WHO DRUG

INFORMATION

VOLUME 9 • NUMBER 4 • 1995

PROPOSED INN LIST 74 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 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 relevant decisions on this subject have to be taken.

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

ISSN 1010-9609 Volume 9, Number 4, 1995 World Health Organization, Geneva

WHO Drug Information

Contents

General Policy Topics Reports on Individual Drugs HIV: will effective treatment demand Acetylsalicylic acid: a protective effect against early diagnosis? 193 colorectal cancer 210 analogues: premonitory Update on AIDS experience in therapy of viral hepatitis 212 Amphotericin: a candidate for first-line 1. Antiretroviral drugs treatment of visceral leishmaniasis? 215 The cellular biology of HIV replication 196 Nuceloside analogues 196 The potential of combination therapy 197 General Information Other enzyme inhibitors 197 Polypharmacy, parenteral treatment, and The case for early intervention 198 blood-borne 217 Some ground rules for effective antiretroviral Increasing concerns about pneumococcal therapy 198 drug-resistance 217 2. Vaccines and genetic manipulation Regulatory Matters The immune response to HIV infection 201 Nifedipine: danger of short-acting formulations 220 Fundamental problems in vaccine Oral contraceptives and thromboembolism 221 development 202 Naftidrofuryl infusion withdrawn 222 Recombinant subunit vaccines: fresh doubts on feasibility 203 Attenuated vaccines: feasibility and risks 203 Essential Drugs A re-evaluation of strategy 204 WHO Model List (December 1995 revision) 223 New avenues of research 204 The potential of gene therapy 204 Proposed International Prospects for immune restitution 205 Rapid progress with vaccines 205 Nonproprietary Names: List 74 235 A globally-relevant option? 205

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World Health Organization, Geneva WHO Drug Information Volume 9, 1995: Index

A E ACE inhibitors, (2) 62 Emergence of newly-resistant strains, (1) 2 renal failure, (1) 16 Enalapril, (1) 17 Acetylsalicylic acid, (1) 36, (2) 62 Erythromycin, (2) 75, (3) 143 colorectal cancer, (4) 210 Essential drugs, (2) 79 Acinetobacter, hospital-acquired infection, (1) 25 model list, (4) 235 AIDS update, (4) 196 Albendazole, (3) 135 Aminophylline, (2) 54 F Aminosalicylates, (3) 158 Fake drugs, (3) 127 Amphotericin, (4) 215 Fluconazole, cryptococcal meningitis, (1) 23 Antibiotic resistance, (1) 15 Antibiotics in eclipse, (1) 1 G Antibiotics, (3) 127 Gene therapy, HIV, (4) 204 Antimicrobial susceptibility tests, (3) 158 Glibenclamide, (2) 61 Antiretroviral therapy, (4) 198 Guidelines on defining the scope, (2) 77 Antistreptococcal vaccine, (1) 22 Azathioprine, (2) 68 H B Hepatitis B vaccination, (3) 146 Bacterial resistance, (1) 1 Herbal preparations, (3) 148 Bednets, malaria, (3) 151 HIV test, oral fluid, (1) 33 Bifidobacterium, (1) 14 HIV treatment, (4) 193 Budesonide, (2) 68 HIV vaccine development, (4) 202 Homoeopathy, (3) 149 C Hydroxyurea and sickle-cell disease, (1) 26 Captopril, (1) 16, (2) 63 Cefalosporins, (3) 142 I Chloraquine, (1) 39 Ibuprofen, (1) 37 Chlorpropamide, (2) 61 Indometacin, (1) 38 Ciclosporin, (2) 68 Influenza, vaccine, (3) 138 Clomifene, (3) 159 Informed consent in emergencies, (3) 154 Clozapine, (1) 34 INN lists, (2) 81, (3) 165, (4) 235 Community-acquired , (2) 43 pranobex, (4) 205 Contraceptives, spermicide, (3) 163 strength, (3) 163 Corticosteroids, (2) 68 Integrase inhibitors, (4) 197 Coumarin, (3) 159 Interferon alfa, (4) 205 Cyproterone acetate, (1) 30, (3) 162 Interferon gamma, (4) 205 Cysticidal drugs, (3) 135 lnterleukin-2, (4) 205 Iron chelation, beta-thalassaemia, (1) 28 D Iron-containing drugs, (3) 159 Deferiprone, (2) 57 Ivermectin, (3) 132, (3) 144 Defining the scope of the licensing procedure, (2) 77 K , (3) 135 Kanamycin, (3) 142 Diabetes, non-insulin therapy, (2) 60 , (4) 196 Diethylcarbamazine, (3) 132 L Diethylene glycol, (3) 127 Labelling, paediatric, (1) 32 Ditiocarb sodium, (4) 205 , (4) 196 Diuretics, (2) 70 Licence variations, (2) 73 DMPA, breast cancer, (1) 20 Licensing procedure, (2) 77 Drug resistance, (2) 44 Lymphatic filariasis, (3) 132

