increase mortality among vulnerable should be excluded before a decision is taken to post-infarction patients, albeit to a lesser degree administer antiarrhythmic drugs. However, since than the other drugs. the danger of cardiac arrest is ever present in sustained ventricular tachycardia, a compromise Given these findings, and supporting electrophysio­ has to be made between diagnostic accuracy and logical evidence (5-8), sotalol is an obvious can­ the need for prompt intervention. didate drug for acute termination of spontaneous sustained ventricular tachycardia in conscious References patients. Yet, after 40 years, intravenous lidocaine remains widely used for this purpose, notwith­ 1. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and standing that its efficacy is low, that early recur­ flecainide on mortality in a randomized trial of arrhythmia rence is a frequent event (9-11), and that its use suppression after myocardial infarction. New England appears to increase overall mortality post-infarction Journal of Medicine, 321: 406-412 (1989). (12, 13) 2. The Cardiac Arrhythmia Suppression Trial The anticipated superiority of sotalol in sustained Investigators. II. Effect of the antiarrhythmic agent ventricular tachycardia has now been demonstrated moricizine on survival after myocardial infarction. New England Journal of Medicine, 327: 227-233 (1992). in a small randomized, double-blind, cross-over trial (14) in which 33 conscious patients — most of 3. Ward, D., Camm, A. Dangerous ventricular arrhythmias whom had a history of previous cardiac infarction — — can we predict drug efficacy? New England Journal of received either 100 mg lidocaine or 100 mg sotalol Medicine, 329: 498-499 (1993). intravenously over 5 minutes. Those who remained unresponsive 15 minutes later additionally received

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4. Mason, J. for the Electophysiologic Study versus Electrocardiographic Monitoring Investigators. A Oral contraceptives: no comparison of seven antiarrhythmic drugs in patients with apparent association with ventricular tachyarrhythmias. New England Journal of Medicine, 329: 452-458 (1993). diabetic complications

5. Senges, J., Langfelder, W., Jauering, R. et al. In developed countries diabetic microvascular Electrophysiologic testing of therapy with sotalol for disease is now the foremost cause of renal failure sustained ventricular tachycardia. Circulation, 69: 577-584 and blindness in adult patients (1-3), and diabetes (1984). is now recognized to be the most important pre­ disposing factor to ischaemic heart disease in 6. Brachman, J., Senges, J., Langfelder, W. et al. young women (4). Contribution of delayed ventricular repolarization to the anti-arrhythmic efficacy of sotalol. European Heart Oral contraceptives are frequently prescribed for Journal, 6(suppl D): 171-174 (1985). young women with insulin-dependent diabetes 7. Nademanee, K., Feld, G., Hendrickson, J. et al. mellitus, yet there has been speculation that their Electrophysiologic and antiarrhythmic effects of sotalol in use might accelerate the development of both patients with life-threatening ventricular tachyarrhythmias. microvascular complications and atherosclerosis. Circulation, 72: 555-564 (1985). This is because these preparations tend to raise blood pressure (5), and because the progestogen 8. Singh, S., Cohen, A., Chen, Y. et al. Sotalol for component of these preparations can both reduce refractory sustained ventricular tachycardia and nonfatal glucose tolerance, possibly by increasing insulin cardiac arrest. American Journal of Cardiology, 62: 399- resistance (6, 7), and increase serum cholesterol 402(1988). concentrations (8-10). 9. Armengol, R., Graff, J., Baerman, J., Swiryn, S. Lack of effectiveness of lidocaine for sustained, wide QRS There is independent evidence that diabetic complex tachycardia. Annals of Emergency Medicine, 18: patients with even marginally raised blood pressure 254-257 (1989). (11, 12) and also those with a poor record of blood glucose control (13, 14) are at increased risk of 10. Gorgels, A., van den Dool, A., Hofs, A. et al. Procaine renal and retinal vascular damage. However, few is superior to lidocaine in terminating sustained ventricular data have been compiled to indicate whether use of tachycardia. Circulation, 80(suppl II): 652 (1989). oral contraceptives significantly augments this risk (15, 16). 11. Griffith, M., Linker, N., Garratt, C. et al. Relative efficacy and safety of intravenous drugs for termination of sustained tachycardia. Lancet, 336: 670-673 (1990). One small cross-sectional study has suggested, paradoxically, that exposure to oral contraceptives 12. MacMahon, S., Collins, R., Peto, R. et al. Effects of might actually reduce diabetic retinal damage (15). prophylactic lidocaine in suspected acute myocardial Now, a larger retrospective case-control study has infarction: an overview of results from the randomized, also failed to demonstrate a positive association controlled trials. Journal of the American Medical either of retinopathy or serum cholesterol con­ Association, 260: 1910-1916 (1988). centrations with oral contraceptive use (16). 13. Hine, L, Laird, N., Hewitt, P., Chalmers, T. Meta- analytic evidence against prophylactic use of lidocaine in These reassuring results have important practical acute myocardial infarction. Archives of Internal Medicine, significance. Pregnancy is known to be an impor­ 149: 2694-2698 (1989). tant risk factor for retinal damage in diabetic women (17). It would be a sad irony if an intervention 14. Ho, D., Zecchin, R., Richards, D. et al. Double-blind intended to protect diabetic women from an impor­ trial of lignocaine versus sotalol for acute termination of tant risk factor for vascular disease, were itself spontaneous sustained ventricular tachycardia. Lancet, shown to constitute a risk factor for the same 344: 18-23 (1994). condition. This concern can now be rejected with reasonable confidence: oral contraceptives, it 15. Hill, B., Hunt, A., Courtney, K. Reentrant tachycardia seems, do not pose an additional risk for the in a thin layer of ventricular subepicardium: effects of d- sotalol and lidocaine. Journal of Cardiovascular development of early diabetic microvascular Pharmacology, 16: 871-880 (1990). disease or atherosclerosis.

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References 14. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of 1. Klein, R., Klein, B., Moss, S. et al. The Winsconsin diabetes on the development and progression of long- Epidemiologic Study of Diabetic Retinopathy, II: term complications in insulin-dependent diabetes mellitus. prevalence and risk of diabetic retinopathy when age at New England Journal of Medicine, 329: 977-986 (1993). diagnosis is less than 30 years. Archives of Ophthalmology, 102: 520-526 (1984). 15. Klein, B., Moss, S., Klein, R. Oral contraceptives in 2. Klein, R., Klein, B., Moss, S. et al. The Winsconsin women with diabetes. Diabetes Care, 13: 895-898 (1990). Epidemiologic Study of Diabetic Retinopathy, III: prevalence and risk of diabetic retinopathy when age 16. Garg, S., Chase, P., Marshall, G. et al. Oral contra­ at diagnosis is more than 30 years. Archives of Ophthal­ ceptives and renal and retinal complications in young mology, 102: 527-532 (1984). women with insulin-dependent diabetes. Journal of the American Medical Association, 271: 1099-1102 (1994). 3. Health Care Financing Administration. Research report: end stage renal disease. Office of Research and 17. Klein, B., Moss, S., Klein, R. Effect of pregnancy on Demonstration. Publication No. 032741987 (1985). progression of diabetic retinopathy. Diabetes Care, 13: 34-40 (1990). 4. Barrett-Connor, E., Wingard, D. Sex differential in ischemic heart disease mortality in diabetes: a prospective population-based study. American Journal of Epidemi­ Oral contraceptive use and ology, 118: 489-496 (1983). protection against ovarian cancer 5. Wilson, E., Cruickshank, J., McMaster, M., Weir, R. A prospective controlled study of the effect on the blood The first epidemiological indications that use of pressure of contraceptive preparations containing different combined oral contraceptives reduces the risk of types of dosages and progestogen. British Journal of ovarian cancer emerged some 15 years ago (1-5). Obstetrics and Gynaecology, 91: 1254-1260 (1984). Since then, the association has been consistently 6. Kalkhoff, R. Metabolic effects of progesterone. confirmed in a variety of settings. Recent analysis American Journal of Obstetrics and Gynecology, 142: of data derived from 12 case-control studies 735-738 (1982). involving more than 2000 US women has confirmed that the protective effect develops gradually and 7. Perlmann, J., Russell-Briefel, R., Ezzati, T., progressively (6). It first becomes apparent in Lieberknecht, G. Oral glucose tolerance and the potency women who have used oral contraceptives of contraceptive progestins. Journal of Chronic Diseases, 38: 857-864 (1985). continuously for some 3 years and, within a period of 6 years, it is fully developed. Overall, the 8. Wahl, P., Walden, C., Knopp, R. et al. Effect of available data suggest that, independently of age or estrogen/progestin potency on lipid/lipoprotein cholesterol. parity, sustained use of these products for 5 years New England Journal of Medicine, 308: 862-867 (1981). or more is associated with a reduction in the incidence of ovarian cancer of some 40-50%. 9. Cruickshanks, K., Orchard, T., Becker, D. The cardiovascular risk profile of adolescents with insulin- It has been proposed that this drug-induced dependent diabetes mellitus. Diabetes Care, 8: 118-124 protective effect results from reversible inhibition of (1985). ovulation (7). It seems, however, from data 10. Garg, S., Chase, H., Marshall, G. et al. Cholesterol presented in several case-control studies that levels and early diabetic renal and retinal damage in protection, once achieved, persists for 10 years or subjects with type 1 diabetes. Journal of Diabetes, more (5, 8-11 ). Indeed, two recent studies suggest Nutrition and Metabolism. 5: 205-209 (1992). that it may well last longer (12, 13). No pharmaco­ logical mechanism has been proposed to explain 11. Chase, H., Garg, S., Harris, S. et al. High-normal such a prolonged action. blood pressure and early diabetic nephropathy. Archives of Internal Medicine, 150: 639-641 (1990). There is also a suggestion that the newer lower- 12. Chase, H., Garg, S., Jackson, W. et al. Blood pressure dose formulations, and — with less certainty — and retinopathy in type 1 diabetes. Ophthalmology, 97: progestogen-only contraceptives, may provide a 155-159 (1990). similar degree of protection as higher dose 13. Chase, H., Jackson, W., Hoops, S. et al. Glucose contraceptive products (13, 14). Further information control and the renal and retinal complications of insulin- on the latter preparations will be of particular dependent diabetes. Journal of the American Medical interest since their contraceptive action results Association, 261: 1155-1160 (1989). primarily from changes in the physical properties of

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the cervical mucosa rather than their relatively risk of ovarian cancer associated with oral contraceptive inefficient suppressive effect on ovulation. As yet, use. New England Journal of Medicine, 316: 650-655 insufficient information has been generated to (1987). assess the effect of biphasic and triphasic 13. Rosenberg, L, Palmer, J., Zauber, A. et al. A case- preparations. control study of oral contraceptive use and invasive epithelial ovarian cancer. American Journal of References Epidemiology, 139: 654-661 (1994). 1. Newhouse, M., Pearson, R., Fullerton, J. et al. A case- control study of carcinoma of the ovary. British Journal of 14. Rosenblatt, K., Thomas, D., Noonan, E. et al. High- Preventive and Social Medicine, 31: 148-153 (1977). dose and low-dose combined oral contraceptives: protection against epithelial ovarian cancer and the length 2. Weiss, N., Lyon, J., Liff, J. et al. Incidence of ovarian of the protective effect. European Journal of Cancer, 28A: cancer in relation to the use of oral contraceptives. 1872-1876 (1992). International Journal of Cancer, 28: 669-671 (1981). 3. Hildreth, N., Kelsey, J., LiVoIsi, V. et al. An epidemio­ Postmenopausal use of estrogens: logic study of epithelial carcinoma of the ovary. American Journal of Epidemiology, 114: 398-405 (1981). a risk factor for breast cancer

4. Rosenberg, L., Shapiro, S., Slone, D. et al. Epithelial A large proportion of older women in developed ovarian cancer and combination oral contraceptives. countries are now prescribed estrogens both to Journal of the American Medical Association, 247: 3210- relieve menopausal symptoms (1, 2) and, in the 3212 (1982). longer term, to prevent or treat postmenopausal osteoporosis (3). This is illustrated in a recent 5. Cramer, D., Huchinson, G., Welch, R. et al. Factors record linkage study which has shown that, among affecting the association of oral contraceptives and women resident in the province of Saskatchewan, ovarian cancer. New England Journal of Medicine, 307: 1047-1051 (1982). Canada, who were aged between 43 and 49 years in 1976, almost one-third received supplementary 6. Whittemore, A., Harris, R., Itnyre, J. et al. Charac­ estrogens within the next decade (4). On average, teristics relating to ovarian cancer risk: collaborative these were taken for a period of some 28 months. analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. American Sustained use of estrogens among women of this Journal of Epidemiology, 136: 1184-1203 (1992). age group has other incidental effects. It alters blood lipid profiles to an extent that is highly 7. Casagrande, J., Pike, M., Ross, R. et al. Incessant protective against coronary atherosclerosis (5, 6), ovulation and ovarian cancer. Lancet, 2: 170-173 (1979). but it has also been associated with an increased 8. Tzonou, A., Day, N., Trichopoulos, D. et al. The incidence of endometrial cancer (7, 8) and — more epidemiology of ovarian cancer in Greece. European speculatively — of breast cancer (9). Given the high Journal of Cancer and Clinical Oncology, 20: 1045-1052 incidence of breast cancer and the large number of (1984). peri- and postmenopausal women using estrogens, even a small rise in relative risk associated with 9. The WHO Collaborative Study of Neoplasia and Steroid exposure would represent a large number of Contraceptives. Epithelial ovarian cancer and combined additional cases of the disease. oral contraceptives. International Journal of Epidemiology, 18: 538-545 (1989). Whether estrogen use really is associated with 10. Booth, M., Beral, V., Smith P. Risk factors for ovarian breast cancer is an issue that has long been cancer: a case-control study. British Journal of Cancer, contested. Fundamental inconsistencies exist in the 60: 592-598 (1989). results obtained from epidemiological studies (10). One aspect on which there is substantial agree­ 11. Parazzini, F., LaVecchia, C, Negri, E. et al. Pooled ment is that previous use of estrogens seems to analysis of 3 case-control studies of epithelial ovarian improve survival among postmenopausal women cancer. III. Oral contraceptive use. International Journal of with breast cancer (11-15). One possible, but Cancer, 49: 61-65 (1991). worrying, explanation is that this exposure might have promoted development of estrogen- 12. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute for dependent breast cancers that wither upon Child Health and Human Development. The reduction in estrogen withdrawal (16). A rationale consequently

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exists for postulating a positive relationship as of endometrial cancer in older women. Balanced between estrogen therapy and breast cancer. Such against these risks is not only protection against a relationship has not been detected in most of the menopausal symptoms and osteoporosis, but also published studies, but several larger studies have a reduction in the incidence of ischaemic heart suggested that long-term use of either conjugated disease which is estimated to be as high as 40- or unconjugated estrogens is associated with a 50% (1,4, 34-36). Provided that this lipid-lowering relative risk of the order of 1.5 to 1.8 (12,16-20). effect is sustained throughout the period of exposure, it has previously been possible to argue Analysis of the Canadian record linkage study, that even a small reduction in the risk of heart which involved a cohort of over 33 000 women of disease would more than offset all adverse effects whom almost 750 developed primary breast cancer of treatment (37, 38). during the period of surveillance, has provided further evidence to support the existence of such an It has also been emphasized that the excess risk of association. Some 11 000 of these women used endometrial cancer can be largely averted by estrogens unopposed by progestagens, and among concomitant administration of progestagens (36- these the average incremental risk — which only 38), although there is contention as to whether their became evident among women who had received use might at the same time attenuate the lipid- estrogens for periods in excess of 2-3 years— was lowering effect (37, 39). In contrast, there is no firm estimated, in a linear model, to be of the order of assurance that progestagens offset or attenuate the some 7% for each year of exposure (relative risk risk of breast cancer. Given the nature, prognosis 1.072, 95% confidence interval 1.02-1.13; and high prevalence of the disease, prolonged use p=0.008). This indicates a relative risk of approxi­ of postmenopausal estrogen, particularly by women mately 1.4 after 5 years of continuous use. with independent risk factors for breast cancer, now Only some 800 women included in this cohort had merits critical reappraisal. received progestagens concomitantly with Guidelines for counselling postmenopausal women estrogens. No incremental risk of breast cancer about preventive hormone therapy published by the was evident within this group, but the confidence American College of Physicians exemplify the interval was wide. Data obtained in other studies difficulty of advising patients in this context. The have been inconsistent: some provide evidence of guidelines support intervention in women at protection (21, 22), others do not (23, 24). Whereas increased risk for coronary heart disease; they supplementary progestagens protect against question whether the risks might outweigh the estrogen-induced endometrial cancer (25-27), it benefits for women at increased risk for breast remains possible but uncertain that they exert an cancer; and they advocate that women with no analogous protective effect in the breast. independent risk factors should be encouraged to formulate their own decisions once the potential In contrast, it is becoming clear that combined use benefits and risks have been explained (40). The of estrogens and progestagens in oral contra­ American College of Obstetricians and Gyne­ ceptive formulations provides no protection against cologists considers breast cancer a contraindication carcinoma of the breast in older women. The to estrogen therapy (1), but even this advice has Canadian study has indicated that sustained use of been questioned having regard to the severity of these preparations by some 3000 women menopausal changes resulting from ovarian failure experiencing a late menopause increased their risk induced by adjuvant chemotherapy (15). Only of breast cancer almost two fold, year by year, than continued epidemiological investigation can unopposed estrogens (relative risk 1.144, 95% confidence interval 1.05 -1.24; p=0.002). This consolidate the basis on which these finely equates to a relative risk of breast cancer of 1.96 balanced decisions are taken. for 5 years of continuous use. Relative risks The Saskatchewan Health Prescription Drug-Plan approaching this level have been identified in Database has demonstrated the potential that several of the many surveys in which the use of record linkage offers within a broad coverage health combined contraceptives by older women has been care system for generating data on the scale studied (1,28-33). necessary to support complex epidemiological research. Its continued funding was once in doubt. The implication of these studies is that therapeutic Its contribution to public health medicine should not use of estrogens in excess of periods of 2-3 years only have assured its future: its performance should is a significant risk factor for breast cancer as well sensitize governments and medical research

138 WHO Drug Information Vol. 8, No. 3, 1994 Reports on Individual Drugs

councils elsewhere to the advantages of maintain­ 12. Hunt, K., Vessey, M., McPherson, K. et al. Long-term ing an effective epidemiological research base as a surveillance of mortality and cancer incidence in women facility for monitoring the effects of important receiving hormone replacement therapy. British Journal of Obstetrics and Gynaecology, 94: 620-635 (1987). medical interventions. 13. Criqui, M., Suarez, L, Barrett-Connor, E. et al. Post­ References menopausal estrogen use and mortality. American Journal 1. American College of Obstetricians and Gynecologists. of Epidemiology, 128: 606-614 (1988). Hormone replacement therapy, p 166. American College of Obstetricians and Gynecologists, Washington, DC. 14. Henderson, B., Paganini-Hill, A., Ross, R. Decreased 1992. mortality in users of estrogen replacement therapy. Archives of Internal Medicine, 151: 71 -78 (1991). 2. Wiklund, I., Hoist, J., Karlberg, J. et al. A new methodological approach to the evaluation of quality of life 15. Cobleigh, M., Berris, R., Bush, T. et al. Estrogen in postmenopausal women. Maturitas, 14: 211-224 replacement therapy in breast cancer survivors: a time for (1992). change. Journal of the American Medical Association, 272: 540-545 (1994). 3. Grady, D., Rubin, S., Petitti, D. et al. Hormone therapy to prevent disease and to prolong life in post-menopausal 16. Hoover, R., Glass, A., Finkle, W. et al. Conjugated women. Annals of Internal Medicine, 15: 1016-1037 estrogens and breast cancer risk in women. Journal of the (1992). National Cancer Institute, 67: 815-820 (1981). 4. Risch, H., Howe, G. Menopausal hormone usage and breast cancer in Saskatchewan: a record-linkage cohort 17. Ewertz, M. Influence of non-contraceptive exogenous study. American Journal of Epidemiology, 139: 670-683 and endogenous sex hormones on breast cancer in (1994). Denmark. International Journal of Cancer, 42: 832-838 (1988). 5. Stampfer, M., Colditz, G., Willet, W. et al. Post­ menopausal estrogen therapy and cardiovascular disease 18. Bergkvist, L, Adami, H., Persson, I. et al. The risk of — ten-year follow-up from the Nurses' Health Study. New breast cancer after estrogens and estrogen-progestin England Journal of Medicine, 325: 756-762 (1991). replacement. New England Journal of Medicine, 321: 293- 297 (1989). 6. Bush, T., Miller, V. Effects of pharmacologic agents during the menopause: impact on lipids and lipoproteins. 19. Ross, R., Paganini-Hill, A., Gerkins, V. et al. A case- In: Mischell, D. ed. Menopause physiology and control study of menopausal estrogen therapy and breast pharmacology. Year Book Medical, Chicago, pp.187-208 cancer. Journal of the American Medical Association, 243: (1986). 1635-1639 (1980).