1 WHO Drug Information Volume 9, Index 1995

M S Macrolide antibiotics, (3) 162 Saccharomyces boulardii, (1) 15 Magnesium sulfate, (2) 63, (3) 130 , (3) 160 Malaria, (3) 151 Silver , (3) 142 vaccine, (3) 135 Simvastatin, (3) 161 Measles vaccine, vitamin A, (3) 138 Socially-responsive development of Medical records, (3) 150 medicines, 11 (1) 1, III (2) 43 errors, (3) 157 Spectinomycin, (3) 142 Mercaptopurine, (2) 68 Starting materials, pharmaceuticals, (3) 156 Metformin, (1) 30, (2) 61 , (4) 196 Methotrexate, (1) 41, (2) 54, (2) 68 Streptokinase, (2) 62 Multidrug resistance, (1) 3 Sulfamethoxazole/trimethoprim, (3) 161 Myocardial infarction, (2) 62 Sulfasalazine, (1) 40, (2) 68 N Naftidrofuryl infusion, (4) 222 T Naltrexone, (1) 33 Tacrolimus, (3) 161 Natural medicines, (3) 147 Tamoxifen, (2) 72 Natural remedies, (3) 155 Tetracycline 1%, (3) 142 Nifedipine, (4) 220 Thiacetazone, (2) 55 Nucleoside analogues, (4) 196, 212 Tocolytics, (3) 160 Nucleic acid vaccines, (4) 205 Traditional eye medicines, (3) 152 Trimethoprim/sulfamethoxazole, (3) 161 O Triple-drug HIV regimens, (4) 197 Oral contraceptives, breast cancer, (1) 18 Tropical disease research, (3) 164 thromboembolism, (4) 221 Orphan drugs, (2) 72 u OTC advertising, (1) 10 Update on AIDS, (4) 196 P Use of essential drugs, (2) 79 Paediatric labelling, (1) 32 Pancreatic enzyme factor, (2) 58 V Pancreatins, (1) 30 Vaccine development, HIV, (4) 203 Penicillamine, (1) 40 new horizons, (2) 47 Penicillin, AIDS, (2) 66 Vaccine, antistreptococcal, (1) 22 Penicillin, neurosyphilis, (2) 66 hepatitis B, (3) 145 Pimozide, (1) 32 influenza, (3) 138 Pneumococcal drug-resistance, (4) 217 malaria, (3) 135 Poliomyelitis vaccine, (2) 59 measles, vitamin A, (3) 139 Polypharmacy, (4) 217 poliomyelitis, (2) 59 Povidone-iodine, (3) 142 rotavirus, (1) 14 Praziquantel, (3) 135 nucleic acid, (4) 205 Prednisolone, (1) 42, (2) 68 Vigabatrin, (2) 75 Product information, (2) 79 Vitamin A, (3) 141 Protease inhibitors, (4) 197 measles vaccine, (3) 139 Q Quality assurance, (3) 128 W Quinacrine, (1) 33 Warfarin, (3) 162 Quinolones, (3) 160 WHO Model List, (4) 223 R Reporting requirements, (2) 75 Z Resistant strains, (1) 3 , (4) 196 Rheumatoid arthritis, (1) 35 , (4) 193, 196 Rotavirus vaccine, (1) 14

2 WHO Drug Information Vol. 9, No. 4, 1995

General Policy Topics

HIV: will effective treatment widespread reticence exists (8). Throughout London as few as 12% of the total number of demand early diagnosis? pregnant women known to be HIV-positive by anonymous testing are currently consenting to The estimated number of persons with AIDS in the voluntary named testing, after being counselled to world increases inexorably year by year. Many do so in antenatal clinics (9). Similar reticence cases of the underlying HIV infection are now typifies attitudes within the USA (10). transmitted heterosexually and the proportion of women among those infected is rising. The risk of It has been suggested that, as management of the mother-to-child (or vertical) transmission of the condition is improved and as stigmata attached to disease has been estimated to range from some HIV infection and AIDS are eroded, HIV testing may 15% in Europe to as high as 35% in Africa (1), and come to be accepted as "routine" alongside testing the disease is already reported to exert a for rubella, syphilis, and hepatitis B virus (11). This substantial impact on childhood mortality both in is doubtless true, but passive community accept­ developed and developing countries (2, 3). These ance of routine testing will not, of itself, be suffi­ demographic trends have been determined by cient: evidence is now rapidly accumulating that maintaining national registers of HIV-infected improved management of the condition is depend­ children, and by anonymous testing of antenatal ent upon early diagnosis and this seems set to and neonatal blood samples (4). For as long as become decisive in the management of HIV therapeutic intervention was without demonstrable infection. influence on the risk of transmission, this post facto record of events simply served to alert the world to Two independently-conducted studies reported in the gravity of the disease. the same issue of The New England Journal of However, the situation has now changed with the Medicine within the past few months suggest that, demonstration that perinatal use of zidovudine to be effective in ameliorating the course of the HIV greatly reduces the risk of vertical transmission (5, infection, zidovudine needs to be started during the 6). There is even speculation that antiseptic primary infection rather than later in the asympto­ applications to the birth canal may have the same matic period (12, 13). Indeed, there is now effect (7). Wherever effective treatment can be optimism that it may prove possible to suppress, or made available, it has become of vital importance even to eradicate HIV infection by using two or to both mother and child for HIV infection to be three different types of antiretroviral drugs in identified well in advance of parturition. However, combination at the first indication of infection (14). there is still much to be achieved. The results of further clinical studies conducted in different That the evidence to support this expectation was settings are needed to provide a basis for refining collected at all demonstrates the dedication and and simplifying perinatal zidovudine therapy. The commitment of the investigators involved: it took, aim must be to reduce the complexity and the cost for instance, 33 months for clinicians at 27 centres of the intervention to the fullest extent possible in eight highly-developed countries to recruit 77 without loss of efficacy in order that the benefits can patients in the phase of primary HIV infection. Yet, be extended to as many as possible. in a future that may not be far distant, early diag­ nosis may be the major determinant of whether the This programme of clinical investigation cannot be patient's disease is cured, or whether it will pro­ realized unless pregnant women who have risked gress to AIDS. infection are prepared to come forward promptly to seek medical advice. Yet many are dissuaded from Zidovudine now holds far more promise than was doing so by perceived or valid concerns that breach credited to it a year ago. Several analogous drugs of confidentiality could expose them to social and are already available, and more are under develop­ administrative discrimination. Even in countries ment, which attack different stages in the replication where official policy encourages early consultation, mechanism. During their clinical development, they

193 General Policy Topics WHO Drug Information Vol. 9, No. 4, 1995

will need to be compared with each other; they will scant benefit from tangible technical advances need to be tested in combination; optimum dosage taken for granted elsewhere. Diagnostic tests have regimens will need to be defined; and unwanted been developed for screening blood for transfusion effects will need to be monitored and investigated. against HIV and other pathogenic viruses. To achieve all of this within the timeframe that Advances have been made in the diagnosis and urgency demands will require the collaboration of therapy of pathogenic and opportunistic infections. many patients in the earliest stage of infection. But tangible — often prohibitive — expense is involved in assuring the safety of a unit of blood, or Scientific discovery cannot be advanced by in prescribing a reserve antibiotic when an infection proclamation, and to attempt to do so risks placing fails to respond to primary therapy. In fact, a gulf science itself in disrepute. Clinical studies of has been cleaved everywhere between what is zidovudine have been plagued in the past by cycles technically feasible and what is affordable in the of over-optimism followed by disillusionment; by health sector. desperation among the patients whose lives are at stake; and by calls from politicians and the public at This creates a dilemma for governments, a quan­ large to accelerate the clinical assessment of dary for its legal institutions and, above all, an candidate drugs. A picture has recently been inextricable predicament for the medical and allied portrayed of disillusioned and desperate HIV- professions. Governments and doctors must not be infected patients prepared to "cheat to get into forced to compromise standards through lack of clinical trial protocols, fail to follow the trial resources in seeking to contain HIV infection. The protocols, and drop out in record numbers" (15). development of a protective vaccine or a drug that either cures the infection, or suppresses it to the It is a tribute to scientists in the United States and extent of interrupting transmission must be Europe that, against this background, so much regarded as an issue of global relevance. Even the secure fundamental knowledge about HIV and the most dramatic of therapeutic advances will be of disease that it causes has been generated over the little avail if persons who are infected or at risk of past decade. The opportunity may now well exist to infection remain inaccessible. An open and convert this investment into secure therapeutic benevolent attitude towards the disease has to be gain. If, at best — and it remains far from certain at encouraged. If all countries are to benefit from the this stage — it should prove possible to cure HIV technical advances that are now in the making, they infection by hitting the virus early and hard with must inculcate attitudes towards HIV infection that combinations of antiretroviral drugs (14), the will facilitate the development of therapies. pressure will be on to achieve global eradication and to move ahead as quickly as possible before References the virus evolves its own defence against attack. 1. Newell, M., Peckham, C. Risk factors for vertical transmission of HIV-1 and early markers of HIV-1 infection This feat has never yet been accomplished with a in children. AIDS, 7 (suppl): 91-97 (1993). sexually transmitted disease. In any circumstance, it will be a challenge of virtually unprecedented 2. Chu, S., Buehler, J., Oxtoby, M., Kilbourne, B. Impact of scale and complexity. It will be impossible for as the human immunodeficiency virus epidemic on mortality long as the disease is perceived as a stigma that in children, United States. Pediatrics, 87: 806-810 (1991). merits discrimination, for as long as society is judgemental rather than compassionate in its 3. Nicoll, A., Timaeus, I., Kigadye, R. et al. The impact of HIV-1 infection on mortality in children under 5 years of attitude, and for as long as those afflicted feel a age in sub-Saharan Africa: a demographic and epidemio­ need to hide away. Much can be accomplished by logical analysis. AIDS, 8: 995-1005. education, but little by repression. Now that the promise of real therapeutic gains are on the 4. Peckham, C, Gibb, D. Mother-to-child transmission of horizon, the reticence of those infected to seek help the human immunodeficiency virus. New England Journal voluntarily could prove to be the greatest impedi­ of Medicine, 333: 298-302 (1995). ment to success in controlling the disease. 5. Boyer, P., Dillon, M., Navaie, M. et al. Factors predic­ tive of maternal-fetal transmission of HIV-1 : preliminary Policy-makers in developing countries will analysis of zidovudine given during pregnancy and/or undoubtedly question the relevance of these delivery. Journal of the American Medical Association, developments to their own circumstances. Too 271: 1925-1930 (1994). often in the past, their populations have reaped

194 WHO Drug Information Vol. 9, No. 4, 1995 General Policy Topics

6. Connor, E., Sperling, R., Gelber, Ft. et al for the Pedi­ 11. Minkoff, H., Willoughby, A. Pediatric HIV disease, atric AIDS Clinical Trials Group. Reduction of maternal- zidovudine in pregnancy, and unblinding heelstick infant transmission of human immunodeficiency virus surveys: reframing the debate on prenatal HIV testing. type-1 with zidovudine treatment. New England Journal of Journal of the American Medical Association, 274: 1165- Medicine, 331: 1173-1180 (1994). 1168 (1995).

7. Strategies for prevention of perinatal transmission of 12. Kinloch-de Loës, S., Hirschel, B., Hoen, B. et al. A HIV infection: report of a consensus workshop, Siena, controlled trial of zidovudine in primary human immunode­ Italy, June 1995. Journal of AIDS and Human Virology, 8: ficiency virus infection. New England Journal of Medicine, 161-175 (1995). 333:408-413 (1995).

8. Department of Health. Guidelines for offering voluntary 13. Volberding, P., Lagakos, S., Grimes, J. et al for the named HIV antibody testing to women receiving antenatal AIDS Clinical Trials Group. A comparison of immediate care. London, 1994. with deferred zidovudine therapy for asymptomatic HIV- infected adults with CD4 counts of 500 or more per cubic 9. Department of Health. Unlinked anonymous HIV millimetre. New England Journal of Medicine, 333: 401- serosurveys steering group report. Unlinked Anonymous 407 (1995). HIV Seroprevalence Monitoring Programme in England and Wales. London, 1995. 14. Ho, D. Time to hit HIV, early and hard. New England Journal of Medicine, 333: 450-451 (1995). 10. Chrystie, I., Wolfe, C, Kennedy, J. et al. Voluntary, named testing for HIV in a community-based antenatal 15. Nowak, R. AIDS researchers, activists fight crisis in clinic: a pilot study. British Medical Journal, 311: 928-931 clinical trials. Science, 269: 1666-1667 (1995). (1995).

195 WHO Drug Information Vol. 9, No. 4, 1995

Update on AIDS

The importance of basic research It is probable, assuming the accuracy of earlier estimates, that some 20 million individuals around the world — men, women and children — are now infected with the human immunodeficiency virus (HIV). Of greater certainty, is that the highest concentration of cases is in sub-Saharan Africa, that the infection is spreading with explosive rapidity in many parts of Asia, and that it is now strongly associated with deprivation and poverty (1-6).