7. Hulka, B., Kaufmann, D., Fowler, W. et al. Pre­ 20. Brinton, L, Hoover, R., Fraumeni, J. Menopausal dominance of early endometrial cancers after long-term oestrogens and breast cancer risk. British Journal of estrogen use. Journal of the American Medical Cancer, 54: 825-832 (1986). Association, 244: 2419-2421 (1980). 21. Gambrell, R. Cancer and the use of estrogens. 8. Paganini-Hill, A., Ross, R., Henderson, B. Endometrial International Journal of Fertility, 31: 112-122 (1986). cancer and patterns of use of oestrogen replacement therapy: a cohort study. British Journal of Cancer, 59: 22. Nachtigall, L, Nachtigall, R.H., Nachtigall, R.D. et al. 445-447 (1989). Estrogen replacement therapy. II. A prospective study in the relationship to carcinoma and cardiovascular and 9. Steinberg, K., Thaker, S., Smith, S. et al. A meta­ metabolic problems. Obstetrics and Gynecology, 54: analysis of the effect of estrogen replacement therapy on 74-79 (1979). the risk of breast cancer. Journal of the American Medical Association, 265: 1985-1990 (1991). 23. Kaufman, D., Palmer, J., de Mouzon, J. et al. Estrogen replacement therapy and the risk of breast cancer: results 10. Henrich, J. The post-menopausal estrogen/breast from the Case-Control Surveillance Study. American cancer controversy. Journal of the American Medical Journal of Epidemiology, 134: 1375-1385 (1991). Association, 268: 1900-1902 (1992). 24. Colditz, G., Stampfler, M., Willett, W. et al. Type of 11. Gambrell, D. Proposal to decrease the risk and menopausal hormone use and risk of breast cancer: 12- improve the prognosis in breast cancer. American Journal year follow-up from the Nurses' Health Study. Cancer of Obstetrics and Gynecology, 150: 119-128 (1984). Causes Control, 3: 433-439 (1992).

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25. Persson, I., Adami, H., Bergkvist, L. et al. Risk of 39. Postmenopausal estrogen therapy: requirement for endometrial cancer after treatment with estrogens alone concomitant estrogen therapy. WHO Drug Information, 8: or in combination with progestagens: results of a 66-67 (1994). prospective study. British Medical Journal, 298: 147-151 (1989). 40. American College of Physicians. Guidelines for counselling postmenopausal women about preventive 26. Kennedy, D., Baum, C, Forbes, M. Noncontraceptive hormone therapy. Annals of Internal Medicine, 117: 1038- estrogens and progestins: use patterns over time. 1041 (1992). Obstetrics and Gynaecology, 65: 441-446 (1985).

27. Voigt, L, Weiss, N., Chu, J. et al. Progestagen supplementation of exogenous estrogens and risk of Nicotine substitution therapy endometrial cancer. Lancet, 338: 274-277 (1991). Smoking is the single most important cause of cancer. Estimates typical of developed countries 28. Fasal, E., Pfaffenbarger, R. Oral contraceptives as related to cancer and benign lesions of the breast. Journal indicate that approximately 30% of all deaths from of the National Cancer institute, 55: 767-773 (1975). cancer are attributable to smoking. These include up to 90% of deaths from carcinomas of the lung; a 29. Jick, H., Walker, K., Watkins, R. et al. Oral substantial proportion of deaths from cancers of the contraceptives and breast cancer. American Journal of oral cavity, the pharynx, the larynx, the oeso­ Epidemiology, 112: 577-585 (1980). phagus, the major airways, and the bladder; some deaths from cancer of the pancreas, the kidneys, 30. Vessey, M., Barron, J., Doll, R. et al. Oral contra­ the stomach, the uterine cervix, and possibly also ceptives and breast cancer: final report of an from leukaemia (1). epidemiological study. British Journal of Cancer, 47: 455-462 (1983). Strategies to help people stop smoking are 31. Rosenberg, L., Miller, D., Kaufmann, D. et al. Breast increasingly centred upon nicotine substitution (2). cancer and oral contraceptive use. American Journal of At first, it seemed that nicotine could be con­ Epidemiology, 119: 167-176 (1984). veniently administered orally in chewing gum. However, disadvantages soon became apparent; 32. Lipnick, R., Buring, J., Hennekens, C. et al. Oral patients complained of gastric irritation (3); absorp­ contraceptives and breast cancer: a prospective cohort tion was impaired by tea and acid drinks (4); the study. Journal of the American Medical Association, 255: value of substitution in primary care settings was 58-61 (1986). questioned, since a positive response often 33. Kay, C, Hannaford, P. Breast cancer and the pill - a seemed to be determined by supplementary further report from the Royal College of Practitioners' oral counselling (5); moreover, some patients seemed contraceptive study. British Journal of Cancer, 58: 675- to be transferring their dependence from cigarettes 680 (1988). to the gum (4). None the less, the conclusion has been drawn in one survey of published trials that 34. Postmenopausal estrogen therapy: checks and 4 mg nicotine gum is the most effective form of balances. WHO Drug Information, 5: 162-163 (1991). replacement therapy (6). It produces the highest blood levels of nicotine (7); it is claimed to be 35. Bush, T. The epidemiology of cardiovascular disease effective in the most dependent smokers; and point in postmenopausal women. Annals of the New York Academy of Sciences, 592: 263-271 (1990). estimates of efficacy have been used to indicate that it is effective in over 30% of patients (8). 36. Stampfer, M., Colditz, G. Estrogen replacement therapy and coronary heart disease: a quantitative Other delivery devices, including transdermal assessment of the epidemiological evidence. Preventive nicotine patches, inhalers and nasal sprays have Medicine, 20: 47-63 (1991). been developed in an attempt to circumvent some of the difficulties encountered with gum. Thus far, 37. Henderson, B., Ross, R., Lobo, R. et al. Re-evaluation only the transdermal patches have become the role of progestogen therapy after the menopause. available for routine use. Results obtained from two Fertility and Sterility, 49 (Suppl 2): 9-15 (1988). large randomized, placebo-controlled trials 38. Cummings, S., Black, D., Rubin, S. Lifetime risks of undertaken in the United Kingdom (9-11) are hip, Colles', or vertebral fracture and coronary heart typical of findings which derive largely from the UK disease among white menopausal women. Archives of and the USA, and on which several surveys and Internal Medicine, 149: 2445-2448 (1989). meta-analyses have been based (5, 6, 12-15).

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The design of the larger of these two trials (10, 11), advised to warn their patients of the dangers of which involved almost 1700 subjects, was particu­ smoking for as long as the patch is applied. larly rigorous insofar as cessation of smoking — as reported by the subjects — was confirmed by Nicotine replacement assists a minority of smokers measuring salivary cotinine concentrations or who are highly motivated to achieve their objective exhaled carbon monoxide. Nicotine or placebo of relinquishing the habit. Of far greater importance patches in various sizes (and starting with a content from the public health perspective is the need to of 21 mg) were applied over 12 weeks. At the end prohibit promotional activities directed to encourag­ of the treatment period some 11 % of subjects who ing young persons to take up smoking in the first had received placebo and almost 20% of those who place (18). Virtually all smokers become committed had received the active treatment remained before adulthood (19). In the United States alone, it abstinent (10). No more than 10% of subjects who is estimated that some 3000 new smokers must be were unlikely to have responded to placebo thus recruited each day to replace those lost by death or initially benefitted from treatment, and this abstention (20). The industry, it seems, claims that percentage was substantially attenuated after one its marketing is not aimed at children. Regardless of year, by which time some 50% of the responsive the intent, it is the effect that matters. The evidence subjects had resumed smoking (11). has been presented that, for girls and adolescent women in particular, advertising is a potent lure (18, A meta-analysis which incorporated results from 17 19). studies undertaken in the United States, and which References involved over 5000 subjects (15), has generated essentially identical information on the efficacy of 1. Austoker, J., Sanders, D., Fowler, G. Smoking and nicotine patches. It has also indicated that no cancer: smoking cessation. British Medical Joumal, 308: advantage is to be gained by extending therapy 1478-1482 (1994). beyond 8 weeks, notwithstanding recommendations offered by some manufacturers that they be applied 2. Gourlay, S., McNeil, J. Anti-smoking products. Medical for as long as 18 weeks. Journal of Australia, 153: 699-707 (1990). 3. Henningfield, J., Radzius, A., Cooper, T., Clayton, R. No mention is made in the meta-analysis of any Drinking coffee and carbonated beverages blocks absorp­ adverse haemodynamic events that might have tion of nicotine from nicotine polacrilex gum. Journal of the resulted from absorption of nicotine. Manufacturers American Medical Association, 264: 1560-1564 (1990). advise against nicotine replacement during preg­ nancy on the grounds that nicotine, by reducing 4. Hughes, J., Hatsukami, D., Skoog, K. Physical placental blood flow, may contribute to the fetal dependence on nicotine in gum. Journal of the American hypoxia and growth retardation associated with Medical Association, 255: 3277-3279 (1986). maternal smoking (16). However, there is no direct 5. Lam, W., Sze, P., Sachs, H., Chalmers, T. Meta­ evidence of this risk. analysis of randomised controlled trials of nicotine chewing-gum. Lancet, 2: 27-30 (1987). It has been claimed that use of nicotine has a lesser effect on blood pressure and heart rate than 6. Jin Ling Tang, Law, M., Wald, N. How effective is cigarette smoking (17). None the less, several case nicotine replacement therapy in helping people to stop reports submitted to the Australian regulatory smoking? British Medical Journal, 308: 21-26 (1994). authority indicate a possible association between therapy and occasional but serious cardiovascular 7. Benowitz, N., Peyton, J., Savanapridi, C. Determinants reactions (17). Typical of several events, which of nicotine intake while chewing nicotine polacrilex gum. Clinical Pharmacology and Therapeutics, 41: 467-473 were reversible on withdrawal of the patch, are (1987). signs of a cerebrovascular event which slowly resolved over a period of 10 days; an attack of 8. Blöndal, T. Controlled trial of nicotine polacrilex gum anginal pain which was immediately relieved by with supportive measures. Archives of Internal Medicine, removing the patch and taking glyceryl trinitrate; 149: 1818-1821 (1989). and severe chest pain radiating to the left arm which lasted several days. These events, together 9. Imperial Cancer Research Fund General Practice with 11 cases of gastrointestinal symptoms in which Research Group. Effectiveness of a nicotine patch in nausea predominated, have been tentatively helping people to stop smoking: results of a randomised attributed to nicotine overdosage. Prescribers are trial in general practice. British Medical Journal, 306: 1304-1308 (1993).

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10. Imperial Cancer Research Fund General Practice 15. Fiore, M., Smith, S., Jorenby, D., Baker, T. The Research Group. Randomised trial of nicotine patches in effectiveness of the nicotine patch for smoking cessation: general practice: results at one year. British Medical a meta-analysis. Journal of the American Medical Journal, 308: 1476-1477 (1994). Association, 271: 1940-1947 (1994).

11. Russell, M., Stapleton, J., Feyerabend, C. et al. 16. Benowitz, N. Nicotine replacement therapy during Targeting heavy smokers in general practice: randomised pregnancy. Journal of the American Medical Association, controlled trial of transdermal nicotine patches. British 266: 3174-3177 (1991). Medical Journal, 306: 1308-1312 (1993). 17. Adverse Drug Reactions Advisory Committee, Australian Adverse Drug Reactions Bulletin, 13: No. 2, 12. Fiore, M., Jonerby, D., Baker, T., Kenford, S. Tobacco May 1994. dependence and the nicotine patch. Journal of the American Medical Association, 268: 2687-2694 (1992). 18. Kaufman, N. Smoking and young women: the physician's role in stopping an equal opportunity killer. 13. Palmer, K., Buckley, M., Faulds, D. Transdermal Journal of the American Medical Association, 271: 629- nicotine: a review of its pharmacodynamic and pharmaco­ 630 (1994). kinetic properties, and theraprutic efficacy as an aid to smoking cessation. Drugs, 44: 498-529 (1992). 19. Pierce, J., Lee, L., Gilpin, E. Smoking initiation by adolescent girls, 1944 through 1988: an association with 14. Sigaly, C., Mant, D., Fowler, D., Lodge, M. Meta­ targeted advertising. Journal of the American Medical analysis on efficacy of nicotine replacement therapies in Association, 271: 608-611 (1994). smoking cessation. Lancet, 343: 139-142 (1994). 20. Pierce, J., Fiore, M., Novotny, T. et al. Trends in cigarette smoking in the United States. Journal of the American Medical Association, 261: 61-65 (1989).

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General Information

Management of acute lymphoblastic "central nervous system prophylaxis" based upon intrathecal administration of methotrexate and leukaemia: a need for compromise cranial irradiation has substantially increased between extended survival and 5-year survival which is now estimated to exceed 70% (12). But this gain, in turn, has been achieved long-term toxicity? at some cost. The survivors — and particularly young children (13) — are at risk of delayed The steady progress that has been made over the irradiation-induced toxicity (12, 14, 15) which can past 20 years in the management of the leukae­ result in intellectual impairment, stunted growth, mias, a group of diseases resulting from malignant (16-23) and second malignant tumours in the CNS proliferation of bone-marrow cells, is one of the (24, 25). most impressive accomplishments of modern medicine (1-4). Treatment now offers an expecta­ tion of remission, an acceptable quality of life for a Several randomized, prospective multicentre period of years and, in some cases, a prospect of studies have been organized both in Europe and long-term survival. North America to explore whether cranial irradiation can be reduced or excluded without substantial loss Acute lymphoblastic leukaemia, which is the of efficacy. Each has compared the efficacy and the commonest form of leukaemia in children, is the toxicity of methotrexate-based chemotherapy — most responsive of these diseases to conventional administered either intrathecally or at high systemic chemotherapy. With adequate treatment, children dosage — with irradiation alone and irradiation with the disease now have more than a 70% combined with chemotherapy (12). The final results chance of cure (or 5-year survival). This survival obtained in three such studies have now been rate has been achieved through multi-agent chemo­ published (26-28), but they provide no firm therapy, better supportive care and the develop­ conclusion. Indeed, fundamental inconsistencies ment of prophylactic therapy to prevent involvement have emerged. of the central nervous system. One retrospective non-randomized study indicates The antimetabolite drugs mercaptopurine and that moderate irradiation (1800cGy) is associated methotrexate were the first chemotherapeutic with a significant decline in the intelligence quotient agents used to induce remission in acute lympho­ (IQ) throughout childhood, whereas no such blastic leukemia (5). Subsequently, a combination association was apparent among those who of vincristine and prednisolone — which is claimed received chemotherapy, including high-dose to have a specific cytotoxic effect in this variety of methotrexate, alone (26). Another study, in leukaemia (6) — was shown to be less toxic to the contrast, finds that 20% of children who received bone marrow (7). Other agents, including anthra¬ high-dose methotrexate subsequently showed cyclines and L-asparaginase, were later added to abnormalities on tomographic brain-scanning and the induction regimen (8). The subsequent significant deterioration in IQ (27, 28). Neither of introduction of maintenance therapy based on these studies assesses the influence of treatment smaller doses of 6-mercaptopurine and metho­ on survival. However, a third study conducted in trexate was an important landmark in management some 1400 patients, initially considered to be at of the disease (9). Cure rates of some 40% were "intermediate risk", indicates that exposure to reported (10) and these rose progressively irradiation is associated with a significant throughout the 1980s as more intensive remission advantage in survival (29). and post-remission chemotherapy was used (3). More studies need to be undertaken, it seems, to It became apparent, however, that up to one-third establish the relative risks and benefits of irradiation of the patients who responded well to initial chemo­ and intrathecal methotrexate. There is no doubt, therapy subsequently developed leukaemia of the however, that sustained low-dose oral adminis­ central nervous system (11). The development of tration of methotrexate or mercaptopurine exerts an

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apparently specific antileukaemic effect that is 8. Mauer, A. Therapy of acute lymphoblastic leukemia in exclusive to acute lymphoblastic leukaemia (30, childhood. Blood, 56: 1-10 (1980). 31). This finding underlies much of the impressive progress that has been made in the management of 9. Pinkel, D. Curing children of leukemia. Cancer, 59: this condition (32, 33) and it contrasts strikingly with 1683-1691 (1987). general experience that high-dose chemotherapy 10. Gale, R., Butturini, A. Maintenance chemotherapy and using two or more agents in rotation is needed to cure of childhood acute lymphoblastic leukaemia. Lancet, reduce the emergence of drug resistance (34). The 338: 1315-1318 (1991). theory has been advanced that acute lymphoblastic 11. Omara, G., Moffitt, S., Vogler, R., Sutter, M. Com­ leukaemia arises in precursor cells normally pro­ bination chemotherapy of adult acute lymphoblastic grammed to die, and that low-dose maintenance leukemia with randomised central nervous system chemotherapy does not kill these cells but controls prophylaxis. Blood, 55: 199-204 (1980). growth of the leukaemia clone so that programmed death can occur (31). 12. Jenney, M. Limitation of therapy in the treatment of childhood cancer: toxicity versus cure. Lancet, 344: 210- 211 (1994). Much has been achieved through empiricism in the management of acute lymphoblastic leukaemia. 13. Jannoun, L. Are cognitive and educational develop­ The results have been impressive but, as survivors ment affected by age at which prophylactic therapy is live longer, the long-term adverse sequelae of given in acute lymphoblastic leukaemia? Archives of Diseases of Children, 58: 953-958 (1983). treatment begin to weigh as heavily in the balance as the risk of recurrence. It seems that a second 14. Riccardi, R., Brouwers, P., Di Chiro, G., Poplack, D. generation of prospective clinical studies must now Abnormal computed tomography brain scans in children be undertaken in which the long-term effects of with acute lymphoblastic leukemia: serial long-term follow therapy are evaluated as carefully as the intended up. Journal of Clinical Oncology, 3: 12-19 (1985). therapeutic response (12). 15. Poplack, D., Brouwers, P. Adverse sequelae of central nervous system therapy. Clinical Oncology, 4: 263-285 References (1985). 1. Jacobs, A., Gale, R. Recent advances in the biology 16. Moss, H., Nannis, E., Poplack, D. The effects of and treatment of acute lymphoblastic leukemia in adults. prophylactic treatment of the central nervous system on New England Journal of Medicine, 311: 1219-1231 the intellectual functioning of children with acute lympho­ (1984). cytic leukemia. American Journal of Medicine, 71: 47-52 (1981). 2. Juttner, C. Changing concepts in the management of leukaemia. Medical Journal of Australia, 151: 4351 17. Rowland, J., Glidewell, O., Silbey, R. et al. Effects of (1989). different forms of central nervous system prophylaxis on neuropsychologic function in childhood leukemia. Journal 3. Pochedly, C, Civin, C. eds. Childhood acute of Clinical Oncology, 2: 1327-1335 (1984). lymphoblastic leukemia. Part II. Hematology and Oncology Clinics of North America, 4: 871 -1017 (1990). 18. Clayton, P., Shalet, S., Morris-Jones, P., Price, D. Growth in children treated for acute lymphoblastic 4. Rivera, G., Raimondi, S., Hancock, M. et al. Improved leukaemia. Lancet, 1: 460-462 (1988). outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination 19. Cousens, P., Waters, B., Said, J., Stevens, M. chemotherapy. Lancet, 337: 61-66 (1991). Cognitive effects of cranial irradiation in leukaemia: a survey and meta-analysis. Journal of Child Psychology 5. Frei, E., Freireich, E., Gehan, E. et al. Studies of and Psychiatry, 29: 839-852 (1988). sequential and combination antimetabolite therapy in acute leukemia: 6-mercaptopurine and methotrexate. 20. Shalet, S. Endocrine consequences of treatment of Blood, 18: 431-454 (1961). malignant disease. Archives of Diseases of Children, 64: 1635-1641 (1989). 6. Donohue, S., Charlton, C. Drug treatment of acute leukaemia: current status. Drugs, 37: 926-938 (1989). 21. Brouwers, P., Poplack, D. Memory and learning sequelae in long-term survivors of acute lymphoblastic 7. Aviles, A., Sinco, A., Rivera, R. et al. Treatment of adult leukemia: association with attention deficit. American acute lymphoblastic leukemia with adriamycin, vincristine Journal of Pediatric Hematology and Oncology, 12: 174- and prednisolone. Medical and Paediatric Oncology, 11: 181 (1990). 141-145 (1983).

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22. Rubenstein, C, Varni, J., Katz, E. Cognitive 34. Goldie, J., Coldman, A. The genetic origin of drug functioning in long-term survivors of childhood leukemia: a resistance in neoplasm: implications for systemic therapy. prospective analysis. Journal of Developmental and Cancer Research, 44: 3643-3653 (1984). Behavioural Pediatrics, 11: 301-305 (1990).

23. Moore, I., Kramer, J., Wara, W. et al. Cognitive function in children with leukemia. Effect of radiation dose Drug toxicity and P-glycoproteins and time since irradiation. Cancer, 68: 1913-1917 (1991) Within the past 20 years, a family of large cell 24. Rimm, I., Tarbell, F., Winston, K., Sallan, S. Brain membrane proteins known as P-glycoproteins has tumors after cranial irradiation for childhood acute been recognized to be of fundamental importance lymphoblastic leukemia. Cancer, 59: 1506-1508 (1987). in protecting cells and organ systems from noxious, naturally-occurring substances. Each consists of 25. Neglia, J., Meadows, A., Robison, L. et al. Second two similar arms comprising an intracellular ATP neoplasms after acute lymphoblastic leukemia in child­ binding site and six putative transmembrane loci hood. New England Journal of Medicine, 325: 1330-1336 (1, 2). Interest in these substances was first (1991). generated when they were shown to induce drug resistance in mammalian tumour cells by actively 26. Jankovic, M., Brouwers, P., Valsecchi, M. et al. Association of 1800 cGy cranial irradiation with intellectual extruding hydrophobic chemotherapeutic agents, function in children with acute lymphoblastic leukaemia, including actinomycins, anthracyclines, epipodo¬ Lancet, 344: 224-227 (1994). phyllotoxins, taxanes and vinca alkaloids (3-5). Much effort has since been directed to developing 27. Ochs, J., Milhern, R., Fairclough, D. et al. Comparison specific inhibitors of value not only in reversing of neuropsychologic functioning and clinical indicators of acquired resistance in cancer cells (12), but also in neurotoxicity in long-term survivors of childhood leukemia reversing the resistance of malaria parasites to given cranial radiation or parenteral methotrexate: a antimicrobial agents (13, 14). Moreover, since the prospective study. Journal of Clinical Oncology, 9: 145- penetration of many drugs into the central nervous 151 (1991). system can be increased by short-term pharmaco­ 28. Milhern, R., Fairclough, D., Ochs, J. A prospective logical blockade of P-glycoproteins, the same comparison of neuropsychologic performance of children approach might also be used to enhance the surviving leukemia who received 18-G, 24-G, or no cranial delivery of antibiotics and psychoactive agents to irradiation. Journal of Clinical Oncology, 9: 1348-1356 the central nervous system. (1991). As yet, however, the success of this research is far 29. Tubergen, D., Gilchrist, G., O'Brien, R. et al. from guaranteed. Animal species have evolved Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: comparison of cranial radiation because they have developed efficient mechanisms and intrathecal methotrexate and the importance of that protect them against the plethora of potentially systemic therapy: a Children's Cancer Group report. toxic substances in their diet and in their general Journal of Clinical Oncology, 11: 520-526 (1993). environment (15). P-glycoproteins are a vital component of these defences. They are strategic­ 30. Advisory Committee of the International Bone Marrow ally located in the brush border of the proximal Transplant Registry. Effect of methotrexate on relapse renal tubules, at the biliary surface of hepatocytes, after bone-marrow transplantation for acute lymphoblastic at the apical surface of mucosal cells in the small leukemia. Lancet, 1: 535-537 (1989). and large intestine, and in the capillary endothelial cells of the brain and various other vital organs 31. Gale, R., Butturini, A. Maintenance chemotherapy and (16-18). This distribution assures active excretion cure of childhood acute lymphoblastic leukaemia. Lancet, of toxic xenobiotics into bile, urine and the intestinal 338: 1315-1318 (1991). lumen, and prevents their accumulation in critically 32. Lonsdale, D., Gehan, E., Fernbach, D. et al. Inter­ important tissues including the brain, adrenal rupted vs continued maintenance therapy in Childhood cortex, testis, ovary and placental trophoblasts. leukemia. Cancer, 36: 341-352 (1975). Among currently-available drugs, both verapamil 33. Working party on leukaemia in childhood. Improve­ and ciclosporin reversibly block P-glycoprotein ment in treatment for children with acute lymphoblastic leukaemia. Lancet, 1: 408-411 (1986). activity (19). Each of these drugs has been shown in animal models (20) and in clinical studies (21) to

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potentiate the toxic effects of vincristine, etoposide, established. Nor has any substantive evidence daunorubicin, and doxorubicin. emerged to suggest that comparably sensitive individuals exist in human populations. Indeed, the The potential benefits of P-glycoprotein blockade suggestion has been made that lack of expression may thus be seriously offset by increased drug- of either of the two P-glycoproteins that have been induced toxicity. Two fundamental drawbacks identified in human subjects (29-33) is incompatible compromise therapeutic application of the with life (18). approach. Firstly, there is at present no means of targeting blockade to a specific type of cell. Thus far, some 5 million patients with onchocer­ Secondly, many commonly used potent drugs, ciasis have received one or more annual doses of including digoxin and morphine, are P-glycoprotein ivermectin (34). Its availability on this scale, and its substrates (22, 23) with a potential to cause serious general lack of toxicity has transformed the toxicity should their tissue distribution be signifi­ management of this disease. None the less, one cantly altered (5, 24). fatal case of unexplained central neurological depression following administration of ivermectin is Confirmation of the importance of maintaining the on record (35). This single and manifestly rare integrity of P-glycoprotein activity has recently been event provides no grounds for equivocating over obtained from experiments undertaken on mice the acknowledged therapeutic value of ivermectin. lacking the gene encoding for a drug-transporting However, evidence that the safety of the drug is so P-glycoprotein found largely in the intestine, liver, vitally dependent upon the integrity of of the P- brain and testis. (25). Under normal conditions glycoprotein system offers the occasion to rethink these animals remain physiologically normal. whether further basic research or monitoring of its However, exposure to small doses of a chemo¬ performance may still be needed. therapeutic agent such as vinblastine induce severe toxicity that results from anomalously high plasma In a broader context, an understanding of the role and tissue concentrations. of P-glycoproteins in cellular transport mechanisms may create a variety of new therapeutic possibi­ The consequences of such pharmacokinetic mani­ lities. Much will depend on success in developing pulation can be massive. Whereas, within this blocking agents that are without other significant animal model, sensitivity to the toxic effects of pharmacological activity and that act transiently, vinblastine were increased some three fold, the focally, and predictably upon the system. Mean­ minimum lethal dose of the semi-synthetic, broad- while, more detailed characterization of the system spectrum anthelmintic, ivermectin, was reduced by and comprehensive listings of substrate drugs may an estimated 50 to 100-fold (26). Entry of iver­ well elucidate some of the more arcane intricacies mectin into the brain was correspondingly of drug interaction charts. increased, with the result that a single oral dose only 4-fold higher than that generally used in References veterinary and human medicine induced central 1. Chen, C, Chin, J., Ueda, K. et al. Internal duplication nervous depression that progressed first to coma and homology with bacterial transport proteins in the and then to death. mdr1(P-glycoprotein) gene from multidrug-resistant human cells. Cell, 47: 381-389 (1986). Similar sensitivity to ivermectin has been demon­ strated in an inbred strain of collie dog (27) and in a 2. Gros, P., Croop, J., Housman, D. Mammalian multidrug resistance gene: complete cDNA sequence indicates herd of Murray Grey cattle (28). In these animals, a strong homology to bacterial transport proteins. Cell, 47: dose of 200 µg/kg ivermectin, often used experi­ 371-380 (1986). mentally in humans for treating onchocerciasis and lymphatic filariasis, has induced severe central 3. Juliano, R., Ling, V. A surface glycoprotein modulating nervous system toxicity. In a wide range of normal drug permeability in Chinese hamster ovary cell mutants. mammals single doses of ivermectin up to 100-fold Biochemica and Biophysica Acta, 455: 152-162 (1976). higher are without demonstrable toxicity (27). In these genetically-sensitive strains the concentration 4. Endicott, J., Ling, V. The biochemistry of P-glycoprotein of ivermectin in the brain was shown to be much mediated multidrug resistance. Annual Reviews of higher than is generally found in these species at Biochemistry, 58: 137-171 (1989). large. It has not yet been confirmed whether this 5. Gottesman, M., Pastan, I. Biochemistry of multidrug finding is associated with genetic deficiency of a resistance mediated by the multidrug transporter. Annual P-glycoprotein, although this could readily be Reviews of Biochemistry, 62: 385-427 (1993).

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6. Ban, T. Pleiotropic, multidrug-resistant phenotype and 19. Ross, D., Wooten, P., Sridhara, R. Enhancement of P-glycoprotein: a review. Chemotherapy, 38: 191-196 daunorubicin accumulation, retention and cytotoxicity by (1992). verapamil or cyclosporin A in blast cells from patients with previously untreated acute myeloid leukemia. Blood, 82: 7. Biedler, J. Genetic aspects of multidrug resistance. 1288-1299 (1993). Cancer, 70 (6 suppl): 1799-1809 (1992). 20. Horton, J., Thimmaiah, K., Houghton, J. Modulation by 8. Hait, W., Aftab, D. Rational design and pre-clinical verapamil of vincristine pharmacokinetics and toxicity in pharmacology of drugs for reversing multidrug resistance. mice bearing human tumor xenografts. Biochemistry and Biochemistry and Pharmacology, 43: 103-107 (1992). Pharmacology, 38: 1727-1736 (1989).

9. Germann, U., Pastan, I., Gottesman, M. P-glyco¬ 21. Sikic, B. Modulation of multidrug resistance: at the proteins: mediators of multidrug resistance. Seminars in threshold. Journal of Clinical Oncology, 11: 1629-1635 Cellular Biology, 4: 63-76 (1993). (1993). 22. Callaghan, R., Riordan, J. Synthetic and natural 10. Lum, B., Gosland, M., Kuubisch, S., Sikic, B. opiates interact with P-glycoprotein in multi-drug resistant Molecular targets in oncology: implications of multidrug cells. Journal of Biological Chemistry, 268: 16059-16064 resistance gene. Pharmacotherapy, 13: 88-109 (1993). (1993). 11. Raderer, M., Scheithauer, W. Clinical trials of agents 23. Tanigawara, Y., Okamura, N., Hirai, M. et al. that reverse multidrug resistance. Cancer, 72: 3553-3563 Transport of digoxin by P-glycoprotein expressed in a (1993). porcine kidney epithelial cell line. (LLC-PK1). Journal of Pharmacology and Experimental Therapeutics, 263: 840- 12. Greig, N., Soncrant, T., Shetty, H. et al. Brain uptake 845(1992). and anticancer activities of vincristine and vinblastine are restricted by their low cerebrovascular permeability and 24. Ford, J., Hait, W. Pharmacology of drugs that alter binding to plasma constituents in rat. Cancer multidrug resistance in cancer. Pharmacological Reviews, Chemotherapy and Pharmacology, 26: 263-268 (1990). 42: 155-199 (1990).

13. Cowman, A., Karcz, S. Drug resistance and the P- 25. Schinkel, A., Smit, J., van Tellingen, O. Disruption of glycoprotein homologues of Plasmodium falciparum. the mouse mdr1a P-glycoprotein gene leads to a Seminars in Cellular Biology, 4: 29-35 (1993). deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell, 77: 491-502 (1994). 14. Wilson, C, Volkman, S., Thaithong, S. et al. Amplification of pfmdr 1 associated with mefloquine and 26. Fisher, M., Mrozik, H. The chemistry and pharma­ halofantrine resistance in Plasmodium falciparum from cology of avermectins. Annual Reviews of Pharmacology Thailand. Molecular Biochemistry and Parasitology, 57: and Toxicology, 32: 537-553 (1992). 151-160 (1993). 27. Pulliam, J., Seward, R., Henry, R., Steinberg, S. 15. Ames, B., Profet, M., Gold, L. Nature's chemicals and Investigating ivermectin toxicity in collies. Veterinary synthetic chemicals: comparative toxicology. Proceedings Medicine, 80: 33-40 (1985). of the National Academy of Sciences, USA, 87: 7782- 7786 (1990). 28. Seaman, J., Eagleson, J., Carrigan, M., Webb, R. Avermectin B1 toxicity in a herd of Murray Grey cattle. 16. Thiebaut, F., Tsuruo, T., Hamada, H. et al. Cellular Australian Veterinary Journal, 64: 284-285 (1987). localization of the multidrug resistance gene product in normal human tissues. Proceedings of the National 29. Gros, P., Ben-Neriah, Y., Croop, J., Housman, D. Academy of Sciences, USA, 84: 7735-7738 (1987). Isolation and expression of a complementary DNA that confers multidrug resistance. Nature, 323: 728-731 17. Cordon-Cardo, C, O'Brien, J., Casals, D. et al. (1986). Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. 30. Roninson, I., Chin, J., Choi, K. et al. Isolation of Proceedings of the National Academy of Sciences, USA, human mdr DNA sequences amplified in multidrug- 86: 695-698 (1989). resistant KB carcinoma cells. Proceedings of the National Academy of Sciences, USA, 83: 4538-4542 (1986). 18. Thiebaut, F., Tsuruo, T., Hamada, H. et al. Immuno¬ histochemical localization in normal tissues of different 31. Ueda, K., Carderelli, C, Gottesman, M., Pastan, I. epitopes in the multidrug transport protein P170: evidence Expression of a full-length cDNA for the human "mdr1" for localization in brain capillaries and cross-reactivity of gene confers resistance to colchicine, doxorubicin and one antibody with a muscle protein. Journal of Histo­ vinblastine. Proceedings of the National Academy of chemistry and Cytochemistry, 37: 159-164 (1989). Sciences, USA, 84: 3004-3008 (1987).

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32. van der Bliek, A., Kooiman, P., Schneider, C, required. The available purified polyvalent pneumo­ Borst, P. Sequence of mdr3 cDNA encoding a human coccal polysaccharide vaccines are suitable for P-glycoprotein. Gene, 71: 401-411 (1988). elderly and infirm adults at high risk of infection (15). However, they lack immunogenicity in a 33. Schinkel, A., Roelofs, M., Borst, P. Characterization substantial proportion of children under two years of the human MDR3 P-glycoprotein and its recognition by P-glycoprolein-specific monoclonal antibodies. Cancer (who are at highest risk for pneumococcal otitis Research, 51: 2628-2635. media and bacteraemia) (16, 17). Immunogenicity is likely to be increased, as is the case with 34. Mectizan Donation Program. Status Report. Mectizan Haemophilus influenzae type b vaccines, when the Program Notes, No. 9, May 1994. polysac-charide antigens are coupled to a protein in a conjugated vaccine (16). Unfortunately, because 35. Ivermectin: possible neurotoxicity. WHO Drug of their high cost, such vaccines may never become Information, 5: 127-128 (1991). widely available, and the search is already engaged for more immunogenic antigens. Drug-resistant pneumococcal Pending the availability of affordable vaccines, clinicians everywhere are now faced with the need infections: a fast deteriorating to start antibiotic therapy in suspected pneumo­ situation coccal disease before the results of susceptibility tests are available. In meningitis and other critical The dangers resulting from the emergence of infections two third-generation cefalosporins — penicillin-resistant strains of Streptococcus ceftriaxone sodium and cefotaxime — are often pneumoniae have been discussed before in this used successfully. But treatment failures have journal (1). Such strains were first identified some already been recorded (18, 19). In such cases, 30 years ago (2, 3). They have subsequently vancomycin has been used as the treatment of last spread widely (4-7) and their prevalence has resort (7). increased to the extent that they are now of major The lack of laboratories equipped to provide infor­ concern both to public health services and mation on antibiotic susceptibility, the frequently clinicians (8). prohibitive cost of second-line antibiotic therapy, By 1987, a nationwide surveillance programme set and the spiralling increase in the prevalence of up in the United States 8 years earlier had collected resistant strains places developing countries at dire only one isolate of S. pneumoniae with an MIC to disadvantage. Sooner or later, recognition must penicillin greater than 2 µg/mL (9). In 1991, how­ emerge that drug-resistant infections cannot be ever, this degree of resistance was detected in tackled effectively at national or regional level. 1.3% of 567 isolates collected, and lesser degrees Global strategies are demanded that must be of resistance were detected in a further 5.3 % (7). placed on the political agenda. In all, a total of 16.4% of isolates collected in this References one year were resistant to at least one of the types of antibiotics most commonly used against this 1. Second generation pneumococcal vaccines. WHO Drug organism, namely penicillin, cefalosporins, macro¬ Information, 7: 12-14 (1993). lides, trimethoprim/sulfamethoxazole, and 2. Appelbaum, P. World-wide development of antibiotic chloramphenicol. resistance in pneumococci. European Journal of Clinical Microbiology, 6: 376-377 (1987). In the absence of laboratories at community level in most countries that are equipped to maintain 3. Klugman, K. Pneumococcal resistance to antibiotics. surveillance of resistance and to guide clinicians in Journal of Clinical Microbiology Reviews, 3: 171-196 selecting appropriate therapy, the emergence of (1990). resistance must now be expected to accelerate (7). It is already evident that inappropriate and pro­ 4. Munoz, R., Coffey, T., Daniels, C. et al. Intercontinental phylactic use of antibiotics are risk factors for the spread of a multiresistant clone of serotype 23F Streptococcus pneumoniae. Journal of Infectious spread of drug-resistant pneumococcal strains, Diseases, 164: 302-306 (1991). particularly in institutional settings (10-14). 5. McDougal, L, Fackiam, R., Reeves, M. et al. Analysis The prevalence of resistant strains in developing of multiply antimicrobial resistant isolates of Streptococcus countries is unknown, but is likely to be substantial. pneumoniae from the United States. Antimicrobial Agents Effective pneumococcal vaccines are urgently and Chemotherapy, 36: 2176-2184 (1992).

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6. Versaioic, J., Kapur, E., Mason, O. et al. Penicillin- 19. Friedland, I., Shelton, S., Paris, M. et al. Dilemmas in resistant Streptococcus pneumoniae strains recovered in diagnosis and management of cephalosporin-resistant Houston: identification and molecular characterization of Streptococcus pneumoniae meningitis. Pediatric multiple clones. Journal of Infectious Diseases, 167: 850- Infectious Diseases Journal, 12: 196-200 (1993). 856 (1993). 7. Breiman, R., Butler, J., Tenover, F. et al. Emergence of drug-resistant pneumococcal infections in the United Osteoporosis in chronic States. Journal of the American Medical Association, 271 : 1831-1835 (1994). inflammatory disease: a need to 8. Simberkoff, M. Drug-resistant pneumococcal infections reevaluate corticosteroid therapy? in the United States: a problem for clinicians, laboratories, and public health. Journal of the American Medical Localized osteoporosis adjacent to diseased joints Association, 271: 1875-1876 (1994). is a characteristic feature of early rheumatoid arthritis (1). Generalized osteoporosis, which is 9. Spika, J., Facklam, R., Plikaytis, B., Oxtoby, M. for the usually recognized later in the course of the Pneumococcal Surveillance Working Group. Antimicrobial disease (2, 3), has been shown to be associated resistance of Streptococcus pneumoniae in the United with an increased risk of bone fractures (4), States, 1979-1987. Journal of Infectious Diseases, 163: particularly in the vertebrae and the hip (5, 6). It has 1273-1278 (1991). been assumed that this generalized type of bone 10. Jacobs, M., Koomhof, H., Robins-Browne, R. et al. loss develops gradually, in part as a result of active Emergence of multiply resistant pneumococci. New disease, but largely as a consequence of diminish­ England Journal of Medicine, 299: 735-740 (1978). ed mobility (7). This view is now challenged, since it seems that significant bone loss may be an 11. Radetsky, M., Istre, G., Johansen, T. et al. Multiply inevitable consequence of the inflammatory resistant pneumococcus causing meningitis: its epidemiology within a day-care centre. Lancet, 2: 771-773 process. (1981). Osteoporosis in rheumatoid arthritis has been 12. Jackson, M., Shelton, S., Nelson, J., McCracken, G. attributed in recent years to release of bone Relatively penicillin-resistant pneumococcal infections in pediatric patients. Pediatric Infectious Diseases Journal, resorbing cytokines, which activate osteoclasts, 3: 129-132 (1984). from inflamed synovium. The synovial fluid of patients with active disease contains high concen­ 13. Pallares, R., Gudiol, F., Linares, J. et al. Risk factors trations of interleukins 1 and 6 which are also and response to antibiotic therapy in adults with detectable in plasma (8, 9). These cytokines also bacteremic pneumonia caused by penicillin-resistant stimulate production in the liver of C reactive pro­ pneumococci. New England Journal of Medicine, 317: 18- tein (CRP). Close correlation between osteoclastic 22 (1987). activity and various biochemical markers of active 14. Reichler, M., Allphin, A., Breiman, R. et al. The spread rheumatic disase, including plasma levels of CRP, of multiply resistant Staphylococcus pneumoniae at a day has been established (10, 11). center in Ohio. Journal of Infectious Diseases, 166: 1346- 1353 (1992). Until recently, only a few small longitudinal studies of bone turnover in patients with early rheumatoid 15. Shapiro, E., Berg, A., Austrian, R., et al. The arthritis had been conducted (12-14). Results of a protective efficacy of polyvalent pneumococcal poly­ more ambitious study have now been reported saccharide vaccine. New England Journal of Medicine, which have important clinical implications (15). This 325: 1453-1460 (1991). involved serial radiological measurements of bone 16. Robbins, J., Schneerson, R. Polysaccharide-protein mineral density in the lumbar spine and the hip conjugates: a new generation of vaccine. Journal of which were conducted in some 150 patients with Infectious Diseases, 161: 821-832 (1990). early rheumatoid arthritis. Among patients with continuously active disease, bone mineral loss 17. Peeters, C., Tenbergen-Meekes, A., Haagmans, B. et ranged from 5.5 to 10% within two years. Serum C al. Pneumococcal conjugate vaccines. Immunology Letter, reactive protein was a consistent predictor of 30: 267-274 (1991). mineral loss at both sites. Serum C reactive protein 18. Sloas, M., Barbett, F., Chesney, J. et al. Cephalo­ was reduced and bone density was largely sporin treatment failure in penicillin and cephalosporin- stabilized by suppressing disease activity with resistant Streptococcus pneumoniae meningitis. Pediatric cortocosteroids. Infectious Diseases Journal, 11: 662-666 (1992).