The impact of education in altering high-risk behaviour has been significant but limited (7-8). Prospects of providing a protective vaccine remain viable yet distant and, whereas tangible progress is being made in antiretroviral therapy, the benefits that these drugs currently offer remain modest and their cost remains prohibitive in all but the most affluent of countries.

At the same time, research capacity has been rising across a broad front. The annual allotment for the AIDS programme directed by the US National Institutes of Health now exceeds US$ 1300 million (2). Coordinated activity is now also developing within the private sector: a consortium of 15 pharmaceutical companies is collaborating in trials of drug combinations (9). These two contributions provide an interactive balance of fundamental and applied research that is at once providing important insights into the mechanisms of HIV infection and advancing both therapeutic and preventive strategies (2, 10-12).

1. Antiretroviral drugs The cellular biology of HIV replication a complex system of genetic regulation. This basic An understanding of the cellular biology of HIV knowledge provides vital therapeutic leads: several infection is central to any attempt to develop different steps in the replication process have been antiretroviral drugs and vaccines. To replicate, the identified as possible targets for antiretroviral virus must first bind to the cell surface and sub­ intervention (14) sequently fuse with the lipid membrane layers of the target CD4 lymphocytes; viral reverse trans­ Nucleoside analogues criptase then transmutes the single-stranded RNA Zidovudine and other first-generation antiretroviral genome into double-stranded DNA which integrates drugs — didanosine (15-18), zalcitabine (18-20), into the chromosomal apparatus of the cell; this stavudine (21) and lamivudine (22) — are nucleo­ inserted DNA (or provirus) generates new retroviral side analogues which, after phosphorylation in vivo, RNA through the normal mechanisms of cellular inhibit viral reverse transcriptase by frustrating the transcription; structural proteins are synthesized construction of nucleic acid chains (23). Thus far, and processed by proteolytic enzymes; and the their value has been seriously compromised by progeny are released after maturation in the cell acute toxic effects and the emergence of resistant membranes. variants of HIV. Daily administration of zidovudine can result in clinically-evident drug-resistance within Recent evidence indicates that this process a few weeks. This has been attributed to a high involves yet further intricacies: for instance, frequency of mutations in the HIV reverse transcriptional activity and production of progeny is transcription gene (24, 25). Typically, the effect favoured by a specific gene within the virus which develops progressively, since it results from the arrests the target cell in an activated state early in accumulation of several independent mutations, mitosis (13). In all, HIV has nine known genes and each coding for zidovudine resistance (26).

196 WHO Drug Information Vol. 9, No. 4, 1995 Update on AIDS

Didanosine and zalcitabine have each been antiviral nucleoside analogues might augment assessed in patients who have become mitochondrial damage (31). The therapeutic value unresponsive to zidovudine or who can no longer of these compounds reflects the selectivity with tolerate its toxic effects (15, 16). Sequential which they disrupt viral DNA synthesis, but this administration of alternative nucleoside analogues selectivity is not absolute. Aside from bone-marrow in these circumstances offers some advantage, but depression, reports of skeletal and cardiac the gains have been modest (17, 18). Greater myopathy, peripheral neuropathy, and damage to benefits are likely to derive from combination liver and pancreas have been associated with therapy. Persuasive clinical evidence of such prolonged use of zidovudine. Similar, but distinctive benefit has been obtained by using zidovudine in patterns of adverse effects have resulted from combination with lamivudine. High-level HIV clinical use of other nucleoside analogues. In part, resistance to lamivudine — which results from a at least, these effects probably result from inhibition single mutation in the reverse transcriptase enzyme of human mitochondrial DNA polymerase (32-34). — emerges rapidly when it is used alone (27). The need for rigorous monitoring of adverse effects None the less, when it is given together with associated with these drugs, when they are used zidovudine, serum HIV-1 RNA concentrations are either singly or in combination, has recently been lowered more effectively than by either drug alone. heightened by an exceptional incident. Several The mutation which induces resistance to fatalities resulting from acute hepatic failure and lamivudine is even claimed to render zidovudine- lactic acidosis occurred among patients with resistant mutants phenotypically sensitive (28): chronic viral hepatitis who were participating in a most HIV samples obtained from patients who had trial of a fluorinated antiviral , received both drugs for 24 weeks remained fully fialuridine (35), a substance which has since been sensitive to zidovudine, and attempts to generate shown to be a potent inhibitor of hepatic DNA co-resistance to zidovudine and lamivudine in vitro polymerase (36, 37). (See also p. 212.) were unsuccessful. Other enzyme inhibitors The potential of combination therapy In addition to the nucleoside analogues, several This finding has accentuated interest in the broader classes of non-nucleoside reverse transcriptase potential of combination therapy. Promising inhibitors — exemplified by , a substance preliminary reports have been issued on the already under development — have been identified progress of large-scale multicentre studies in the course of random screening (38). These conducted respectively in the USA and in Europe/ block DNA polymerization non-competitively, and Australia (29, 30). Each of these studies, one of they are also claimed to bind the phosphorylated which was conducted in children (30), indicates that derivatives of nucleoside inhibitors strongly and regimens based on zidovudine in combination with nonproductively to the viral enzyme. Their clinical either didanosine or zalcitabine offer advantages — potential when used alone or in combination with a both in terms of disease progression and survival nucleoside inhibitor has yet to be explored. — over monotherapy with zidovudine, particularly among patients in the early stages of infection and Rapid progress is also being made in the develop­ those who have not previously been treated with ment of inhibitors of other HIV enzymes, notably zidovudine. This advantage was considered to be protease and integrase. The clinical assessment of sufficiently important to warrant early termination of several inhibitors of viral protease, including two studies on ethical grounds: 2-year mortality was , and , is now well reduced by 38% in the European/Australian study, advanced (39), and other candidate substances are while the study involving children was terminated being studied. The target enzyme is involved in the when the combination therapies were shown to synthesis of structural proteins of the viral core and confer important advantages in survival, growth essential enzymes, including reverse transcriptase rate, and incidence of opportunistic infections and and protease itself (40). In vitro, inhibition of these neurological deficit. processes results in arrested maturation and generation of immature, non-infectious virions (41, Thus far, there is no evidence from these studies 42). HIV variants resistant to these inhibitors have that combined regimens of nucleoside analogues been identified both in cell culture and in patients, are associated with an increased risk of toxicity and it seems that resistance induced against one of (29). The possibility cannot yet be excluded, these drugs extends to the whole class (43). however, that co-administration of two or more A third potential enzyme target, viral integrase,