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At this early stage of the disease, non-steroidal 2. Ng, K., Revell, A., Beer, M. et al. Incidence of metabolic anti-inflammatory drugs have been generally bone disease in rheumatoid arthritis and osteoarthritis. Annals of Rheumatic Diseases, 43: 370-377 (1984). preferred. Only when these no longer control the disease, has the use of corticosteroids been 3. Mellish, R., O'Sullivan, M., Garrahan, N., Compston, J. considered and often, even then, only as a means Iliac crest trabecular bone mass and structure in patients of suppressing inflammation while benefit from with non-steroid treated rheumatoid arthritis. Annals of second-line drugs — antimetabolites and gold Rheumatic Diseases, 46: 830-836 (1987). compounds — is awaited (16). Increasingly, however, this "pyramid approach" to treatment is 4. Beat, A., Bloch, D., Fries, J. Predictors of fractures in being questioned on the grounds that both first and early rheumatoid arthritis. Journal of Rheumatology, 18: second-line drugs are associated with a similar 804-808 (1991). incidence of clinically-significant drug-related 5. Hooyman, J., Melton, L, Nelson, A. et al. Fractures adverse effects (16-18). If it is confirmed that after rheumatoid arthritis. Arthritis and Rheumatism, 27: substantial generalized loss of skeletal bone occurs 1353-1361 (1984). early in the course of the disease, a fundamental reappraisal of the management of rheumatoid 6. Spector, T., Hall, G., McCloskey, E., Kanis, J. Risk of arthritis may follow. vertebral fracture in women with rheumatoid arthritis. British Medical Journal, 306: 558 (1993). As yet, however, early use of corticosteroids in 7. Sambrook, P., Eisman, J., Champion, D. et al. rheumatoid arthritis remains controversial (7, 19, Determinants of axial bone loss in rheumatoid arthritis. 20), not least because administration of predniso­ Arthritis and Rheumatism, 30: 721-728 (1987). lone in excess of the accepted physiological relacement dose of 5-7.5 mg daily results in 8. Gowan, M., Wood, D., Ihrie, E. et al. An interleukin 1- substantial acceleration of bone loss and other like factor stimulates bone resorption in vivo. Nature, 306: 378-380 (1983). catabolic effects. Even within this low-dose range it has been suggested that catabolic effects may 9. Brozik, M., Rosztoczy, I., Meretey, K. et al. Interleukin increase bone loss (21, 22), but other studies do 6 levels in synovial fluids of patients with different arthri¬ not support this finding (13, 23, 24). Reduction of tides: correlation with local IgM rheumatoid factor and the dose to even lower levels, on the other hand, systemic acute phase protein production. Journal of is unlikely to inhibit the synovial inflammation res­ Rheumatology, 19: 63-68 (1992). ponsible for the progression of the disease (25). 10. Eggelmeijer, E., Pappoulos, S., Westedt, M. et al. The hope is that a dosage "window" exists within Bone metabolism in rheumatoid arthritis: relation to which the anti-inflammatory action of corticosteroids disease activity. British Journal of Rheumatology, 32: will outweigh their adverse effects on bone meta­ 387-391 (1993). bolism (15) 11. Gough, A., Peel, N., Eastell, R. et al. Excretion of pyridinoline crosslinks with disease activity and Regardless of any change in attitude over the use appendicular bone loss in early rheumatoid arthritis. of corticosteroids in the management of rheumatoid Annals of Rheumatic Diseases, 53: 14-17 (1994). arthritis, these new findings emphasize the need to take every precaution to reduce generalized bone 12. Sambrook, P., Ansell, B., Foster, S. et al. Bone loss through regular exercise, adequate calcium turnover in early rhematoid arthritis: 2. Longitudinal intake, and estrogen therapy in post-menopausal bone-density studies. Annals of Rheumatic Diseases, 44: 580-584 (1989). women (26). Eventually, a role may also be defined for specific inhibitors of osteoclastic activity such as 13. Sambrook, P., Cohen, M., Eisman, J. et al. Effects biphosphonate pamidronate (27). In a wider of low dose corticosteroids on bone mass in rheumatoid context, the catabolic effect of the inflammatory arthritis: a longitudinal study. Annals of Rheumatic process on bone may well prove to be of import­ Diseases, 48: 535-538 (1989). ance in other chronic inflammatory diseases, such as ulcerative colitis, in which osteoporosis is a 14. Verstraeten, A., Dequeker, J., Nijs, J., Geusens, P. recognized complication (28). Prevention of postmenopausal bone loss in rheumatoid patients: a two year prospective study. Clinical and Experimental Rheumatology, 7: 351-358 (1989). References 1. Arneri, F., Edworthy, S., Block, D et al. The American 15. Gough, A., Lilly, J., Eyre, S. et al. Generalised bone Association 1987 - revised criteria for the classification of loss in patients with early rheumatoid arthritis. British rheumatoid arthritis. Arthritis and Rheumatism, 31: 315- Medical Journal, 344: 23-27 (1994). 324(1988).

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16. Fries, J. Re-evaluating the therapeutic approach to 23. Felder, M., Ruegsegger, P. Bone loss in patients with rheumatoid arthritis: the sawtooth strategy. Journal of rheumatoid arthritis — effect of steroids measured by Rheumatology, 17 (suppl 22): 12-15 (1990). low- dose quantitative computed tomography. Rheumatology International, 11: 41 -44 (1991). 17. Wilske, K., Healey, L. Remodelling the pyramid: a concept whose time has come. Journal of Rheumatology, 24. Leboff, M., Wade, J., MacKowiak, J. et al. Low dose 16: 565-567 (1989). prednisolone does not affect calcium homeostasis or bone density in menopausal women with rheumatoid arthritis. 18. Cash, J., Klipple, J. Second-line drug therapy for Journal of Rheumatology, 18: 339-344 (1991). rheumatoid arthritis. New England Journal of Medicine, 330: 1368-1375 (1994). 25. Byron, M., Mowat, A. Corticosteroid prescribing in rheumatoid arthritis: the fact and the fiction. British Jour­ 19. Sambrook, P. Osteoporosis in rheumatoid arthritis: nal of Rheumatology, 24: 164-166 (1985). what is the role of antirheumatic therapy? Lancet, 344: 3-4 (1994). 26. Hall, G., Daniels, M., Huskisson, E., Spector, T. A randomised controlled trial of the effect of hormonal 20. Reid, D., Kennedy, N., Smith, M. et al. Total body replacement therapy on disease activity in post­ calcium in rheumatoid arthritis: effects of disease activity menopausal rheumatoid arthritis. Annals of Rheumatic and corticosteroid treatment. British Medical Journal, 285: Diseases, 53: 112-116 (1994). 330-332 (1982). 27. Ralston, S., Hacking, L, Willocks, I. et al. Clinical, 21. Laan, R., Van Riel, P., Van de Putte, P. Low-dose biochemical and radiographic effects of aminohydroxy- prednisolone induces rapid reversible axial bone loss in propylidene biphosphonate treatment in rheumatoid patients with rheumatoid arthritis. Annals of Internal arthritis. Annals of Rheumatic Diseases, 48: 396-399 Medicine, 119: 963-968 (1993). (1989).

22. Verstraeten, A., Dequeker, J. Vertebral and peripheral 28. Compston, J., Judd, D., Crawley, E. et al. Osteo­ bone mineral content and fracture incidence in post­ porosis in patients with inflammatory bowel disease. menopausal patients with rheumatoid arthritis: effect of Gut, 28: 410-415 (1987). low-dose corticosteroids. Annals of Rheumatic Diseases, 45: 852-857 (1986).

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Regulatory Matters

Large-scale • the anticipated difficulty of recruiting the 4500 volunteers required to show with reasonable HIV vaccine trials deferred statistical confidence whether the vaccines are either effective or ineffective in at least one-third of United States of America — Plans to conduct recipients; large-scale trials of two preventive HIV vaccines (developed respectively by Genentech and Biocine, • concern that public opinion might be unimpressed a joint venture between Chiron and Ciba) in the by a vaccine that protects only 30% to 50% of United States have been shelved by the National persons who are immunized; and Institute of Allergy and Infectious Diseases (1). The decision reflects reservations expressed by its • the projected cost of the trial, at present estimated AIDS Research Advisory Committee that the at US$ 20 million annually for a minimum of 4 degree of protection conferred by the candidate years. vaccines — both based on gp120, a glycoprotein component of the viral coat — may not be high The advisory panel has emphasized that its enough to warrant testing in the US population. decision applies exclusively to the USA and that, as such, it should not preempt or prejudice plans to Since 1988, the Institute has supported 17 early conduct clinical studies in other countries. A stage trials involving 12 vaccines and 1400 healthy meeting will be convened later this year under the volunteers at risk of infection. As recently as April aegis of WHO to consider whether to proceed as 1994 the Institute proposed that two of these planned with large-scale efficacy trials of the candidate vaccines be tested against placebo in existing vaccines in one or more developing 4500 persons at high risk of HIV infection. countries. The prospect of a delay of several years in full-scale preventive vaccine trials is a matter that The Advisory Committee's reappraisal was is viewed with dismay in those countries suffering prompted by news that 10 of these volunteers — 8 the greatest burden of HIV infection and where the of whom had received an active vaccine — had prevalence of the disease continues to rise steeply. subsequently become infected. These cases, it is accepted, must have resulted from high-risk sexual Source: behaviour. They could not have been a direct consequence of vaccination, since none of the 1. National Institute of Allergy and Infectious Diseases. vaccines contains infectious material. However, Press release, 17 June 1994. because the cases were distributed with similar frequency among vaccinated and unvaccinated 2. Scrip, No. 1930, 10 June 1994. individuals (only about one-fifth of the volunteers received placebo), the effectiveness of vaccination 3. Marketletter, 27 June 1994. has been brought into question. Indeed, there has been speculation that immune changes induced by 4. Macilwain, US puts large-scale AIDS vaccine trials on the vaccine may render the recipient more ice as 'premature'. Nature, 369: 593 (1994). vulnerable to HIV infection. The evidence on which these doubts are based is both speculative and Antidepressants tenuous since no more than three individuals to receive any one vaccine among the 12 preparations and hyponatraemia tested, have subsequently become infected, and preliminary evidence indicates that at least some of United Kingdom — The Committee on Safety of these subjects may not have received the full Medicines has received 52 reports of reversible recommended immunizing dose. hyponatraemia associated with use of anti­ depressant drugs. In most cases the patients have been elderly (mean age, 73 years) and the degree Several other factors are reported to have influ­ of sodium depletion has been sufficient in some enced the decision to defer large-scale trials (2-4): cases to induce neurological symptoms or signs

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including drowsiness, confusion or convulsions. It concludes that current elimination/inactivation Over half the patients were found to have plasma procedures are effective against enveloped viruses sodium levels below 120 mmol/l, but only some such as HIV, hepatitis B and hepatitis C, but that 20% were taking diuretics or ACE inhibitors. they have limited efficacy against non-enveloped viruses such as hepatitis A and parvovirus B19. It is suggested that hyponatraemia may result from Product licence-holders have consequently been inappropriate secretion of antidiuretic hormone. The requested to develop and validate additional virus data are insufficient to indicate whether the effect is elimination/inactivation procedures as a matter of more likely to occur with any particular type of urgency for all currently-authorized blood derived antidepressant or any specific product. medicinal products, in order to improve protection against transmission of non-enveloped viruses. Source: Committee on Safety of Medicines. Current Problems in Pharmacovigilance. Vol. 20, May 1994. In the meantime, the Committee has recommended that consideration be given to appropriate vaccina­ tion of patients to whom these products are Azapropazone and photosensitivity administered. United Kingdom — The Committee on Safety of Source: Committee for Proprietary Medicinal Products. Medicines has advised doctors that it has received Background document on medicinal products derived from over 450 reports of photosensitivity reactions human blood or plasma. Commission of the European associated with use of azapropazone (see also Communities, 16 March 1994. p. 155). The incidence with which this reaction is reported is estimated to be some 50 times greater than is the case with other nonsteroidal anti­ Bromocriptine: no longer inflammatory drugs. recommended to suppress lactation The Committee has recommended that doctors and United States of America/Canada — In advance pharmacists should advise all patients taking of intended restrictive action by the US Food and azapropazone to avoid direct exposure to sunlight Drug Administration (1), the manufacturer of the or to use sunblocking preparations. dopamine receptor antagonist, bromocriptine (Parlodel®, Sandoz) has voluntarily withdrawn the Source: Committee on Safety of Medicines. Current indication for suppression of physiological post­ Problems in Pharmacovigilance, Vol. 20, May 1994. partum lactation, both in the USA and in Canada (2). The FDA action was based upon a re- Blood: safeguards to prevent evaluation of 24 studies that were initially submitted to it in 1978 to support the inclusion of this transmission of pathogens indication in the labelling.

European Commission — The Committee for In August this year, the FDA announced its Proprietary Medicinal Products has issued a intention to withdraw approval for this indication background document on the risk of transmission of because "the benefit of using bromocriptine to infective agents via medicinal products prepared prevent pysiological lactation is limited by a number from human blood or plasma, in the light of recent of factors" and because bromocriptine "is not shown consultations with representatives of interested to be safe" for this purpose. industries. In its statement, the FDA weighs the therapeutic The Committee accepts that this risk cannot be benefit of treatment against the risk of adverse totally excluded but that it must be reduced to a effects. Suppression of lactation, it emphasizes, minimum by: can be induced within a few days when need arises • applying stringent controls to the selection of simply by using cold packs, compression bandages donors and donations; and and analgesics. Rebound lactation, which many women experience after taking bromocriptine for up • removing or inactivating contaminating viruses to three weeks, is unlikely to occur when traditional during the production process. methods are used.

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Moreover, it seems that the FDA has new infor­ Sources: mation suggesting that use of bromocriptine can 1. Written parliamentary reply by Under-Secretary of State result in serious adverse consequences, including for Health, 16 March 1994. paralysis and death, in patients at risk. It expresses concern that patients at high risk of adverse effects 2. Medicines Control Agency, Class 1 Drug Alert, 21 — including women with epilepsy and those at risk March 1994. of cerebrovascular complications of hypertension — cannot be adequately identified. Felbamate and aplastic anaemia The agency concludes that "in the light of the limited benefit of using bromocriptine for the United States of America — Following prevention of lactation, and the effectiveness and consultation with the Food and Drug Administration, lack of serious adverse effects of conservative the manufacturer of the newly introduced treatments such as breast binding with or without antiepileptic agent, felbamate (Felbatol®; Carter- mild analgesics, the risk that bromocriptine may Wallace) has issued an open letter to doctors cause a serious adverse effect in post-partum urging them to withdraw patients from the drug women is unacceptable". immediately "unless in the physician's judgement, an abrupt withdrawal would be deemed to pose a Sources: more serious risk for the patient" (1, 2). 1. US Food and Drug Administration. Federal Register, 23 August 1994. Felbamate was first introduced in the USA in September 1993 as a novel treatment for two 2. Scrip, No. 1954/1955. 2/6 September 1994. specific types of epilepsy that are often poorly responsive to other drugs — partial seizures in adults either with or without secondary generali­ Counterfeit medicines: zation (3-5), and childhood epileptic encephalo­ a growing concern pathy (Lennox-Gastaut syndrome) (6). It is a dicarbamate structurally similar to, but pharmaco­ United Kingdom — In a written reply to a parlia­ logically distinct from the anxiolytic agent, mepro¬ mentary question, the Department of Health has bamate. On the basis of preclinical data, the stated that reports of counterfeit medicines within compound was judged to be effective in a wide the UK are now made at a rate of 20 to 30 per year, range of seizure models and to have little specific and that the Medicines Control Agency is directing toxicity although it interacts significantly with other more attention to the problem than it had antiepileptic compounds (7, 8). previously. Because of the considerable profits that derive from such trade, the manufacture of counter­ No long-term efficacy studies had been undertaken feit products is expected to increase. Leading brand before marketing approval, but data obtained in 200 products — and more recently, anabolic steroids — patients treated for more than 6 months were are most frequently involved. reassuring (7). Nonetheless, within one year, during which felbamate is estimated to have been However, some 80 per cent of reports relate, not to prescribed for some 100 000 patients, its use had illicitly manufactured counterfeits, but to products been associated with 10 cases of aplastic anaemia, that are legitimately manufactured for export to nine of which were reported from within the USA. overseas markets at discount prices. With This number of cases is some 50-fold higher than increasing frequency, these are later diverted back expected within the US population at large. illegally to the UK where they are sold at con­ No patient developed signs of aplastic anaemia siderable profit. within 10 weeks of starting treatment with felba­ mate. At the time the warning letter was prepared Almost coincidental with the timing of this reply, a two of the patients had died, but insufficient data press release by the Medicines Control Agency were available to provide a reliable estimate of the warned that a counterfeit, unsterile injectable form case fatality rate. The company and the FDA of the anabolic steroid, stanozolol (Winstrol Depot emphasize that close monitoring of the blood count, 50 injection®, Sanofi-Winthrop) was unlawfully although advisable, is of limited value since bone available from fitness clubs and gymnasiums. No marrow failure is well advanced by the time that injectable form of stanozolol has been accorded a changes are detectable in the peripheral blood. product licence in the UK.

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Sources: The Committee advises that neuroleptics, when 1. Open letter issued to all US doctors by Wallace they are necessary, should be administered to Laboratories on 29 July 1994. elderly patients at very low initial dosage which is then cautiously titrated against the clinical state. 2. FDA Press Release: Suspension of Felbatol use urged. 1 August 1994. References

3. Leppik, I., Dreifuss, F., Pledger, G. et al. Felbamate for 1. McKeith, I., Fairbaim, A., Perry, R. et al. Neuroleptic partial seizures: results of a controlled clinical trial. sensitivity in patients with senile dementia of Lewy body Neurology, 41: 1785-1788 (1991). type. British Medical Journal, 305: 673-678 (1992).

4. Theodore, W., Raubertas, R., Porter, R. et al. 2. Committee on Safety of Medicines. Current Problems in Felbamate: a clinical trial for complex partial seizures. Pharmacovigilance, Vol. 20, May 1994. Epilepsia, 32: 392-397 (1991).

5. Sachdeo, R., Kramer, L, Rosenberg, A., Sachdeo, S. Nonsteroidal anti-inflammatory Felbamate monotherapy: controlled trial in patients with partial onset seizures. Annals of Neurology, 32: 386-392 drugs: relative safety (1992). United Kingdom —The Committee on Safety of 6. Felbamate Study Group in Lennox-Gastaut Syndrome. Medicines has reviewed 10 published epidemio­ Efficacy of felbamate in childhood epileptic encephalo­ logical studies of the gastrointestinal risks pathy (Lennox-Gastaut syndrome). New England Journal associated with individual nonsteroidal anti­ of Medicine, 328: 29-33 (1993). inflammatory drugs (NSAIDs). It has then compared the results of these studies with the frequencies 7. Brodie, M. Felbamate: a new antiepilepsy drug. Lancet, with which these events have been notified for the 341: 1445-1446 (1993). most widely prescribed NSAIDs in the UK (1).

8. Wagner, M., Leppik, I., Graves, N. et al. Felbamate Within the published surveys, ibuprofen, which serum concentrations: effect of valproate, carbamazepine, was included in 7 of the studies, was consistently phenytoin and phenobarbital. Epilepsia, 31: 642 (abstr) associated with the lowest risk. Conversely, (1990). azapropazone was included in only 2 studies, but in both of these it was associated with the highest Neuroleptic sensitivity in dementia risk. Among the other drugs included in these studies, diclofenac, indometacin, ketoprofen, United Kingdom — It is well appreciated that naproxen and piroxicam were consistently elderly patients with dementia are particularly intermediate in the rank order of risk. susceptible to extrapyramidal reactions provoked or exacerbated by neuroleptic drugs. It is now The same ranking has been demonstrated in the recognized that up to one-fifth of all elderly frequencies with which these reactions have been demented patients in the United Kingdom are reported (as per 100 000 prescriptions) in the UK probably suffering from the recently described Lewy between 1989 and 1993. Spontaneous reporting of body type dementia (1), and the Committee on other serious reactions to these drugs — including Safety of Medicines has alerted doctors that this renal and hepatic damage, blood disorders, group of patients is apparently vulnerable to life- anaphylaxis and other allergies — conforms to the threatening sensitivity to neuroleptic drugs (2). same general pattern. In the light of these findings the Committee has Lewy body type dementia is characterized by a recommended that NSAIDS associated with low widely fluctuating mental state with clouding of risk should generally be preferred; treatment should consciousness, visual hallucinations, paranoid be started at the lowest recommended dose; delusions, depression and a tendency to fall. In concurrent use of two or more such drugs is these patients, neuroleptics may result in sudden discouraged and all NSAIDS are contraindicated in onset of extrapyramidal rigidity, immobility, postural patients with peptic ulceration. instability, profound confusion and reduced will to eat and drink, sometimes resulting in sudden life- Azapropazone, it is proposed, should be reserved theratening deterioration. for patients with rheumatoid arthritis, ankylosing

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spondylitis and acute gout who have not responded The practice has been portrayed in Congress as an to other NSAIDs. (See also p.153). It should never inappropriate influence on prescribing, and as a be prescribed for patients with a history of peptic threat to public health. Notwithstanding strict ulceration. Patients over 60 years of age requiring regulation, samples continue to be illegally re­ treatment over extended periods should not take packaged and sold and, in some cases, they have more than 600 mg daily. been deliberately adulterated during the course of diversion. Source: Committee on Safety of Medicines. Current Problems in Pharmacovigilance, Vol. 20, August 1994. Source: US Congress. Prescription Drug Marketing Reform Act, 1994 (S 2168). China to work with the European Pharmacopoeia Commission Theophylline potentiated Strasbourg — China has been granted observer by fluvoxamine status with the European Pharmacopoeia. This will United Kingdom — The Committee on Safety of enable it to participate in the Commission's Medicines has received 5 reports indicative of an scientific work and to have access to information on interaction between theophylline and the anti­ work being undertaken on analytical methods and depressant agent, fluvoxamine — a selective on quality control of medicines. serotonin re-uptake inhibitor (1). Symptoms of nausea, vomiting, headache and agitation were In all, 22 states are contracting parties to the reported in patients receiving both drugs. Convention on the elaboration of a European Pharmacopoeia which was drawn up under the Four similar cases were described in 1993 (2). aegis of the Council of Europe in 1964. Seven Subsequently it was shown that plasma theo­ eastern European countries have more recently phylline concentrations are raised some three fold been accorded observer status: Albania, Bulgaria, by concomitant administration of fluvoxamine, the Czech Republic, Hungary, Lithuania, Poland which is presumed to inhibit hepatic metabolism of and Slovenia. China joins two other non-European theophylline (3). As yet, interactions with theo­ countries, Australia and Canada, in being granted phylline have not been reported for other drugs of this status. this class. The second edition of the European Pharmaco­ The Committee recommends that fluvoxamine and poeia contains 1000 monographs and 250 analy­ theophylline preparations should not be adminis­ tical methods which are applied as official tered concomitantly. Where this cannot be avoided, standards in the contracting states, including all 12 the dose of theophylline should be halved and countries of the European Union. The texts also plasma levels monitored. have official status in Australia and Canada. References Source: Council of Europe. Press Release No. 343 (94). 2 August 1994. 1. Committee on Safety of Medicines. Current Problems in Pharmacovigilance, Vol. 20, August 1994. Move to ban distribution 2. Puranik, A. et al. Care of the Elderly, 5: 237 (1993). of drug samples 3. Donaldson, K. et al. British Journal of Clinical United States of America — A bill intended to Pharmacology, 37: 492P (1994). prohibit the distribution of drug samples to doctors has been introduced in the US Senate. It is esti­ Tiaprofenic acid and severe cystitis mated that many hundreds of millions of drug samples are distributed by US drug manufacturers An association between the nonsteroidal anti­ each year. The practice has long been regarded inflammatory agent, tiaprofenic acid (Surgam®, within the USA as a controversial promotional Roussel), and occasional cases of bladder irritation practice, but it is also sometimes used to assist low- which progresses to severe cystitis if treatment was income and uninsured patients to obtain supplies of continued was first described in 1991 (1). Further essential drugs that they could otherwise not afford. cases subsequently notified to the regulatory The bill provides for exemptions in such cases. authority in Australia were described in 1993 (2, 3).

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Among these were four cases of cystitis confirmed The decision has been taken on the basis of infor­ by cystoscopy and biopsy, while other patients mation generated in two clinical studies (see page reported symptoms of dysuria, haematuria, 131). The recommended dosage regimen is frequency of micturition, hesitancy and strangury. identical to that used in the trial: 500 mg orally each day starting on or after the 14th week of pregnancy The UK Committee on Safety of Medicines now and continuing until the 34th week. Throughout provides data to show that this reaction has been labour zidovudine is administered intravenously, under-recognized (3). Since the product was first firstly in a loading dose of 2mg/kg and then by marketed in the UK in 1982 it has been associated continuous infusion at a rate of 1mg/kg/hour. Sub­ with 69 reports of cystitis and 32 reports of related sequently, the baby receives zidovudine syrup at a urinary tract symptoms. Many of these reactions dose of 2mg/kg daily for the first 6 weeks of life. became evident within one month of starting treatment, and rapid recovery was the rule when Source: FDA Press Release, 9 August 1994. the drug was promply withdrawn. However, in most cases treatment was continued while the patients underwent extensive investigation. On cystoscopy Ethical criteria for and biopsy the findings were consistent with a diagnosis of idiopathic interstitial cystitis. In some medicinal drug promotion cases this resulted in appropriate surgical inter­ WHO'S ethical criteria for medicinal drug promotion ventions: these included 4 cystectomies and 2 were originally published in 1988, in the six official urinary diversions. languages. Their implementation is discussed in The Committee has consequently recommended this issue on pages 123 and 124. Resolution WHA that: 47.16 adopted by the Forty-seventh World Health Assembly in May 1994 requests the Director- • tiaprofenic acid should not be prescribed for General of WHO, inter alia, to give special attention patients with pre-existing urinary tract disorders; to wide dissemination of the WHO ethical criteria to all Member States and other concerned parties. • patients should be advised to stop taking tiaprofenic acid and to report to their doctor Introduction promptly if they develop urinary tract symptoms 1. Following the WHO Conference of Experts on such as increased frequency, nocturia, urgency, the Rational Use of Drugs held in Nairobi in pain on urinating or blood in their urine; and November 1985, WHO prepared the revised drug • tiaprofenic acid should be withdrawn if urinary strategy which was endorsed by the Thirty-ninth symptoms are confirmed. World Health Assembly. This strategy includes, among other components, the establishment of References ethical criteria for drug promotion based on the criteria originally established in 1968 by the Twenty- 1. Ahmed, M., Davidson, O. British Medical Journal, 303: first World Health Assembly in resolution 1376 (1991). WHA21.41. The criteria that follow have been 2. Australian Adverse Drug Reactions Bulletin, 12 (1): 2prepare d in compliance with the above on the basis (1993), and 13 (1): 2 (1994) of a draft elaborated by an international group of experts. 3. Committee on Safety of Medicines. Current Problems in Pharmacovigilance, Vol. 20, August 1994. Objective 2. The main objective of these criteria is to support Zidovudine approved to prevent HIV and encourage the improvement of health care through the rational use of drugs. transmission in pregnancy Ethical criteria United States of America — The Food and Drug 3. The interpretation of what is ethical varies in Administration has reacted rapidly to endorse a different parts of the world and in different societies. recommendation from its antiviral advisory The issue in all societies is what is proper beha­ committee that zidovudine be approved for viour. Ethical criteria for drug promotion should lay reducing the risk of transmission of the human the foundation for proper behaviour concerning the immunodeficiency virus (HIV) from infected promotion of medicinal drugs, consistent with the pregnant women to their babies.

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search for truthfulness and righteousness. The claims concerning medicinal products should be criteria should thus assist in judging if promotional reliable, accurate, truthful, informative, balanced, practices related to medicinal drugs are in keeping up-to-date, capable of substantiation and in good with acceptable ethical standards. taste. They should not contain misleading or unverifiable statements or omissions likely to Applicability and implementation of criteria induce medically unjustifiable drug use or to give 4. These criteria constitute general principles for rise to undue risks. The word "safe" should only be ethical standards which could be adapted by used if properly qualified. Comparison of products governments to national circumstances as should be factual, fair and capable of sub­ appropriate to their political, cultural, social, stantiation. Promotional material should not be educational, scientific and technical situation, laws designed so as to disguise its real nature. and regulations, disease profile, therapeutic 8. Scientific data in the public domain should be traditions and the level of development of their made available to prescribers and any other person health system. They apply to prescription and non­ entitled to receive it, on request, as appropriate to prescription medicinal drugs ("over-the-counter their requirements. Promotion in the form of drugs"). They also apply generally to traditional financial or material benefits should not be offered medicines as appropriate, and to any other product to or sought by health care practitioners to influence promoted as a medicine. The criteria could be used them in the prescription of drugs. by people in all walks of life: by governments; the pharmaceutical industry (manufacturers and 9. Scientific and educational activities should not be distributors); the promotion industry (advertising deliberately used for promotional purposes. agencies, market research organizations and the like); health personnel involved in the prescription, Advertising dispensing, supply and distribution of drugs; (a) Advertisements in all forms to physicians and universities and other teaching institutions; health-related professionals professional associations; patients' and consumer groups; and the professional and general media 10. The wording and illustrations in advertisements (including publishers and editors of medical journals to physicians and related health professionals and related publications). All these are encouraged should be fully consistent with the approved to use the criteria as appropriate to their spheres of scientific data sheet for the drug concerned or other competence, activity and responsibility. They are source of information with similar content. The text also encouraged to take the criteria into account in should be fully legible. developing their own sets of ethical standards in 11. Some countries require that advertisements their own field relating to medicinal drug promotion. should contain full product information, as defined by the approved scientific data sheet or similar 5. The criteria do not constitute legal obligations; document, for a given period from the date of first governments may adopt legislation or other promotion or for the full product life. Advertisements measures based on them as they deem fit. that make a promotional claim should at least Similarly, other groups may adopt self-regulatory contain summary scientific information. measures based upon them. All these bodies should monitor and enforce their standards. 12. The following list, based on the sample drug information sheet contained in the second report of Promotion the WHO Expert Committee on the Use of Essential 6. In this context, "promotion" refers to all infor­ Drugs, can serve as an illustration of the type of mational and persuasive activities by manufacturers information that such advertisements should usually and distributors, the effect of which is to induce the contain, among others: prescription, supply, purchase and/or use of medicinal drugs. • the name(s) of the active ingredient(s) using either 7. Active promotion within a country should take international nonproprietary names (INN) or the place only with respect to drugs legally available in approved generic name of the drug; the country. Promotion should be in keeping with • the brand name; national health policies and in compliance with national regulations, as well as with voluntary • content of active ingredient(s) per dosage form or standards where they exist. All promotion-making regimen;

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• name of other ingredients known to cause public should contain, taking into account the media problems; employed:

• approved therapeutic uses; • the name(s) of the active ingredient(s) using either international nonproprietary names (INN) or the • dosage form or regimen; approved generic name of the drug; • side-effects and major adverse drug reactions; • the brand name; • precautions, contra-indications and warnings; • major indication(s) for use; • major interactions; • major precautions, contra-indications and warnings: • name and address of manufacturer or distributor; • name and address of manufacturer or distributor. • reference to scientific literature as appropriate. Information on price to the consumer should be 13. Where advertisements are permitted without accurately and honestly portrayed. claims (reminder advertisements), they ought to include at least the brand name, the international Medical representatives nonproprietary name or approved generic name, 17. Medical representatives should have an the name of each active ingredient, and the name appropriate educational background. They should and address of the manufacturer or distributor for be adequately trained. They should possess the purpose of receiving further information. sufficient medical and technical knowledge and integrity to present information on products and (b) Advertisements in all forms to the general public carry out other promotional activities in an accurate and responsible manner. Employers are respon­ 14. Advertisements to the general public should sible for the basic and continuing training of their help people to make rational decisions on the use representatives. Such training should include of drugs determined to be legally available without instruction regarding appropriate ethical conduct a prescription. While they should take account of taking into consideration the WHO criteria. In this people's legitimate desire for information regarding context, exposure of medical representatives and their health, they should not take undue advantage trainees to feedback from the medical and allied of people's concern for their health. They should professions and from independent members of the not generally be permitted for prescription drugs or public, particularly regarding risks, can be salutary. to promote drugs for certain serious conditions that can be treated only by qualified health practitioners, 18. Medical representatives should make available for which certain countries have established lists. to prescribers and dispensers complete and To fight drug addiction and dependency, scheduled unbiased information for each product discussed, narcotic and psychotropic drugs should not be such as an approved scientific data sheet or other advertised to the general public. While health source of information with similar content. education aimed at children is highly desirable, drug advertisements should not be directed at 19. Employers should be responsible for the state­ children. Advertisements may claim that a drug can ments and activities of their medical representa­ cure, prevent, or relieve an ailment only if this can tives. Medical representatives should not offer be substantiated. They should also indicate, where inducements to prescribers and dispensers. applicable, appropriate limitations to the use of the Prescribers and dispensers should not solicit such drug. inducements. In order to avoid over-promotion, the main part of the remuneration of medical represen­ 15. When lay language is used, the information tatives should not be related to the volume of sales should be consistent with the approved scientific they generate. data sheet or other legally determined scientific basis for approval. Language which brings about Free samples of prescription drugs fear or distress should not be used. for promotional purposes 20. Free samples of legally available prescription 16. The following list serves as an illustration of the drugs may be provided in modest quantities to type of information advertisements to the general prescribers, generally on request.

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Free samples of non-prescription drugs to 27. Substantiated information on hazards the general public for promotional purposes associated with medicinal drugs should be reported 21. Countries vary in their practices regarding the to the appropriate national health authority as a provision of free samples of non-prescription drugs priority, and should be disseminated internationally to the general public, some countries permitting it, as soon as possible. and others not. Also, a distinction has to be made between provision of free drugs by health agencies Packaging and labelling for the care of certain groups and the provision of 28. Appropriate information being important to free samples to the general public for promotional ensure the rational use of drugs, all packaging and purposes. The provision of free samples of non­ labelling material should provide information prescription drugs to the general public for consistent with that approved by the country's drug promotional purposes is difficult to justify from a regulatory authority. Where one does not exist or is health perspective. If this practice is legally rudimentary, such material should provide permitted in any country, it should be handled with information consistent with that approved by the great restraint. drug regulatory authority of the country from which the drug is imported or other reliable sources of Symposia and other scientific meetings information with similar content. Any wording and 22. Symposia are useful for disseminating illustration on the package and label should information. The objective scientific content of such conform to the principles of ethical criteria meetings should be paramount, and presentations enunciated in this document. by independent scientists and health professionals are helpful to this end. Their educational value may Information for patients: package inserts, be enhanced if they are organized by scientific leaflets and booklets professional bodies. 29. Adequate information on the use of medicinal 23. The fact of sponsorship by a pharmaceutical drugs should be made available to patients. Such manufacturer or distributor should be clearly stated information should be provided by physicians and in advance, at the meeting and in any proceedings. pharmacists whenever possible. When package The latter should accurately reflect the inserts or leaflets are required by governments, presentations and discussions. Entertainment or manufacturers or distributors should ensure that other hospitality, and any gifts offered to members they reflect only the information that has been of the medical and allied professions, should be approved by the country's drug regulatory authority. secondary to the main purpose of the meeting and If package inserts or leaflets are used for should be kept at a modest level. promotional purposes, they should comply with the ethical criteria enunciated in this document. The 24. Any support to individual health practitioners to wording of the package inserts or leaflets, if participate in any domestic or international prepared specifically for patients, should be in lay symposia should not be conditional upon any language on condition that the medical and obligation to promote any medicinal product. scientific content is properly reflected.

Post-marketing scientific studies, surveillance 30. In addition to approved package inserts and and dissemination of information leaflets wherever available, the preparation and 25. Post-marketing clinical trials for approved distribution of booklets and other informational medicinal drugs are important to ensure their material for patients and consumers should be rational use. It is recommended that appropriate encouraged as appropriate. Such material should national health authorities be made aware of any also comply with the ethical criteria enunciated in such studies and that relevant scientific and ethical this document. committees confirm the validity of the research. Intercountry and regional cooperation in such Promotion of exported drugs studies may be useful. Substantiated information on 31. Ethical criteria for the promotion of exported such studies should be reported to the appropriate drugs should be identical with those relating to national health authorities and disseminated as drugs for domestic use. It is desirable that exporting soon as possible. and importing countries that have not already done 26. Post-marketing scientific studies and surveil­ so should use the WHO Certification Scheme on lance should not be misused as a disguised form of the quality of pharmaceutical products moving in promotion. International commerce.

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Essential Drugs

Psoriasis Topical applications Localized psoriasis vulgaris can frequently be Psoriasis affects people of all ages in every country cleared, sometimes for many months, by daily and is one of the most common of the chronic applications of dithranol cream for 2 to 4 weeks. A dermatoses in industrialized countries. It is low strength (0.1%) cream should be applied estimated, overall, to affect about 2% of persons in initially. Higher strengths (up to as much as 1%) the United States and northern Europe. Consider­ may be used subsequently provided that they do able local variations in its prevalence have been not produce irritation or burning. A "short contact" variously attributed to genetic, climatic, nutritional method in which each application is rinsed off within and ecological factors. A wide range of biological 30 minutes causes little, if any, irritation or staining events may trigger its expression, including of normal skin. This is particularly useful for streptococcal or viral infection, an emotional crisis outpatient management. Dithranol should be used or pregnancy. Other cases appear to be related to only under the direction of a physician trained in its the administration of specific drugs including use. There is a risk of severe conjunctivitis if lithium, chloroquine and beta-adrenoreceptor dithranol accidentally enters the eye antagonists. Crude coal tar is also effective in the treatment of Psoriasis vulgaris, the most common form of the psoriasis. The odour, staining and irritant properties disease, is characterized by erythematous, scaly are reduced when refined products are used in plaques of varying size. Typically, these are cream-based vehicles. Some preparations also scattered over the trunk, the extensor surface of the contain salicylic acid as a keratolytic. Good results limbs and the scalp. Pitting, thickening, and yellow­ are often obtained when repeated applications or ish coloration of the nails are frequent. Acute baths are combined with ultraviolet irradiation or inflammatory exacerbations characterized by a sun exposure. severe febrile reaction and pustule formation may be a consequence of over-treatment. About 5-10 % Emollients containing low concentrations of salicylic of patients develop a destructive peripheral inflam­ acid (2-6%) are a useful adjunct to treatment, matory arthritis of the hands and feet which is particularly where there is thick scaling. sometimes associated with ankylosing spondylitis. Psoriasiform lesions, often associated with severe Topical corticosteroids are widely used in mild or forms of seborrheic dermatitis and Reiter's moderate psoriasis. However, when extensive syndrome, are often seen in patients with AIDS. areas of the body surface are treated, such as in Erythrodermic psoriasis, or fine, diffuse desqua­ erythrodermic psoriasis, they can induce systemic mative scaling over the entire body surface, adrenal suppression. Rebound is likely to occur sometimes develops when lesions are widespread. after withdrawal, and this may result in a more unstable form of the disease. Systemic cortico­ Guttate psoriasis, occurs mainly in children. It is steroids should not be used because severe often triggered by a streptococcal infection, but it exacerbations frequently occur when they are also sometimes develops during an acute exacer­ withdrawn. bation of chronic psoriasis vulgaris. It is character­ ized by the sudden widespread appearance of Recently, it has been shown that calcipotriol, a relatively small psoriasiform lesions. The condition vitamin D3 analogue, which promotes the differen­ sometimes resolves spontaneously, but may tiation of epidermal keratinocytes, offers an ultimately transform into psoriasis vulgaris. effective and acceptable form of topical therapy, but the preparation is very expensive. Management Many different approaches to treatment are used. Systemic treatment Each has advantages and shortcomings and none Several options exist for the systemic treatment of reliably assures remission from relapse. patients with psoriasis vulgaris unresponsive to

161 Essential Drugs WHO Drug Information Vol. 8, No. 3, 1994

topical therapy. Each, however, is associated with Use in pregnancy hazards. These forms of therapy which involve the Safe use in pregnancy has not been established use of antimetabolites, immuno-suppressants, but no adverse effects have been reported. ciclosporin, or oral retinoids are not discussed here. They should be administered only by specialists Adverse effects and refractory cases should be treated by Contact with the eyes may cause severe conjunc­ dermatologists in secondary or tertiary level care tivitis. Skin irritation is common. facilities. It is prudent, when treating patients who require extended systemic treatment, to change the Sunlight may exacerbate inflammatory reactions regimen from time to time to reduce the risk of and provoke photosensitivity reactions. cumulative toxicity. The risk of serious adverse Excessive erythema may occur on adjacent normal effects, the need for close patient monitoring, and skin. the high cost of these treatment regimens are factors that determine the need for specialist Storage management. Dithranol ointment should be stored in tightly closed Streptococcal-induced guttate psoriasis requires containers protected from light. oral antibiotic, anti-streptococcal therapy. SALICYLIC ACID DITHRANOL ointment or paste: 2—6% ointment: 0.1-2% A keratolytic agent that is readily absorbed through Dithranol slows epidermal cell division and inhibits intact skin and is excreted slowly in the urine. excessive proliferation and keratinization in patients with psoriasis. It is not significantly absorbed Uses through the skin. Topical treatment of hyperkeratotic conditions. Uses Dosage and administration Topical management of moderately severe Initially 2% ointment is applied daily. The psoriasis. concentration is progressively increased to a maximum of 6%, and applications are continued Dosage and administration until remission is obtained. Dithranol should be applied only under the super­ vision of a specialist dermatologist. Treatment Contraindications and precautions should be started with the 0.1% ointment. After one The ointment should not be applied to broken or week, the concentration may be increased to 0.25% inflamed skin. and subsequently doubled, if necessary, at weekly intervals to a maximum strength of 2%. When Young children require specialist care. dithranol is used for "short contact" therapy, the ointment should be scrupulously rinsed off within 30 Adverse effects minutes. Allergic contact dermatitis has rarely been reported. Systemic salicylism has occurred when large areas Contraindications are treated, particularly in children. Dithranol should never be used on the face, on acute eruptions or acutely inflamed areas. Storage The preparation should be stored in well-closed Precautions containers. If the initial treatment produces severe soreness, or if the lesions spread, the frequency of application should be reduced and, in severe cases, TAR PRODUCTS discontinued. solution Patients should be warned that staining of the skin ointment and hair may occur and that some fabrics may be permanently stained. The concentration depends upon the choice of pre­ paration: coal tar solution 5-10%; crude coal tar 1%.