197 Update on AIDS WHO Drug Information Vol. 9, No. 4, 1995

which has yet to be studied clinically, splices the the virus remains largely dormant within the viral DNA into the host chromosome (9). It lymphoreticular tissues for years before its resembles a group of human cellular enzymes — reactivation results in symptomatic disease. This the polynucleotidal transferases which manipulate concept has now been shown to be misconceived. chromosomal DNA — but its structure is Throughout all phases of the disease there is a sufficiently distinctive to make it possible for highly massive cellular immune reaction to HIV infection specific inhibitors to be devised. which results in a high turnover of both circulating plasma virions and of infected CD4 lymphocytes, The declared objective of the consortia of com­ which are continuously destroyed by HIV-specific panies pledged to collaborate in trials of drug cytotoxic T lymphocytes. combinations is to devise triple-drug regimens that target viral reverse transcriptase, protease and It is estimated that the half-life of the HIV virus and integrase simultaneously (9). The hope is that of infected CD4 cells is no more than two days. multidrug therapy will eventually provide a realistic This implies that at least 30% of the circulating virus basis for extended treatment by greatly reducing population and 30% of the infected cells in which the rate at which resistant HIV variants otherwise these virions are generated must be replenished emerge. daily. The colossal turnover of some 108 to 109 virions daily and the sustained recruitment and loss The case for early intervention of CD4 cells within a short-lived virus-expressing The need to inhibit the emergence of drug-resistant pool provides a persuasive explanation of several variants implies a requirement for early anti¬ features characteristic of HIV infection: retroviral therapy, yet until recently no advantage had been found to accrue from starting mono­ • the sustained plasma viraemia that persists in therapy with zidovudine before the disease HIV-infected individuals throughout the latent progresses to AIDS. Although the US AIDS Clinical phase of the disease (53); Trials Group initially reported that zidovudine slowed the clinical progression to AIDS in infected • the abrupt fall in circulating viral protein and the but asymptomatic subjects (44), it later revised its concomitant increase in the numbers of circulating conclusion (45). Its own results, together with CD4 cells at the outset of effective antiretroviral those of a large Anglo/French study (46) have therapy; shown that treatment of asymptomatic patients with CD4 counts in excess of 500/mm3 confers no • the huge potential for the emergence of genetic advantage over deferred zidovudine therapy, either variants through mutation which has been estimated to occur in reverse transcriptase with a in prolonging survival or in extending the 3 4 asymptomatic phase of infection. frequency as high as 1:10 to 10 per base (54);

This conclusion, in turn, now requires revision in • the rapidity with which resistant variants are order to accommodate highly-promising results selected during antiretroviral monotherapy; and obtained in a further generation of clinical trials. Perinatal administration of zidovudine has been • the progressive fall in numbers of CD4 cells as the shown to be remarkably successful in reducing the immune system is ultimately overwhelmed in the risk of vertical transmission of HIV infection from symptomatic phases of the disease. mother to child (47-49), while its administration to adults for a period of six months from the time of Some ground rules for effective primary infection (substantially earlier than is the antiretroviral therapy case in other trials) has been shown within a These findings have fundamental relevance to the European/Australian trial to increase the CD4 cell use of antiretroviral drugs since the relative count substantially and to reduce the frequency of homogeneity of the viral population at the time of minor opportunistic infections throughout a follow- initial infection (55, 56) should favour early up period of 15 months (50). intervention (57). None the less, the characteristic brisk rise in the CD4 count at the outset of antiviral Fortuitously, two recent studies on the patho­ therapy suggests that a capacity for substantial genesis of HIV infection have provided a regeneration of immunological mechanisms persuasive explanation for these results (51, 52). It remains, even among patients with advanced has long been assumed that, after initial infection, symptomatic disease, for as long as viral replication

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can be effectively suppressed (52). The currently 4. Centers for Disease Control and Prevention. Update: available nucleoside inhibitors of reverse trans­ AIDS among women — United States, 1994. Morbidity criptase are relatively weak antiretroviral agents, and Mortality Weekly Report, 44: 81-84 (1995). which at best lower the viral load by 0.7 log. With the apparent exception of preventive therapy of the 5. Gwinn, M., Pappaioanou, M., George, J. et al. Prev­ alence of HIV infection in childbearing women in the newborn, monotherapy with the agents now avail­ United States. Journal of the American Medical able seems doomed to fail, given the inexorable Association, 265: 1704-1708 (1991). emergence of resistant variants (25, 57-59). 6. Conway, G., Epstein, M., Hayman, C. et al. Trends in Of greater promise are zidovudine and lamivudine HIV prevalence among disadvantaged youth: survey in combination; nevirapine and other non-nucleo¬ results from a national job training programme, 1988 side inhibitors of reverse transcriptase; and through 1992. Journal of the American Medical particularly the HIV protease inhibitors which are at Association, 269: 2887-2889 (1993). least one order more potent (40, 51, 52). In 7. DiClemente, R., Wingood, G. A randomized controlled appropriate combination, it is possible that these trial of an HIV sexual risk-reduction intervention for young drugs might avert the development of resistance African-American women. Journal of the American and hold the virus in check indefinitely. Medical Association, 274: 1271-1276 (1995).

At last there is a note of measured optimism in the 8. Des Jaríais, D., Hagan, H., Friedman, S. et al. Main­ air. "When safe and effective treatment regimens taining low HIV seroprevalence in populations of injecting are defined", it has been said, "the time will be right drug users. Journal of the American Medical Association, to test the concept of ablative treatment in HIV-1 274: 1226-1231 (1995). infection. To stack the deck in favour of success, 9. International Federation of Pharmaceutical we should exert maximum antiviral pressure (using Manufacturers Associations. Infernal HIV: do we finally the optimal regimen) on the virus when it is most have a handle on it? Health Horizons, No. 25, 1995. homogeneous — during the phase of initial infection" (57). 10. Fields, B. AIDS: time to turn to basic science. Nature, 369: 95 (1994). These two principles — early intervention and multiple chemotherapy — have long been applied 11. Cohen, J. AIDS mood upbeat — for a change. with success to the management of tuberculosis. At Science, 267: 959-960 (1995). best, the cost of delivering and supervising such 12. Gallo, R. Human retroviruses in the second decade: a treatment will be considerable. At worst, the attempt personal perspective. Nature Medicine, 1: 753-759 may fail through lack of funds necessary for (1995). diagnosing and treating the infection, through failure of patients to report the primary infection (or 13. Jowett, J., Planelles, V., Poon, B. et al. The human acute retroviral syndrome), or possibly as a result of immunodeficiency virus type 1 vpr gene arrests infected inefficacy or long-term toxicity of the treatment. The T-cells in the G2 + M phase of the cell cycle. Journal of fundamental need to maintain educational pro­ Virology, 69: 6304-6313 (1995). grammes and to search for effective vaccines should not be relaxed in the light of the impressive 14. De Clerq, E. Basic approaches to antiviral treatment. advances that are now being achieved in anti­ Journal of the Acquired Immune Deficiency Syndrome, 4: retroviral therapy. 207-218 (1991). 15. Lambert, J., Seidlin, M., Reichmann, R. et al. 2'-3'- References: dideoxyinosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. 1. Martens, T., Burton, A., Stoneburner, R. et al. Global New England Journal of Medicine, 322: 1333-1334 estimates and epidemiology of HIV infection and AIDS. (1990). AIDS, 8 (Suppl. 1): 361-372 (1994). 16. Cooley, T., Kunches, L, Saunders, C. et al. Once- 2. Paul, W. Re-examining AIDS research priorities. daily administration of 2'-3'-dideoxyinosine (ddl) in patients Science, 267: 633-636 (1995). with the acquired immunodeficiency syndrome or AIDS- related complex. New England Journal of Medicine, 322: 3. Centers for Disease Control and Prevention. HIV/AIDS 1340-1345 (1990). Surveillance Report, 6: 1 (1994).

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17. Kahn, J., Lagakos, S., Richman, D. et al. A controlled 29. Stephenson, J. Other AIDS drug regimens beat AZT trial comparing continued zidovudine with didanosine in alone, reduce clinical progression and mortality. Journal of human immunodeficiency virus infection. New England the American Medical Association, 274: 1183-1184 Journal of Medicine, 327: 581-587 (1992). (1995).

18. Abrams, D., Goldman, A., Launer, C. et al. A 30. Rowe, P. Something better than zidovudine for comparative trial of didanosine or zalcitabine after children. Lancet, 345: 511 (1995). treatment with zidovudine in patients with human immunodeficiency virus infection. New England Journal 31. Lewis, W., Dalakas, M. Mitochondrial toxicity of of Medicine, 330: 657-662 (1994). antiviral drugs. Nature Medicine, 1: 417-422 (1995).

19. Bozzette, S., Kanouse, D., Berry, S., Duan, N. for the 32. Chen, C-H., Cheng, Y-C. Delayed cytotoxicity and Roche 3300/ACTG Study Group. Health status and selective loss of mitochondrial DNA in cells treated with function with zidovudine or zalcitabine as initial therapy for the anti-human immunodeficiency virus compound 2'-3'- AIDS: a randomized controlled trial. Journal of the deoxythymidine. Journal of Biological Chemistry, 264: American Medical Association, 273: 295-301 (1995). 11934-11937 (1989).

20. Fischl, M., Stanley, P., Collier, A. et al. Combination 33. Wright, G., Brown, N. analogs as and monotherapy with zidovudine and zalcitabine in inhibitors and substrates of DNA polymerases. Pharma­ patients with advanced HIV disease. Annals of Internal cology and Therapeutics, 47: 447-497 (1990). Medicine, 122: 24-32 (1995). 34. Wallace, D. Diseases of the mitochondrial DNA. 21. Skowron, G. Biologic effects and safety of stavudine: Annual Reviews of , 61: 1175-1212 (1992). overview of phase I and II clinical trials. Journal of Infectious Diseases, 171 (suppl 2): 113-117 (1995). 35. McKenzie, R., Fried, M., Sallie, R. et al. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investiga­ 22. van Leeuwen, R., Katlama, C, Kitchen, V. et al. tional nucleoside analogue for chronic hepatitis B. New Evaluation of safety and efficacy of 3TC (lamivudine) in England Journal of Medicine, 333: 1099-1105 (1995). patients with symptomatic or mildly asymptomatic human immunodeficiency virus infection: a phase l/ll study. 36. Cui, L, Toon, S., Schinazi, R., Sommadossi, J-P. Journal of Infectious Diseases, 171: 1166-1171 (1995). Cellular and molecular events leading to mitochondrial toxicity of 1 -[2'-deoxy-2'-fluoro-β-D-arabino-furanosyl]-5- 23. Furman, P., Fyfe, J., St Clair, M. et al. Phosphorylation iodouracil in human liver cells. Journal of Clinical of 3'-azido-3'-deoxythymidine and selective interaction of Investigation, 95: 555-563 (1995). the 5'-triphosphate with human immunodeficiency virus reverse transcriptase. Proceedings of the National 37. Lewis, W., Simpson, J., Meyer, R. et al. Mammalian Academy of Sciences, USA, 83: 8333-8337 (1986). DNA polymerases, alfa, beta, gamma, delta and epsilon incorporate fialuridine (FIAU) monophosphate into DNA 24. Japour, A., Welles., S, d'Aquila, R. et al. Prevalence and are inhibited competitively by FIAU triphosphate. and clinical significance of zidovudine resistance Biochemistry, 33: 14620-14624 (1994). mutations in human immunodeficiency virus isolated from patients after long-term zidovudine treatment. Journal of 38. Spence, R., Kati, W., Anderson, K., Johnson, K. Infectious Diseases, 171: 1172-1179 (1995). Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science, 267: 988-993 (1995). 25. Loveday, C, Kaye, S., Tenant-Flowers M. et al. HIV-1 RNA serum-load and resistant viral genotypes during 39. Vella, S. Update on a proteinase inhibitor. AIDS, 8 early zidovudine therapy. Lancet, 345: 820-824 (1995). (suppl 3): 25-29 (1994).