162 WHO Drug Information Vol. 8, No. 3, 1994 Essential Drugs

Tar suppresses epidermal cell DNA synthesis and Precautions mitotic activity and restores proliferative activity to Exposure to direct sunlight should be avoided for at normal. least 24 hours after application because of the risk of photosensitivity reactions. A variety of tars, most commonly coal tar, is used to treat chronic skin disease. Although coal tar is a potential carcinogen, there is no evidence that in the doses used therapeutically, Uses coal tar increases the risk of skin cancer. Treatment of widespread, erythrodermic and guttate psoriasis either alone or in combination with Use in pregnancy ultraviolet light. Safe use in pregnancy has not been demonstrated. Treatment should be deferred until after delivery Dosage and Administration whenever possible. Tar baths: 100 ml of solution should be thoroughly mixed with bath water and the patient should soak Adverse effects for 10-20 minutes. This may be repeated daily. Tar preparations are irritant and may rarely cause allergic reactions, including photosensitivity. At least 24 hours should elapse before photo­ therapy is started at which time the tar preparation They frequently stain the skin and hair and, for this should be scrupulously washed from the skin. reason, they are not well accepted by patients.

Contraindications Storage Known hypersensitivity. Tar preparations should be stored in tightly closed Tar preparations should not be applied to inflamed, containers, and protected from light. They should broken or infected skin. not be frozen.

163 WHO Drug Information Vol. 8, No. 3, 1994

Recent Publications

Bioethics: a professional and interventions. Consideration of potential benefits and risks is the very essence of their responsibility training and their practice.

The new-found possibility of mapping and manipu­ The US public is reminded that, year by year, lating the human genome has generated a wide Congress still appropriates funds for the medical debate in recent years. Popular presentation of the care of survivors of the Tuskegee syphilis study in issue has incited both fascination and consterna­ which more than 400 patients were denied penicillin tion, not least as a consequence of the clinical for 40 years so that researchers could study the application of such techniques as in vitro fertiliza­ long-term effects of the disease (2). Now, informa­ tion. General understanding of the biomedical tion has belatedly emerged that a Montreal surgeon implications of these advances is essential if they falsified the records of at least 100 women included are to be applied and controlled in a manner that in a major multicentre project concerned with the serves both the needs of patients and of society. management of early breast cancer, and specifically with an evaluation of the drug tamoxifen Some 30 governments have already established as adjuvant therapy (3, 4). Re-analysis of the national bioethics committees. In the USA, where remaining data is said to indicate that the published there is a long history of federal involvement in conclusions remain valid, but commentators bioethical matters, the options are still under anguish that trust in the research establishment has examination. Definitive decisions are soon likely to been undermined (5, 6). emerge, however, following the recent publication of a report (1) by the US Congress' Office of This event is far from an isolated occurrence, and it Technology Assessment. provides occasion to reflect that, where rigorous oversight of research activity is lacking, misde­ The report notes the current lack of a national meanour and misjudgement will rarely be brought forum for discussion within the USA, but points to to light. important contributions that have been made at local level as a result of both public and private Sources initiatives. These have fostered a diversity of views and an intensity of debate that might never have 1. Biomedical ethics in US public policy. Office of emerged had the issues been regarded, from the Technology Assessment, US Congress, Washington, DC. 1993. outset, as the preserve of central authority. Regardless of the level at which decisions are 2. Nishimi, R. Biomedical ethics in US public policy. taken, the report emphasizes that debate should Journal of the American Medical Association, 270: 2911 remain as free as possible from political influence (1993). and ideology, and that it should be flexible, 3. Fisher, B., Bauer, M., Margolese, R, et al. Five-year transparent and open to a diversity of broadly- results of a randomized clinical trial comparing total based expertise. mastectomy and segmental mastectomy with or without irradiation. New England Journal of Medicine, 312: 665- Several federal initiatives in the bioethics arena, it is 673 (1985). acknowledged, have had positive and lasting 4. Fisher, B., Redmond, C, Poisson, R. et al. Eight-year impact. Current US federal regulations that apply to results of a randomized clinical trial comparing research involving human subjects resulted from mastectomy and lumpectomy with or without irradiation on the work of a national commission. Similarly, an the treatment of breast cancer. New England Journal of earlier presidential commission on the study of Medicine, 320: 822-828 (1989). ethical problems in medicine was influential in 5. Editorial comment. How to lose confidence. Nature, matters relating to patients rights and life-sustaining 368: 674 (1994). treatments. 6. Rennie, D. Breast cancer: how to mishandle In the last analysis, doctors themselves must misconduct. Journal of the American Medical Association, remain personally accountable for their judgements 271: 1205-1207 (1994).

164 WHO Drug Information, Vol. 8, No. 3, 1994 Recommended INN: List 34

International Nonproprietary Names for Pharmaceutical Substances (INN)

Recommended International Nonproprietary Names (Rec. INN): List 34 Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances [Off. Rec. Wld Health Org., 1955, 60, 3 (Resolution EB15.R7); 1969,173, 10 (Resolution EB43.R9)], 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. Lists of Proposed (1-65) and Recommended (1-31) International Nonproprietary Names can be found in Cumulative List No. 8, 1992.

Dénominations communes internationales des Substances pharmaceutiques (DCI)

Dénominations communes internationales recommandées (DCI Rec): Liste 34 Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org. mond. Santé, 1955, 60, 3 (résolution EB15.R7); 1969, 173, 10 (résolution EB43.R9)] les dénominations ci-dessous sont mises à l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes internationales proposées. L'inclusion d'une dénomination dans les listes de DCI proposées n'implique aucune recommandation en vue de l'utilisation de la substance correspondante en médecine ou en pharmacie. On trouvera d'autres listes de Dénominations communes internationales proposées (1-65) et recommandées (1-31) dans la Liste récapitulative No. 8, 1992.

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI)

Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 34 De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (Resolución EB15.R7); 1969, 173, 10 (Resolución EB43.R9)], se comunica por el presente anuncio que las denominaciones que a continuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas. La inclusion de unadenominación en las listas de las Denominaciones Comunes Recomendadas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia. Las listas de Denominaciones Comunes Internacionales Propuestas (1-65) y Recomendadas (1-31) se encuentran reunidas en Cumulative List No. 8, 1992.

165 Recommended INN: List 34 WHO Drug Information, Vol. 8, No. 3, 1994

Recommended INN Chemical name or description and Molecular formula (Latin, English, French, Spanish) DCI Recommandée Nom chimique ou description et Formule brute DCI Recomendada Nombre químico o descriptión y Fórmula empírica

abciximabum abciximab immunoglobulin G (human-mouse monoclonal c7E3 clone p7E3VHhCy4 Fab fragment anti-human glycoprotein llb/llla receptor), disulfide with human-mouse monoclonal c7E3 clone p7E3VKhCK light chain abciximab immunoglobuline G (fragment Fab de l'anticorps monoclonal homme-souris c7E3 clone p7E3VHhCy4 anti-récepteur de la glycoprotéine llb/llla humaine), ponts disulfure avec la chaîne légère de l'anticorps monoclonal homme- souris c7E3 clone p7E3VKhCK abciximab inmunoglobulina G (fragmenta Fab del anticuerpo monoclonal hombre-ratón c7E3 clon p7E3VHhCy4 antireceptor de la glicoproteina llb/llla humana), puentes disulfuro con la cadena ligera del anticuerpo monoclonal hombre-ratón c7E3 clon p7E3VKhCK

acidum incadronicum [(cycloheptylamino)methylene]diphosphonic acid incadronic acid acide [(cycloheptylamino)méthylène]bisphosphonique acide incadronique ácido[(cicloheptilamino)metilen]difosfónico acido incadrónico

C8H19NO6P2 adatanserinum adatanserin N-[2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]-1-adamantanecarboxamide adatansérine N-[2-[4-(pyrimidin-2-yl)pipérazin-1-yl]éthyl]tricyclo[3.3.1.13,7]décane-1- carboxamide adatanserina N-[2-[4-(2-pirimidinil)-1-piperazinil]etil]-1-adamantanocarboxamida

C21H31N5O adelmidrolum N,N'-bis(2-hydroxyethyl)nonanediamide adelmidrol N,N'-bis(2-hydroxyéthyl)nonanediamide adelmidrol adelmidrol N,N'-bis(2-hidroxietil)nonanodiamida

C13H26N2O4 afovirsenum afovirsen 2'-deoxy-P-thiocytidylyl-(5' 3')-P-thiothymidylyl-(5'->3')-2'-deoxy-P-thioguanylyl- (5' 3')-2'-deoxy-P-thiocytidylyl-(5' 3')-P-thiothymidylyl-(5' 3')-2'-deoxy-P- thiocytidylyl-(5' 3')-2'-deoxy-P-thiocytidylyl-(5' 3')-P-thiothymidylyl-(5' 3')-P- thiothymidylyl-(5' 3')-2'-deoxy-P-thiocytidylyl-(5' 3')-P-thiothymidylyl-(5' 3')-2'- deoxy-P-thioadenylyl-(5' 3')-2'-deoxy-P-thiocytidylyl-(5' 3')-2'-deoxy-P- thiocytidylyl-(5' 3')-P-thiothymidylyl-(5' 3')-P-thiothymidylyl-(5' 3')-2'-deoxy-P- thiocytidylyl-(5' 3')-2'-deoxy-P-thioguanylyl-(5' 3')-P-thiothymidylyl-(5' 3')- thymidine

166 WHO Drug Information, Vol. 8, No. 3, 1994 Recommended INN: List 34

afovirsen 2'-désoxy-P-thiocytidylyl-(5' 3')-P-thiothymidylyl-(5' 3')-2'-désoxy-P- thioguanylyl-(5' 3')-2'-désoxy-P-thiocytidylyl-(5' 3')-P-thiothymidylyl-(5' 3')-2'- désoxy-P-thiocytidylyl-(5' 3')-2'-désoxy-P-thiocytidylyl-(5' 3')-P-thiothymidylyl- (5' 3')-P-thiothymidylyl-(5' 3')-2'-désoxy-P-thiocytidylyl-(5' 3)-P-thiothymidylyl- (5'-3')-désoxy-P-thioadénylyl-(5' 3')-2'-désoxy-P-thiocytidylyl-(5'-3')-2'- désoxy-P-thiocytidylyl-(5' 3')-P-thiothymidylyl-(5' 3')-P-thiothymidylyl-(5' 3')-2'- désoxy-P-thiocytidylyl-(5' 3')-2'-désoxy-P-thioguanylyl-(5' 3')-P-thiothymidylyl- (5' 3')-thymidine afovirseno 2'-deoxi-P-tiocitidilil-(5' 3')-P-tiotimidilil-(5' 3')-2'-deoxi-P-tioguanilil- (5' 3')-2'-deoxi-P-tiocitidilil-(5' 3')-P-tiotimidilil-(5' 3')-2'-deoxi-P-tiocitidilil- (5' 3')-2'-deoxi-P-tiocitidilil-(5' 3')-P-tiotimidilil-(5' 3')-P-tiotimidilil-(5' 3')-2'- deoxi-P-tiocitidilil-(5' 3')-P-tiotimidilil-(5' 3')-2'-deoxi-P-tioadenilil-(5'^3')-2'- deoxi-P-tiocitidilil-(5' 3')-2'-deoxi-P-tiocitidilil-(5' 3')-P-tiotimiclilil-(5' 3')-P- tiotimidilil-(5' 3')-2'-deoxi-P-tiocitidilil-(5' 3')-2'-deoxi-P-tioguanilil-(5' 3')-P- tiotimidilil-(5' 3')-timidine

C192H250N57O107P19S19 aglepristonum aglepristone 11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-[(Z)-propenyl]estra-4,9-dien-3-one aglépristone 11β-[4-(diméthylamino)phényl]-17β-hydroxy-17-[(Z)-prop-1-ényl]estra-4,9-dién- 3-one aglepristona 11β-[p-(dimetilamino)fenil]-17β-hidroxi-17-[(Z)-propenil]estra-4,9-dien-3-ona

C29H37NO2 alnespironum (+)-(S)-N-[4-[(5-methoxy-3-chromanyl)propylamino]butyl]-1,1 -cyclopentanediace¬ alnespirone timide (+)-(S)-8-[4-[(5-méthoxy-3,4-dihydro-2H-chromén-3-yl)(propyl)amino]butyl]- alnespirone 8-azaspiro[4.5]décane-7,9-dione (+)-(S)-N-[4-[(5-metoxi-3-cromanil)propilamino]butil]-1,1-ciclopentanodiacetimida alnespirona C26H38N2O4 alvirceptum sudotoxum alvircept sudotox N2-L-methionyl-1-178-antigen CD 4 (human clone pT4B protein moiety reduced) (178 248')-protein with 248-L-histidine-249-L-methionine-250-L-alanine-251 - L-glutamic acid-248-613-exotoxin A (Pseudomonas aeruginosa reduced) alvircept sudotox N2-L-méthionyl-1 -178-antigène CD 4 (partie protéique réduite de la substance issue du clone humain pT4B) (178 248')-protéine avec la 248-L-histidine-249- L-méthionine-250-L-alanine-251-acideL-glutamique-248-613-exotoxine A (Pseudomonas aeruginosa) réduite alvircept sudotox N2-L-metionil-1 -178-antigeno CD 4 (fracción proteica reducida de la sustancia obtenida del clon humano pT4B) (178 248')-proteina con 248-L-histidina-249- L-metionina-250-L-alanina-251-L-ácido glutamico-248-613-exotoxinaA (Pseudomonas aeruginosa reducida)

C2600H4130N748O812S10

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aranidipinum (±)-acetonyl methyl 1,4-dihydro-2,6-dimethyl-4-(o-nitrophenyl)-3,5-pyridinedi= aranidipine carboxylate (RS)-2,6-diméthyl-4-(2-nitrophényl)-1,4-dihydropyridine-3,5-dicarboxylate de aranidipine méthyle et de 2-oxopropyle (±)-acetonil metil 1,4-dihidro-2,6-dimetil-4-(o-nitrofenil)-3,5-piridindicarboxilato aranidipino C19H20N2O7 arteflenum (1S,4R,5R,8S)-4-[(Z)-2,4-bis(trifluoromethyl)styryl]-4,8-dimethyl- arteflene 2,3-dioxabicyclo[3.3.1]nonan-7-one (1S,4R,5R,8S)-4-[(Z)-2-[2,4-bis(trifluorométhyl)phényl]éthényl]-4,8-diméthyl- artéflène 2,3-dioxabicyclo[3.3.1]nonan-7-one (1S,4R,5R,8S)-4-[(Z)-2,4-bis(trifluorometil)estiril]-4,8-dimetil- artefleno 2,3-dioxabiciclo[3.3.1]nonan-7-ona

C19H18F6O3 atevirdinum 1-[3-(ethylamino)-2-pyridyl]-4-[(5-methoxyindol-2-yl)carbonyl]piperazine atevirdine 1-[3-(éthylamino)pyridin-2-yl]-4-[(5-méthoxy-1 H-indol-2-yl)carbonyl]pipérazine atévirdine 1-[3-(etilamino)-2-piridil]-4-[(5-metoxiindol-2-il)carbonil]piperazina atevirdina

C21H25N5O2 azelnidipinum 3-[1-(diphenylmethyl)-3-azetidinyl] 5-isopropyl (±)-2-amino-1,4-dihydro-6-methyl- azelnidipine 4-(m-nitrophenyl)-3,5-pyridinedicarboxylate (RS)-2-amino-6-méthyl-4-(3-nitrophényl)-1,4-dihydropyridine-3,5-dicarboxylate de azelnidipine 3-[1 -(diphénylméthyl)azétidin-3-yle] et de 5-(1-méthyléthyle) 3-[1-(difenilmetil)-3-azetidinil] 5-isopropil (±)-2-amino-1,4-dihidro-6-metil-4-(m- azelnidipino nitrofenil)-3,5-piridindicarboxilato

C33H34N4O6 batimastatum (2S,3R)-5-methyl-3-[[(αS)-a-(methylcarbamoyl)phenethyl]carbamoyl]-2- batimastat [(2-thienylthio)methyl]hexanohydroxamic acid (2S,3R)-N1-hydroxy-N4-[(S)-1-[(méthylamino)carbonyl]-2-phényléthyl]- batimastat 3-(2-méthylpropyl)-2-[(2-thiénylthio)méthyl]butanediarnide ácido (2S,3R)-5-metil-3-[[(αS)-α-(metilcarbamoil)fenetil]carbamoil]-2- batimastat [(2-tieniltio)metil]hexanohidroxamico

C23H31N3O4S2 beciparcilum ρ-[(5-thio-β-D-xylopyranosyl)thio]benzonitrile beciparcil 4-[(5-thio-β-D-xylopyranosyl)thio]benzonitrile béciparcil ρ-[(5-tio-β-D-xilopiranosil)tio]benzonitrilo beciparcilo

C12H13NO3S2

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besipirdinum 1 -(propyl-4-pyridylamino)indole besipirdine (1 H-indol-1 -yl)(propyl)(pyridin-4-yl)amine béslpirdine besipirdina 1 -(propil-4-piridilamino)indol

C16H17N3 biapenemum biapenem 6-[[(4R,5S,6S)-2-carboxy-6-[(1 R)-1-hydroxyethyl]-4-methyl-7-oxo- 1 -aza= bicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydro-5H-pyrazolo[1,2-a]-s-triazol-4-ium hydroxide, inner salt biapénem 6-[[(4R,5S,6S)-2-carboxylato-6-[(1R)-1 -hydroxyéthyl]-4-méthyl-7-oxo-1 -aza= bicycio[3.2.0]hept-2-én-3-yl]thio]-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium biapenem 6-[[(4R,5S,6S)-2-carboxi-6-[(1R)-1-hidroxietil]-4-metil-7-oxo-1-azabiciclo= [3.2.0]hept-2-en-3-il]tio]-6,7-dihidro-5H-pirazolo[1,2-a]-s-triazol-4-io hidroxido, sal interna

C15H18N4O4S bicalutamidum bicalutamide (±)-4'-cyano-α,α,α-trifluoro-3-[(ρ-fluorophenyl)sulfonyl]-2-methyl-m-lactotoluidide bicalutamide (RS)-N-[4-cyano-3-(trifluorométhyl)phényl]-3-[(4-fluorophényl)sulfonyl]-2-hydroxy- 2-méthylpropanamide bicalutamida (±)-4'-ciano-α,α,α-trifluoro-3-[(ρ-fluorofenil)sulfonil]-2-metil-m-lactotoluidida

C18H14F4N2O4S bosentanum ρ-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)- bosentan 4-pyrimidinyl]benzenesulfonamide 4-(1,1 -diméthyléthyl)-N-[6-(2-hydroxyéthoxy)-5-(2-méthoxyphénoxy)- bosentan 2-(pyrimidin-2-yl)pyrimidin-4-yl]benzènesulfonamide ρ-terobutil-N-[6-(2-hidroxietoxi)-5-(o-metoxifenoxi)-2-(2-pirimidinil)- bosentano 4-pirimidinil]bencensulfonamida

C27H29N5O6S candocuronii iodidum 17a,l7a-dimethyl-3β-(1-methylpyrrolidinio)-17a-azonia-D-homoandrost-5-ene candocuronium iodide diiodide diiodure de 17a,17a-diméthyl-3β-(1-méthylpyrrolidinio)-17a-azonia- iodure de candocuronium D-homoandrost-5-ène 17a,17a-dimetil-3β-(1 -metilpirrolidinio)-17a-azonia-D-homoandrost-5-eno diioduro ioduro de candocuronio C26H46I2N2 capromabum capromab immunoglobulin G 1 (mouse monoclonal 7E11-C5.3 anti-human prostatic carcinoma cell), disulfide with mouse monoclonal 7E11 -C5.3 light chain, dimer capromab immunoglobuline G 1 (anticorps monoclonal de souris 7E11-C5.3 anti-cellules de carcinome prostatique humain), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris 7E11 -5.3

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capromab inmunoglobulina G1 (anticuerpo monoclonal 7E11-C5.3 de ratón anticélulas de carcinoma prostático humano), puentes disulfuro con la cadena ligera del anticuerpo monoclonal 7E11-C5.3 de raton, dimero

carvotrolinum 8-fluoro-2,3,4,5-tetrahydro-2-[2-(4-pyridyl)ethyl]-1H-pyrido[4,3-b] indole carvotroline 8-fluoro-2-[2-(pyridin-4-yl)éthyl]-2,3,4,5-tétrahydro-1H-pyrido[4,3-b)]indole carvotroline 8-fluoro-2,3,4,5-tetrahidro-2-[2-(4-piridil)etil]-1H-pirido[4,3-b]indol carvotrolina

C18H18FN3

cedefingolum N-[(1 S,2S)-2-hydroxy-1 -(hydroxymethyl)heptadecyl]acetamide cedefingol N-[(1 S,2S)-2-hydroxy-1 -(hydroxyméthyl)heptadécyl]acétamide cédéfingol N-[(1 S,2S)-2-hidroxi-1 -(hidroximetil)hepfadecil]acetamida cedefingol

C20H41NO3

cefcapenum cefcapene (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-pentenamido]-3-(hydroxymethyl)-8-oxo- 5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, carbamate (ester) cefcapène acide (+)-(6R,7R)-7-[[(Z)-2-(2-aminothiazol-4-yl)pent-2-énoyl]amino]- 3-[[(aminocarbonyl)oxy]méthyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ène-2- carboxylique cefcapeno ácido(+)-hidroximetil(6R,7R)-7-[(Z)-2-(2-amino-4-tiazolil)-2-pentenamido]-3- (hidroximetil)-8-oxo-5-tia-1-azabiciclo[4.2.0]oct-2-en-2-carboxílico

C17H19N5O6S2 certoparinum natricum certoparin sodium Sodium salt of depolymerized heparin obtained by isoamyl nitrite 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-Osulfo- 2,5-anhydro-D-mannose structure at the reducing end of their chain; the average relative molecular mass is 5000 to 7000; at least 70 per cent less than 10 000; the degree of sulfatation is 2 to 2,5 per disaccharidic unit. certoparine sodique sel de sodium d'héparine dépolymérisée obtenue par fragmentation au moyen de nitrite d'isoamyle d'héparine de muqueuse intestinale de porc. La majorité des composants présentent une structure acide 2-O-sulfo-α-L-idopyranosuronique à l'extrémité non réductrice et une structure 6-O-sulfo-2,5-anhydro-D-mannose à l'extrémité réductrice de leur chaîne. La masse moléculaire relative moyenne est de 5000 à 7000, 70 pour cent au moins des composants ayant une masse moléculaire relative inférieure à 10 000. Le degré de sulfatation est de 2 à 2,5 par unité disaccharidique. certoparina sódica Sal sódica de la heparina despolimerizada obtenida por fragmentación con nitrito de isoamilo de la heparina de la mucosa intestinal del cerdo; la mayoría de los compuestos tienen una estructura de ácido 2-O-sulfo-α-L-idopirano-surónico en el extremo no reductor y una estructura de 6-O-sulfo-2,5-anhidro-D-manitol en el extremo reductor de la cadena; la masa molecular relativa media es 5000 a 7000, al menos el 70% es menor de 10 000; el grado de sulfatación es de 2 a 2,5 por unidad de disacárido.