26. Larder, B., Kemp, S. Multiple mutations in HIV-1 40. Ratner, L., Haseltine, W., Patarca, R. et al. Complete reverse transcriptase confer high-level resistance to sequence of the AIDS virus. Nature, 313: 279- zidovudine (AZT). Science, 246: 1155-1158 (1989). 284 (1985).

27. Schuurman, R., Nijhuis, M., van Leeuwan R. et al. 41. Ashorn, P., McQuade, T., Thaisrivongs, S. et al. An Rapid changes in human immunodeficiency virus type 1 inhibitor of the protease blocks maturation of human and RNA load and appearance of drug-resistant virus simian immunodeficiency viruses and spread of infection. populations in persons treated with lamivudine (3TC). Proceedings of the National Academy of Sciences, USA, Journal of Infectious Diseases, 171: 1411-1419 (1995). 87: 7472-7476 (1990).

28. Larder, B., Kemp, S., Harrigan, P. Potential mecha­ 42. McQuade, T., Tomasselli, A., Lui, L. et al. A synthetic nism for sustained antiretroviral efficacy of AZT-3TC HIV protease inhibitor with antiviral activity arrests HIV-like combination therapy. Science, 269: 696-699 (1995). particle maturation. Science, 247: 454-456 (1990).

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43. Condra, J., Schleif, W., Blahy, O. et al. In vivo 55. Wolinsky, S., Wike, C, Korber, B. et al. Selective emergence of HIV-1 variants resistant to multiple protease transmission of human immunodeficiency virus type-1 inhibitors. Nature, 374: 569-571 (1995). variants from mother to infants. Science, 255: 1134-1137 (1992). 44. Volberding, P., Lagakos, S., Grimes, J. et al for the AIDS Clinical Trials Group. Zidovudine in asymptomatic 56. Zhu, T., Mo, H., Wang, N. et al. Genotypic and human immunodeficiency virus infection — a controlled phenotypic characterization of HIV-1 in patients with trial in persons with fewer that 500 CD4-positive cells per primary infection. Science, 261: 1179-1181 (1993). cubic millimeter. New England Journal of Medicine, 322: 941-949 (1990). 57. Ho, D. Time to hit HIV, early and hard. New England Journal of Medicine, 333: 450-451 (1995). 45. Volberding, P., Lagakos, S., Grimes, J. et al for the 58. Coffin, J. HIV population dynamics in vivo: implications AIDS Clinical Trials Group. A comparison of immediate for genetic variation, pathogenesis and therapy. Science, with deferred zidovudine therapy for asymptomatic HIV- 267:483-489 (1995). infected adults with CD4 counts of 500 or more per cubic millimeter. New England Journal of Medicine, 333: 401 - 59. Cao, Y., Ho, D., Todd, J. et al. Clinical evaluation of 407 (1995). branched DNA signal amplification for quantifying HIV type 1 in human plasma. AIDS Research and Human 46. Concorde Coordinating Committee. Concorde: MRC/ Retroviruses, 11: 353-361 (1995). ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet, 343: 871-881 (1994). 2. Vaccines and genetic 47. Boyer, P., Dillon, M., Navaie, M. et al. Factors manipulation predictive of maternal-fetal transmission of HIV-1: preliminary analysis of zidovudine given during pregnancy The immune response to HIV infection and/or delivery. Journal of the American Medical The ultimate phases of HIV infection are deter­ Association, 271: 1925-1930 (1994). mined by breakdown of the immune system (1). It is now clear that the infection is active and progres­ 48. Connor, E., Sperling, R., Gelber, R. et al for the sive in lymphoid tissue throughout the clinically- Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. Reduction of maternal-infant transmission of latent stage of the disease (2, 3). Indeed, countless human immunodeficiency virus type-1 with zidovudine numbers of CD4 lymphocytes are generated each treatment. New England Journal of Medicine, 331: 1173- day to replace others that are destroyed, as they 1180 (1994). become infected, by HIV-specific cytotoxic T lymphocytes within the secondary lymphoid organs 49. Peckham, C, Gibb, D. Mother-to-child transmission of (4-7). That billions of virions and the CD4 cells from the human immunodeficiency virus. New England Journal which they are derived can be destroyed every day, of Medicine, 333: 298-302 (1995). year after year, before lymph node erosion and impaired immune responses ultimately result in 50. Kinloch-de Loës, M., Hirschel, B., Hoen, B. et al. A controlled trial of zidovudine in primary human immunode­ symptomatic disease, demonstrates extraordinary ficiency virus infection. New England Journal of Medicine, resilience within the immune system. (See also 333:408-413 (1995). page 198.)

51. Ho, D., Neumann, A., Perelson, A. et al. Rapid Of profound importance from the therapeutic turnover of plasma virions and CD4 lymphocytes in HIV-1 standpoint, is an array of observations derived from infection. Nature, 373: 123-126 (1995). different populations of patients which collectively raise an expectation that it may be possible to 52. Wei, X., Ghosh, S., Taylor, E. et al. Viral dynamics in prime immunological defence mechanisms in a way human immunodeficiency virus type 1 infection. Nature, 373: 117-122 (1995). that will contain, if not prevent, infection:

53. Piatak, M., Saag, L, Yang, L. et al. High levels of HIV- • It is estimated that about 5% of HIV-infected 1 in plasma during all stages of infection determined by adults show no sign of progressing to AIDS (8, 9). competitive PCR. Science, 259: 1749-1754 (1993). The ultimate prognosis of these persons remains uncertain, but reports thus far indicate that they 54. Preston, B., Poiesz, B., Loeb, L. Fidelity of HIV-1 have remained healthy for periods ranging up to reverse transcriptase. Science, 242: 1168-1171 (1988). 15 years (10-12) and that their lymph nodes show