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cinalukastum cinalukast 3'-[(E)-2-(4-cyclobutyl-2-thiazolyl)vinyl]-2,2-diethylsuccinanilic acid acide (E)-4-[[3-[2-(4-cyclobutylthiazol-2-yl)éthényl]phényl]amino]-2,2-diéthyl- cinalukast 4-oxobutanoïque ácido 3'-[(E)-2-(4-ciclobutil-2-tiazolil)vinil]-2,2-dietilsuccinanilico cinalukast

C23H28N2O3S ciprokirenum ciprokiren (αS)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydraxypropyl]-α- [(αS)-a-[[[1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]hydrocinnam= amido]imidazole-4-propionamide ciprokirène (S)-N-[(1S,2R,3S)-1-(cyclohexylméthyl)-3-cyclopropyl-2,3-dihydroxypropyl]-2- [[(S)-2-[[[1-methyl-1-[(morpholin-4-yl)carbonyl]éthyl]sulfonyl]méthyl]-3- phénylpropanoyi]amino]-3-(1H-imidazol-4-yl)propanamide ciprokireno (αS)-N-[(1S,2R,3S)-1-(ciclohexilmetil)-3-ciclopropil-2,3-dihidroxipropil]-α-[(αS)- a-[[[1-metil-1-(morfolinocarbonil)etil]sulfonil]metil]hidrocinnamamido]imidazol-4- propionamida

C37H55N5O8S dapabutanum (±)-3-[[3-(dodecylamino)propyl]amino]butyric acid dapabutan acide (RS)-3-[[3-(dodécylamino)propyl]amino]butanoïque dapabutan acido(±)-3-[[3-(dodecilamino)propil]amino]buti'rico dapabutano

C19H40N2O2 darglitazonum (±)-5-[ρ-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]benzyl]-2,4-thiazolidinedione darglitazone (RS)-5-[4-[3-(5-méthyl-2-phényloxazol-4-yl)propanoyl]benzyl]thiazolidine-2,4-dione darglitazone (±)-5-[ρ-[3-(5-metil-2-fenil-4-oxazolil)propionil]bencil]-2,4-tiazolidindiona darglitazona

C23H20N2O4S darifenacinum (S)-1-[2-(2,3-dihydro-5-benzofuranyl)ethyl]-α,α-diphenyl-3-pyrrolidineacetamide darifenacin (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)éthyl]pyrrolidin-3-yl]-2,2-diphénylacétamide darifénacine (S)-1-[2-(2,3-dihidro-5-benzofuranil)etil]-α,α-difenil-3-pirrolidinacetamida darifenacina

C28H30N2O2 desirudinum 63-desulfohirudin [Hirudo medicinalis isolorm HV1) desirudin 63-désulfohirudine (Hirudo medicinalis, isoform HV1 ) désirudine 63-desulfohirudina (isoforma HV1 de Hirudo medicinalis) desirudina

C287H440N80O110S6

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geclosporinum geclosporin cyclo[[(2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-L- norvalyl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D- alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl] géclosporine cyclo[-[(6E)-(2S,3R,4R)-3-hydroxy-4-méthyl-2-(méthylamino)oct-6-énoyl]-L- norvalyl-(N-méthylgylcyl)-(N-méthyl-L-leucyl)-L-valyl-(N-méthyl-L-leucyl)-L- alanyl-D-alanyl-(N-méthyl-L-leucyi)-(N-méthyl-L-leucyl)-(N-méthyl-L-valyl)-] geclosporina ciclo[[(2S,3ff,4fl,6£)-3-hidroxi-4-metil-2-(metilamino)-6-octenoil]-L-norvalil-N- metilglicil-N-metil-L-leucil-L-valil-N-metil-L-leucil-L-alanil-D-alanil-N-metil-L-leucil-N- metil-L-leucil-N-metil-L-valil]

C63H113N11O12 glenvastatinum (4R,6S)-6-[(E)-2-[4-(ρ-fluorophenyl)-2-isopropyl-6-phenyl-3-pyridyl]vinyl]tetra= glenvastatin hydro-4-hydroxy-2H-pyran-2-one (4R,6S)-6-[(E)-2-[4-(4-fluorophényl)-2-(1-méthyléthyl)-6-phénylpyridin- glenvastatine 3-yl]éthényl]-4-hydroxytétrahydro-2H-pyran-2-one (4R,6S)-6-[(E)-2-[4-(ρ-fluorofenil)-2-isopropil-6-fenil-3-piridil]vinil]tetrahidro- glenvastatina 4-hidroxi-2H-piran-2-ona

C27H26FNO3 icometasonii enbutas 9-chloro-11 β, 17, 21 -trihydroxy-16α-methylpregna-1,4-diene-3,20-dione icometasone enbutate 17-butyrate 21 -acetate 21 -acétate 17-butanoate de 9-chloro-11β,17,21 -trihydroxy-16α-méthylprégna- icométasone enbutate 1,4-diène-3,20-dione 9-cloro-11β,17,21-trihidroxi-16α-metilpregna-1,4-dieno-3,20-diona17-butirato enbutato de icometasona 21-acetato

C28H37CIO7 iganidipinum (±)-3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 1,4-dihydro-2,6-dimethyl- iganidipine 4-(m-nitrophenyl)-3,5-pyridinedicarboxylate (RS)-2,6-diméthyl-4-(3-nitrophényl)-1,4-dihydropyridine-3,5-dicarboxylatede iganidipine 2,2-diméthyl-3-[4-(prop-2-ényl)pipérazin-1 -yl]propyle et de méthyle (±)-3-(4-alil-1-piperazinil)-2,2-dimetilpropil metil 1,4-dihidro-2,6-dimetil-4- iganidipino (m-nitrofenil)-3,5-piridindicarboxilato

C28H38N4O6 ilepcimidum 1-[(E)-3,4-(methylenedioxy)cinnamoyl]piperidine ilepcimide 1 -[(E)-3-(1,3-benzodioxol-5-yl)prop-2-énoyl]pipéridine ilepcimide ilepcimida 1 -[(E)-3,4-(metilendioxi)cinnamoil]piperidina

C15H17NO3

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iliparcilum 4-ethyl-7-[(5-thio-β-D-xylopyranosyl)oxy]coumarin iliparcil iliparcil 4-éthyl-7-[(5-thio-β-D-xylopyranosyl)oxy]-2H-chromén-2-one iliparcilo 4-etil-7-[(5-tio-β-D-xilopiranosil)oxi]cumarina

C16H18O6S ilonidapum ilonidap 6-chloro-5-fluoro-3-[(Z)-α-hydroxy-2-thenylidene]-2-oxo-1-indolinecarboxamide ilonidap (Z)-6-chloro-5-fluoro-3-[hydroxy(2-thiényl)méthylène]-2-oxo-2,3-dihydro-1H- indole-1 -carboxamide ilonidap 6-cloro-5-fluoro-3-[(Z)-a-hidroxi-2-tienilidene]-2-oxo-1-indolincarboxamida

C4H8CIFN2O3S iloperidonum 4'-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3'-methoxyaceto= iloperidone phenone 1 -[4-[[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)pipéridin-1 -yl]propyl]oxy]-3-méthoxy= ilopéridone phényl]éthanone 4'-[3-[4-(6-fluoro-1,2-bencisoxazol-3-il)piperidino]propoxi]-3'-metoxiacetofenona iloperidona C24H27FN2O4 imitrodastum 4,5-dihydro-2-(imidazol-1-ylmethyl)benzo[b]thiophene-6-carboxylicacid imitrodast acide 2-[(1 H-imidazol-1 -yl)méthyl]-4,5-dihydrobenzo[b]thiophène-6-carboxylique imitrodast ácido 4,5-dihidro-2-(imidazol-1-ilmetil)benzo[b]tiofeno-6-carboxilico imitrodast

C13H12N2O2S iralukastum iralukast 7-[[(1S,2E,4Z)-9-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-[(αR)-α-hydroxy- m-(trifluoromethyl)benzyl]-2,4-nonadienyl]thio]-4-oxo-4H-1-benzopyran-2- carboxylic acid iralukast acide 7-[[(2E,4Z)-(1 S)-9-(4-acétyl-3-hydroxy-2-propylphénoxy)-1 -[(R)-hydroxy= [3-(trifluorométhyl)phényl]méthyl]nona-2,4-diényl]thio]-4-oxo-4H-chromène-2- carboxylique iralukast ácido7-[[(1S,2E,4Z)-9-(4-acetil-3-hidroxi-2-propiltenoxi)-1-[(αR)-α-hidroxi- m-(trifluorometil)bencil]-2,4-nonadienil]tio]-4-oxo-4H-1-benzopiran-2-carboxílico

C38H37F3O8S laflunimusum laflunimus (Z)-α-cyano-α4',α4',α4'-trifluoro-β-hydroxycyclopropaneacrylo-3',4'-xylidide laflunimus (Z)-2-cyano-3-cyclopropyl-3-hydroxy-N-[3-méthyl-4-(trifluorométhyl)phényl]prop- 2-énamide laflunimus (Z)-α-ciano-α4',α4',α4'-trifluoro-β-hidroxiciclopropanacrilo-3',4'-xylidida

C15H13F3N2O2

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linotrobanum [[5-(2-benzenesulfonamidoethyl)-2-thienyl]oxy]acetic acid linotroban acide 2-[[5-[2-[(phénylsulfonyl)amino]éthyl]-2-thiényl]oxy]acétique linotroban ácido[[5-(2-bencensulfonamidoetil)-2-tienil]oxi]acetico linotroban

C14H15NO5S2 lopobutanum (±)-3-[[3-(dodecyloxy)propyl]amino]butyric acid lopobutan acide (RS)-3-[[3-(dodécyloxy)propyl]amino]butanoïque lopobutan ácido(±)-3-[[3-(dodeciloxi)propil]amino]butírìco lopobutano

C19H39NO3 loviridum (±)-2-(6-acetyl-m-toluidino)-2-(2,6-dichlorophenyl)acetamide loviride (RS)-2-[(2-acétyl-5-méthylphényl)amino]-2-(2,6-dichlorophényl)acétamide loviride (±)-2-(6-acetil-m-toluidino)-2-(2,6-diclorofenil)acetamida lovirida C17H16CI2N2O2 lubeluzolum (+)-(S)-4-(2-benzothiazolylmethylamino)-α-[(3,4-difluorophenoxy)methyl]- lubeluzole 1 -piperidineethanol (+)-(S)-1-[4-[(benzothiazol-2-yl)(méthyl)amino]pipéridin-1-yl]- lubéluzole 3-(3,4-difluorophénoxy)propan-2-ol (+)-(S)-4-(2-benzotiazolilmetilarnino)-α-[(3,4-difluorofenoxi)metil]- lubeluzol 1 -piperidinietanol

C22H25F2N3O2S lurosetronum 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methylimidazol-4-yl)methyl]-1H- lurosetron pyrido[4,3-b]indol-1-one 6-fluoro-5-méthyl-2-[(5-méthyl-1H-imidazol-4-yl)méthyl]-2,3,4,5-tétrahydro-1H- lurosétron pyrido[4,3-b]indol-1-one 6-fluoro-2,3,4,5-tetrahidro-5-metil-2-[(5-metilimidazol-4-il)metil]-1H-pirido= lurosetron [4,3-b]indol-1-ona

C17H17FN4O merafloxacinum (±)-1 -ethyl-7-[3-[(ethylamino)methyl]-1 -pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo- merafloxacin 3-quinolinecarboxylic acid acide (RS)-1 -éthyl-7-[3-[(éthylamino)méthyl]pyrrolidin-1 -yl]-6,8-difluoro-4-oxo- mérafloxacine 1,4-dihydroquinoléine-3-carboxylique àcido(±)-1-etil-7-[3-[(etilamino)metil]-1-pirrolidinil]-6,8-difluoro-1,4-dihidro-4-oxo- merafloxacino 3-quinolincarboxilico

C19H23F2N3O3

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mofarotenun 4-[2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]= mofarotene phenoxy]ethyl]morpholine 4-[2-[4-[(E)-2-(5,5,8,8-tétraméthyl-5,6,7,8-tétrahydronaphtalén-2-yl)prop-1-ényl]= mofarotène phénoxy]éthyl]morpholine 4-[2-[p-[(E)-2-(5,6,7,8-tetrahidro-5,5,8,8-tetrametil-2-naftil)propenil]fenoxi]etil]= mofaroteno morfolina

C29H39NO2 mofegilinum (E)-2-(fluoromethylene)-4-(ρ-fluorophenyl)butylamine mofegiline (E)-3-fluoro-2-[2-(4-fluorophényl)éthyl]prop-2-énylamine mofégiline (E)-2-(fluorometileno)-4-(ρ-fluorofenil)butilamina mofegilina

C11H13F2N naratriptanum N-methyl-3-(1-methyl-4-piperidyl)indole-5-ethanesulfonamide naratriptan N-méthyl-2-[3-(1-méthylpipéridin-4-yl)indol-5-yl]éthanesulfonamide naratriptan N-metil-3-(1-metil-4-piperidil)indol-5-etanosulfonamida naratriptan C17H25N3O2S nedaplatinum cis-diammine(glycolato-O1, O2)platinu m nedaplatin cis-diammine[2-hydroxyacétato(2-)-O1,O2] platine nédaplatine cis-diamina(glicolato-O1,O2)platino nedaplatino

C2H8N2O3Pt nupafantum N-[(S)-1-(ethoxymethyl)-3-methylbutyl]-N-methyl-α-(2-methyl-1H- nupafant imidazo[4,5-c]pyridin-1-yl)-ρ-toluenesulfonamide N-[(S)-1-(éthoxyméthyl)-3-méthylbutyl]-N-méthyl-4-[(2-méthyl-1H- nupafant imidazo[4,5-c]pyridin-1-yl)méthyl]benzènesulfonamide N-[(S)-1-(etoximetil)-3-metilbutil]-N-metil-α-(2-metil-1H-imidazo[4,5-c]piridin- nupafant 1 -il)-ρ-toluensulfonamida

C23H32N4O3S olprinonum 1,2-dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxonicotinonitrile olprinone 5-(imidazo[1,2-a]pyridin-6-yl)-6-méthyl-2-oxo-1,2-dihydropyridine-3-carbonitrile olprinone 1,2-dihidro-5-imidazo[1,2-a]piridin-6-il-6-metil-2-oxonicotinonitrilo olprinona C14H10N4O ormeloxifenum ormeloxifene (±)-1-[2-[ρ-(trans-7-methoxy-2,2-dimethyl-3-phenyl-4-chromanyl)phenoxy]ethyl]= pyrrolidine

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orméloxifène (±)-1-[2-[4-(trans-7-méthoxy-2,2-diméthyl-3-phényl-3,4-dihydro-2H+chromén-4- yl)phénoxy]éthyl]pyrrolidine ormeloxifeno (±)-1-[2-[ρ-(trans-7-metoxi-2,2-dimetil-3-(enil-4-cromanil)fenoxi]etil]pirrolidina

C30H35NO3 oxeclosporinum oxeclosporin cyclo[[(2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-L- 2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L- alanyl-O-(2-hydroxyethyl)-D-seryl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl- L-valyl] oxéclosporine cyclo[-[(6E)-(2S,3R,4R)-3-hydroxy-4-méthyl-2-(méthylamino)oct-6-énoyl]-L- 2-aminobutyryl-(N-méthylglycyl)-(N-méthyl-L-leucyl)-L-valyl-(N-méthyl-L-leucyl)- L-alanyl-[O(2-hydroxyéthyl)-D-séryl]-(N-méthyl-L-leucyl)-(N-méthyl-L-leucyl)- (N-méthyl-L-valyl)-] oxeclosporina ciclo[[(2S,3R,4R,6E)-3-hidroxi-4-metil-2-(metilamino)-6-octenoil]-L- 2-aminobutiril-N-metilglicil-N-metil-L-leucil-L-valil-N-metil-L-leucil-L-alanil-O-(2- hidroxietil)-D-seril-N-metil-L-leucil-N-metil-L-leucil-N-metil-L-valil]

C64H115N11O14 pamicogrelum ethyl 2-[4,5-bis(ρ-methoxyphenyl)-2-thiazolyl]pyrrole-1 -acetate pamicogrel 2-[2-[4,5-bis(4-méthoxyphényl)thiazol-2-yl]-1 H-pyrrol-1 -yl]acétate d'éthyle pamicogrel etil 2-[4,5-bis(ρ-metoxifenil)-2-tiazolil]pirrole-1 -acetato pamicogrel

C25H24N2O4S patamostatum ρ-[(2-succinimidoethyl)thio]phenyl ρ-guanidinobenzoate patamostat 4-guanidinobenzoate de 4-[[2-(2,5-dioxopyrrolidin-1 -yl)éthyl]thio]phényle patamostat ρ- guanidinobenzoato de ρ-[(2-succinimidoetil)tio]fenil patamostat

C20H20N4O4S pazinaclonum (±)-8-[[2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1 -isoindolinyl]acetyl]-1,4-dioxa- pazinaclone 8-azaspiro[4.5]decane (RS)-8-[2-[2-(7-chloro-1,8-naphtyridin-2-yl)-3-oxo-2,3-dihydro-1H-iso-indol- pazinaclone 1 -yl]acétyl]-1,4-dioxa-8-azaspiro[4.5]décane (±)-8-[[2-(7-cloro-1,8-naftiridin-2-il)-3-oxo-1 -isoindolinil]acetil]-1,4-dioxa- pazinaclona 8-azaspiro[4.5]decano

C25H23CIN4O4 pimagedinum aminoguanidine pimagedine aminoguanidine pimagédine aminoguanidina pimagedina

CH6N4

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pobilukastum pobilukast (2S,3R)-3-[(2-carboxyethyl)thio]-3-[o-(8-phenyloctyl)phenyl]lactic acid pobilukast acide (2S,3R)-3-[(2-carboxyéthyl)thio]-2-hydroxy-3-[2-(8-phényloctyl)phényl]= propanoïque pobilukast ácido(2S,3R)-3-[(2-carboxietil)tio]-3-[o-(8-feniloctil)fenil]lactico

C26H34O5S polixetonii chloridum polixetonium chloride poly[oxyethylene(dimethyliminio)ethylene(dimethyliminio)ethylene dichloride] chlorure de polixetonium poly[dichlorure d'oxyéthylène(diméthyliminio)éthylène(diméthyliminio)éthylène] poli[dicloruro de oxietileno(dimetiliminio)etileno(dimetiliminio)etileno] cloruro de polixetonio

(C10H24Cl2N2O)n rabeprazolum rabeprazole 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]benzimidazole rabéprazole 2-[[[4-[(3-méthoxypropyl)oxy]-3-méthylpyridin-2-yl]méthyl]sulfinyl]-1H-benzimi= dazole rabeprazol 2-[[[4-(3-metoxipropoxi)-3-metil-2-piridil]metil]sulfinil]benzimidazol

C18H21N3O3S ramosetronum ramosetron (-)-(R)-1 -methylindol-3-yl 4,5,6,7-tetrahydro-5-benzimidazolyl ketone ramosetron (-)-(R)-(1-méthyl-1H-indol-3-yl)(4,5,6,7-tétrahydro-1H-benzimidazol-5-yl)= méthanone ramosetron (-)-(R)-1-metilindol-3-il 4,5,6,7-tetrahidro-5-bencimidazolil cetona

C17H17N3O rasagilinum (R)-N-2-propynyl-1 -indanamine rasagiline [(R)-2,3-dihydro-1 H-indén-1 -yl](prop-2-ynyl)amine rasagiline (R)-N -2-propinil-1-indanamin a rasagilina

C12H13N reteplasum 173-L-serine-174-L-tyrosine-175-L-glutamine-173-527-plasminogen activator reteplase (human tissue-type) 173-L-sérine-174-L-tyrosine-175-L-glutamine-173-527-activateur du rétéplase plasminogène (type tissulaire humain) 173-L-serina-174-L-tirosina-175-L-glutamina-173-527-activador del reteplasa plasminogeno (tipo tisular humano)

C1736H2653N499O522S22 ricasetronum ricasetron 3,3-dimethyl-N-1αH,5αH-tropan-3α-yl-1 -indolinecarboxamide ricasétron 3,3-diméthyl-N-[(1R,3r,5S)-8-méthyl-8-azabicyclo[3.2.1]oct-3-yl]-2,3-dihydro- 1 H-indole-1-carboxamide

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ricasetron 3,3-dimetil-N-1 αH,5αH-tropan-3α-il-1-indolinacarboxamida

C19H27N3O safingolum (2S,3S)-2-amino-1,3-octadecanediol safingol (2S,3S)-2-aminooctadécane-1,3-diol safingol (2S,3S)-2-amino-1,3-octadecanodiol satingol

C18H39NO2 sameridinum N-ethyl-1-hexyl-N-methyl-4-phenylisonipecotamide sameridine N-éthyl-1-hexyl-N-méthyl-4-phénylpipéridine-4-carboxamide saméridine N-etil-1-hexil-N-metil-4-fenilisonipecotamida sameridina

C21H34N2O saquinavirum saquinavir (S)-N-[(αS)-α-[(1R)-2-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro-2(1H)- isoquinolyl]-1-hydroxyethyl]phenethyl]-2-quinaldamido succinamide saquinavir (2S)-N1-[(1S,2R)-1-benzyl-3-[(3S,4aS,8aS)-3-[[(1,1-diméthyléthyl)amino]= carbonyl]octahydro-isoquinoléin-2(1H)-yl]-2-hydroxypropyl]-2-[[(quinoléin-2-yl)= carbonyl]amino]butanediamide saquinavir (S)-N-[(αS)-α-[(1R)-2-[(3S,4aS,8aS)-3-(terc-butilcarbamoil)octahidro-2(1H)- isoquinolil]-1 -hidroxietil]fenetil]-2-quinaldamida succinamida

C38H50N6O5 selfotelum cis-4-(phosphonomethyl)pipecolic acid selfotel acide cis-4-(phosphonornéthyl)pipéridine-2-carboxylique selfotel ácido cis-4-(fosfonometil)pipecolico selfotel

C7H14NO5P seratrodastum seratrodast (±)-2,4,5-trimethyl-3,6-dioxo-ζ-phenyl-1,4-cyclohexadiene-1 -heptanoic acid sératrodast acide (RS)-7-phényl-7-(2,4,5-triméthyl-3,6-dioxocyclohexa-1,4-dién-1 -yl)= heptanoïque seratrodast ácido (±)-2,4,5-trimetil-3,6-dioxo-ζ-fenil-1,4-ciclohexadieno-1 -heptanoico

C22H26O4 sibopirdinum 5,5-bis(4-pyridylmethyl)-5H-cyclopenta[2,1-b:3,4-b']dipyridine sibopirdine 5,5-bis[(pyridin-4-yl)méthyl]-5H-cyclopenta[2,1-b:3,4-b']dipyridine sibopirdine 5,5-bis(4-piridilmetil)-5H-ciclopenta[2,1-b:3,4-b']dipiridina sibopirdina

C23H18N4

182 WHO Drug Information, Vol. 8, No. 3, 1994 Recommended INN: List 34

sirolimusum sirolimus (3S,6R,7E,9R, 10R, 12R, 14S, 15E, 17E, 19E, 21 S, 23S, 26R, 27R,34aS)-9,10,12,13, 14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1 R)-2- [(1 S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1 -methylethyl]-10,21 -dimethoxy- 6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1 -c][ 1,4]oxaazacyclohen= triacontine-1,5,11,28,29(4H,6H,31 H)-pentone sirolimus (7E,15E,17E,19E)-(3S,6R,9R,10R,12R,14S,21S,23S,26R,27R,34aS)-9,27- dihydroxy-3-[(1R )-2-[(1 S,3R,4R)-4-hydroxy-3-méthoxycyclohexyl]-1 -méthyléthyl]- 10,21 -diméthoxy-6,8,12,14,20,26-hexaméthyl-9,10,12,13,14,21,22,23,24,25,26, 27,32,33,34,34a-hexadécahydro-23,27-époxy-3H-pyrido[2,1-c][1,4]oxaaza= cyclohentriacontène-1,5,11,28,29(4H,6H,31 H)-pentone sirolimus (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13, 14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahidro-9,27-dihidroxi-3-[(1 R)-2- [(1S,3R,4R)-4-hidroxi-3-metoxiciclohexil]-1-metiletil]-10,21-dimetoxi-6,8,12,14, 20,26-hexametil-23,27-epoxi-3H-pirido[2,1 -c][1,4]oxaazaciclohentriacontina- 1,5,11,28,29(4H,6H,31 H)-pentona

C51H79NO13 somatosalmum somatotropin (Oncorhyncus mykiss clone ptGH-ll isoform II reduced) somatosalm somatotropine (isoforme II réduite issue du clone de Oncorhyncus mykiss ptGH-ll) somatosalm somatotropina (isoforma II reducida del clon ptGHII de Oncorhyncus mykiss) somatosalm

C952H1524N266O290S8 spiroglumidum spiroglumide (R)-γ-(3,5-dichlorobenzamido)-δ-oxo-8-azaspiro[4.5]decane-8-valeric acid acide (R)-5-(8-azaspiro[4.5]déc-8-yl)-4-[(3,5-dichlorobenzoyl)amino]-5- spiroglumide oxopentanoïque ácido(R)-γ-(3,5-diclorobenzamido)-δ-oxo-8-azaspiro[4.5]decan-8-valérico espiroglumida

C21H26CI2N2O4 sprodiamidum aqua[N,N-bis[2-[(carboxymethyl)[(methylcarbamoyl)methyl]amino]ethyl]= sprodiamide glycinato(3-)]dysprosium, hydrate aqua[N,N-bis[2-[(carboxyméthyl)[[(méthylamino)carbonyl]méthyl]amino]éthyl]= sprodiamide glycinato(3-)]dysprosium hydraté aquo[N,N-bis[2-[(carboximetil)[(metilcarbamoil)metil]amino]etil]= esprodiamida glicinato(3-)]disprosio, hidrato

C16H28DyN5O9.xH2O suritozolum 3-(m-fluorophenyl)-1,4-dimethyl-Δ2-1,2,4-triazoline-5-thione suritozole 5-(3-fluorophényl)-2,4-diméthyl-2,4-dihydro-3H-1,2,4-triazole-3-thione suritozole 3-(m-fluorofenil)-1,4-dimetil-Δ2-1,2,4-triazolina-5-tiona suritozol C10H10FN3S

183 Recommended INN: List 34 WHO Drug Information, Vol. 8, No. 3, 1994

technetium (99mTc)furifosminum technetium (99mTc) furifosmin (OC-6-13)-[[4,4'-[ethylenebis(nitrilomethylidyne)]bis[dihydro-2,2,5,5-tetramethyl- 3(2H)-furanonato]](2-)-N,N',O3,O3']bis[tris(3-methoxypropyl)phosphine-P][99mTc]= technetium(1 +) chloride technétium (99mTc) furifosmine (OC-6-13)-chlorure de [[4,4'-[éthylènebis(nitrilométhylidyne)]bis= [2,2,5,5-tétraméthyldihydrofuran-3(2H)-onato]](2-)-N,N',O3,O3']bis= [tris(3-méthoxypropyl)phosphine-P][99mTc]technétium(1+) furifosmina de technetium (99mTc) cloruro de (OC-6-13)-[[4,4'-[etilenbis(nitrilometilidina)]bis[dihidro-2,2,5,5- tetrametil-3(2H)-furanonato]](2-)-N,N',O3,O3']bis[tris(3-metoxipropil)fosfina- P][99mTc]tecnecio(1+)

99m C44H84CIN2O10P2 Tc telmisartanum 4'-[[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]- telmisartan 2-biphenylcarboxylic acid acide 4'-[[4-méthyl-6-(1 -méthyl-1 H-benzimidazol-2-yl)-2-propyl-1 H-benzimidazol- telmisartan 1-yl]méthyl]biphényl-2-carboxylique ácido 4'-[[4-metil-6-(1 -metil-2-bencimidazolil)-2-propil-1 -bencimidazoliljmetil]- telmisartan 2-bifenilcarboxílìco

C33H30N4O2 temoporfinum 3,3',3",3'"-(7,8-dihydroporphyrin-5,10,15,20-tetrayl)tetraphenol temoporfin 3,3',3",3"'-(7,8-dihydroporphyrine-5,10,15,20-tétrayl)tétraphénol témoporfine 3,3',3",3'"-(7,8-dihidroporfirin-5,10,15,20-tetrail)tetrafenol temoporfina

C44H32N4O4 tolafentrinum (-)-4'-(cis-1,2,3,4,4a,10b-hexahydro-8,9-dimethoxy-2-methylbenzo[c][1,6]= tolafentrine naphthyridin-6-yl)-ρ-toluenesulfonanilide (-)-N-[4-(cis-8,9-diméthoxy-2-méthyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]= tolafentrine naphtyridin-6-yl)phényl]-4-méthylbenzènesulfonamide (-)-4'-(cis-1,2,3,4,4a,10b-hexahidro-8,9-dimetoxi-2-metilbenzo[c][1,6]= tolafentrina naftiridin-6-il)-ρ-toluenosulfonanilida

C28H31N3O4S tradecamidum 13-hydroxy-N,N-dimethyltridecanamide tradecamide 13-hydroxy-N,N-diméthyltridécanamide tradécamide 13-hidroxi-N, N-dimetiltridecanamida tradecamida

C15H31NO2

ularitidum ularitide L-threonyl-L-alanyl-L-prolyl-L-arginyl-L-seryl-L-leucyl-L-arginyl-L-arginyl-L-seryl- L-seryl-L-cysteinyl-L-phenylalanylglycylglycyl-L-arginyl-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 (11 27)- disulfide

184 WHO Drug Information, Vol. 8, No. 3, 1994 Recommended INN: List 34

ularitide (11 27)-disulfure cyclique de L-thréonyl-L-alanyl-L-prolyl-L-arginyl-L-séryl- L-leucyl-L-arginyl-L-arginyl-L-séryl-L-séryl-L-cystéinyl-L-phénylalanyl-glycyl-glycyl- L-arginyl-L-méthionyl-L-aspartyl-L-arginyl-L-isoleucyl-glycyl-L-alanyl-L-glutaminyl- L-séryl-glycyl-L-leucyl-glycyl-L-cystéinyl-L-asparaginyl-L-séryl-L-phénylalanyl- L-arginyl-L-tyrosine ularitida L-treonil-L-alanil-L-prolil-L-arginil-L-seril-L-leucil-L-arginil-L-arginil-L-seril-L-seril- L-cisteinil-L-fenilalanilglicilglicil-L-arginil-L-metionil-L-aspartil-L-arginil-L-isoleu= cilglicil-L-alanil-L-glutaminil-L-serilglicil-L-leucilglicil-L-cisteinil-L-asparaginil-L-seril- L-fenilalanil-L-arginil-L-tirosina disulfuro ciclico (11 27)

C145H234N52O44S3

valaciclovirum valaciclovir L-valine, ester with 9-[(2-hydroxyethoxy)methyl]guanine valaciclovir (S)-2-amino-3-méthylbutanoate de 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)= méthoxy]éthyle valaciclovir éster de la L-valina, con 9-[(2-hidroxietoxi)metil]guanina

C13H20N6O4

vebufloxacinum (±)-9-fluoro-6,7-dihydro-5-methyl-8-(4-methyl-1 -piperazinyl)-1 -oxo-1H, 5H- vebufloxacin benzo[ij]quinolizine-2-carboxylic acid acide (RS)-9-fluoro-5-méthy]-8-(4-méthylpipérazin-1 -yl)-1 -oxo-6,7-dihydro 1 H, 5H- vébufloxacine benzo[ij]quinolizine-2-carboxylique ácido(±)-9-fluoro-6,7-dihidro-5-metil-8-(4-metil-1-piperazinil)-1 -oxo-1 H,5H- vebufloxacino benzo[ij]quinolizina-2-carboxílìco

C19H22FN3O3 votumumabum votumumab immunoglobulin G3 (human monoclonal 88-BV59 heavy chain anti-human carcinoma-associated antigen), disulfide with human monoclonal 88-BV59 κ-chain, dimer votumumab immunoglobuline G 3 (chaîne lourde de l'anticorps monoclonal humain 88-BV59 anti-antigène associé aux carcinomes humains), dimère du disulfure avec la chaîne κ de l'anticorps monoclonal humain 88-BV59 votumumab inmunoglobulina G3 (cadena pesada del anticuerpo monoclonal 88-Bv59 humano anti-antigeno asociado a los carcinomas humanos), puentes disulfuro con la cadena Κ del anticuerpo monoclonal 88-BV59 humano, dimero

xanomelinum 3-[4-(hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1 -methylpyridine xanomeline 3-[4-(hexyloxy)-1,2,5-thiadiazol-3-yl]-1 -méthyl-1,2,5,6-tétrahydropyridine xanoméline 3-[4-(hexiloxi)-1,2,5-tiadiazol-3-il]-1,2,5,6-tetrahidro-1-metilpiridina xanomelina

C14H23N3OS

185 Recommended INN: List 34 WHO Drug Information, Vol. 8, No. 3, 1994

zolasartanum 1-[[3-bromo-2-(o-1H-tetrazol-5-ylphenyl)-5-benzofuranyl]methyl]-2-butyl-4- zolasartan chloroimidazole-5-carboxylic acid acide 1 -[[3-bromo-2-[2-(1 H-tétrazol-5-yl)phényl]benzofuran-5-yl]méthyl]-2-butyl- zolasartan 4-chloro-1H-imidazole-5-carboxylique ácido 1 -[[3-bromo-2-(o-1 H-tetrazol-5-ilfenil)-5-benzofuranil]metil]-2-butil-4- zolasartan cloroimidazol-5-carboxílìco

C24H20BrCIN6O3 zolimomabum aritoxum zolimomab aritox immunoglobulin G 1 (mouse monoclonal H65-RTA anti-human antigen CD 5 heavy chain), disulfide with mouse monoclonal H65-RTA light chain, dimer, disulfide with ricin (castor-oil plant A-chain protein moiety) zolimomab aritox immunotoxine obtenue par couplage, par une liaison disulfure, de l'immuno= globuline G1 monoclonale de souris H65-RTA dirigée contre l'antigène de surface CD 5 des lymphocytes T humains et de la chaîne A de la ricine zolimomab aritox inmunoglobulina G1 monoclonal de ratón H65-RTA anti(antigeno de superficie CD5 de los linfocitos T humano), unida mediante enlace disulfuro con la cadena ligera de anticuerpo monoclonal de ratón H65-RTA, dimero, disulfuro con la cadena A de la ricina

186 WHO Drug Information, Vol. 8, No. 3, 1994 Recommended INN: List 34

AMENDMENTS TO PREVIOUS LISTS

Supplement to WHO Chronicle Vol. 37, No. 6, 1983 Recommended International Nonproprietary Names (Rec. INN): List 23 p. 5 iloprostum replace the chemical name by the following: iloprost (E)-(3aS,4R,5R,6aS)-hexahydro-5-hydroxy-4-[(E)-(3S,4RS)-3-hydroxy-4- methyl-1 -octen-6-ynyl]Δ2(1H),δ-pentalenevaleric acid

p. 6 mitindomidum replace the chemical name by the following: mitindomide (1R*,2S*,3R*,4S*,5R*,6S*,7S*,8R*)-tricyclo[4.2.2.02,5]dec-9-ene-3,4,7,8- tetracarboxylic 3,4:7,8-diimide

Supplement to WHO Chronicle Vol. 38, No. 6, 1984 Recommended International Nonproprietary Names (Rec. INN): List 24 p. 10 valproatum seminatricum replace the chemical name and the molecular formula by the following: valproate semisodium sodium hydrogen bis(2-propylvalerate), oligomer

(C16H31NaO4)n

WHO Drug Information, Vol. 5, No. 3, 1991 Recommended International Nonproprietary Names (Rec. INN): List 31 p. 2 aprikalimum replace the chemical name by the following: aprikalim (-)-(1R, 2R)-tetrahydro-N-methyl-2-(3-pyridyl)thio-2H-thiopyran-2-carboxamide 1-oxide p. 6 gadodiamidum replace the chemical name and the molecular formula by the following: gadodiamide [N,N-bis[2-[(carboxymethyl)[methylcarbamoyl)methyl]amino]ethyl]glycinato= (3-)gadolinium

C16H26GdN5O8 p. 6 gadoteridolum replace the chemical name by the following: gadoteridol (±)-[10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetato= [(3-)]gadolinium

MODIFICATIONS APPORTÉÉS AUX LISTES ANTÉRIEURES

Supplément à la Chronique OMS, Vol. 37, No. 6, 1983 Dénominations communes internationales recommandées (DCI Rec.): Liste 23 p. 6 mitindomidum remplacer le nom chimique par: mitindomide (1R*,2S*,3R*,4S*,5R*,6S*,7S*,8R*)-tricyclo[4.2.2.02,5]déc-9-ène-3,4,7,8- tétracarboxy-3,4:7,8-diimide

187 Recommended INN: List 34 WHO Drug Information, Vol. 8, No. 3, 1994

Supplément à la Chronique OMS, Vol. 38, No. 6, 1984 Dénominations communes internationales recommandées (DCI Rec): Liste 24 p. 10 valproatum seminatricum remplacer le nom chimique et la formule brute par: valproate semisodique oligomère du complexe d'acide 2-propylpetanoïque et de 2-propylpentanoate de sodium

(C16H31NaO4)n

Informations pharmaceutiques OMS, Vol. 5, No. 3, 1991 Dénominations communes internationales recommandées (DCI Rec): Liste 31 p. 2 aprikalimum remplacer le nom chimique par: aprikalim (-)-(1 R, 2R)-N-méthyl-2-(pyridin-3-yl)tétrahydro-2H-thiopyrane-2- carbothioamide 1-oxyde

p. 6 gadodiamidum remplacer le nom chimique et la formule brute par: gadodiamide [N,N-bis[2- [(carboxyméthyl)[(méthylamino)carbonyl]métriyl]amino]éthyl]glycinato= (3-)gadolinium

C16H26GdN5O8

MODIRCACIONES A LAS LISTAS ANTERIORES

Suplemento de Crónica de la OMS, Vol. 37, No. 6, 1983 Denominaciones Comunes Internacionales Recomendadas (DCI Rec): Lista 23 p. 6 mitindomidum sustituir el nombre quimico por lo siguiente: mitindomida (1R*,2S*,3R*,4S*,5R*,6S*,7S*,8R*)-triciclo[4.2.2.02,5]dec-9-eno-3,4,7,8- tetracarboxílìco 3,4:7,8-diimida

Suplemento de Crónica de la OMS, Vol. 38, No. 6, 1984 Denominaciones Comunes Internacionales Recomendadas (DCI Rec): Lista 24 p. 10 valproatum seminatricum sustituyase el nombre químico y la fórmula empírica por los siguientes: valproato semisódico bis(2-propilvalerato) de hidrogeno y sodio, oligómero

(C16H31NaO4)n

Información Farmacéutica, de la OMS, Vol. 5, No. 3, 1991 Denominaciones Comunes Internacionales Recomendadas (DCI Rec): Lista 31 p. 2 aprikalimum sustituyase el nombre químico por lo siguiente: aprikalim (-)-(1R, 2R)-tetrahidro-N-metil-2-(3-piridil)tio-2H-tiopiran-2-carboxarnida 1 -óxido p. 6 gadodiamidum sustituir el nombre químico y la fórmula empírìca por los siguientes: gadodiamida [N,N-bis[2-[(carboximetil)[(metilcarbamoil)metil]amino]etil]glicinato= (3-) gadolinio

C16H26GdN5O8

188 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 includes 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 concerned 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 rele­ vant decisions on this subject have to be taken.

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ISSN 1010-9609