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no sign of degradation (11). They have excep­ who were HIV negative, 61 subsequently became tionally low levels of circulating viral antigens and HIV-1 positive. Among 187 women who were (or of viral RNA and DNA in peripheral blood mono­ who became) HIV-2 positive, only 7 subsequently nuclear cells. However, virus has been recovered became positive for HIV-1 (relative risk 0.32; consistently from lymph-node cells (11) and their p=0.008). HIV-2 is largely confined to West Africa vigorous immune responses are indicative of and has been estimated, on average, to take twice sustained viral replication. The possibility that as long as HIV infection to progress to AIDS (30). these patients are infected with HIV variants of It is genetically related to HIV-1 with which it low virulence remains open. Such variants have shares a common cellular receptor and shows been widely sought, but they have been reported partial antigenic cross-reactivity (31). It is conse­ only on one occasion when a variant with quently assumed that the observed protection — deletions in the critical nef gene was isolated (12). which has so far been demonstrated for only 3 of Thus far, no special characteristics of the immune at least 9 known subtypes of HIV-1 (32) — results response have been identified in these patients, from cross-reactive immunity to epitopes but they remain a focus of intense interest (13). conserved between HIV-1 and HIV-2. • Evidence has been accumulating for several years Fundamental problems that HIV infection is sometimes abortive in both in vaccine development adults (14, 15) and neonates (16-18). More Notwithstanding this strong inferential evidence of recently, early cellular immune responses — effective immune defence against HIV, several particularly the proliferation of -2 characteristics of the initial stages of infection have following exposure to HIV-specific peptide long indicated that traditional approaches to antigens — have been demonstrated both in vaccination may fail to provide satisfactory adults and neonates who remained seronegative protection against the disease. Most viral vaccines following potential exposure to HIV (19-23). With currently in use prime the immune system to time, it seems that persistence of proviral DNA generate circulating neutralizing antibody as the may provide the only evidence of earlier infection first protection against invasion by the target in such individuals (24). organism, while cell-mediated mechanisms, such as cytotoxic T lymphocytes and other cell-mediated • There are still tantalizing inconsistencies to be defences, serve as scavengers of organisms that resolved in current knowledge regarding vertical transmission of HIV from mother to infant (25). escape neutralization (33). These vaccines Whereas evidence of HIV infection has been consequently operate by countering primary or found in a large majority of fetuses electively secondary viraemia prior to significant viral aborted in the first and second trimesters from replication within target cells. HIV-positive women (26), only some 25% of infants born at term to infected mothers are HIV infection, however, is atypical in several estimated to have evidence of infection (27). important respects (34-36): invasion of CD4 Moreover, two-thirds of these infections can be lymphocytes and other target cells occurs at the prevented by zidovudine (which, in other outset of infection and as a prerequisite to the circumstances, is a relatively weak antiretroviral development of viraemia; virus sequestered within agent) (see p. 199). Particularly intriguing, is the CD4 cells is protected against viral antibody and CT finding that some exposed but apparently lymphocyte clearing mechanisms until progeny uninfected neonates harbour HIV-specific cyto­ virions appear at the cell surface; and rapid toxic T lymphocytes — which are associated in emergence of antigenic variants results in ever- adults with rapidly replicating virus (28). Given its changing configurations within the viral receptor (or allegedly immature immune system, this apparent recognition) sites for antibody and CT lymphocytes. capacity of the fetus to eliminate the virus could Both HiV-binding antibodies and HIV-specific CT provide vital clues to the development of new lymphocytes are generated during the initial therapeutic approaches. viraemia, and neutralizing antibodies become detectable as soon as the viraemia has been • Existing HIV-2 infection has been found to protect controlled (37-40). To be successful, it has been against subsequent HIV-1 infection by some 70% suggested that a vaccine against HIV will need to (29). These results were obtained by following a induce a diverse array of neutralizing antibodies group of some 750 female prostitutes in Dakar, and CT lymphocytes with multiple, diverse HIV- Senegal for a period of nine years. Of 618 women specific recognition sites (34).

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Given this assessment, it has been recognized from binding site has even been found to increase, the outset that live attenuated retrovirus may rather than to decrease the infectivity of a primary ultimately provide the only practicable option for strain of HIV-1 (52). It is suggested that the developing an effective vaccine. Against this, it has antibody, in this instance, alters the configuration of also been recognized that such an approach surrounding glycoprotein in a way that facilitates, constitutes an option of last resort because of the rather than blocks receptor binding and fusion hazards implicit in the possibility of retroviral rever­ between the virus and the CD4 cell. sion to a virulent form, and the theoretical risk of insertional mutagenesis resulting in inactivation of Findings such as these have raised fundamental essential genes (41), or activation of deleterious doubts as to whether neutralizing antibodies have genes, including oncogenes (42). relevance to vaccine-induced protection (45). Inevitably, research strategies are being radically Recombinant subunit vaccines: refocused. Attention has been directed to other fresh doubts on feasibility subunit vaccines based upon internal proteins of Initial efforts to develop HIV vaccines were the virus, particularly on the p24 core protein, which consequently directed largely to non-infectious contain conserved T-cell epitopes and which induce subunit vaccines. Extraordinary advances in many cell-mediated responses (54, 55) but it is premature aspects of cellular biology over the previous decade to speculate on their potential value. and the successful development of a recombinant vaccine against the hepatitis B virus supported and Attenuated vaccines: feasibility and risks encouraged this effort. The site within the viral Interest in live attenuated vaccines has been given envelope glycoproteins (gp120) which binds with momentum by recent experiments on macaque the receptor in CD4 cells was rapidly identified; monkeys. These are vulnerable in the wild to simian neutralizing antibodies were shown to be directed immunodeficiency virus (SIV) and, in the laboratory, to this site; and monoclonal antibody for a specific to closely-related HIV-2. Vaccines based on SIV locus within gp120 vital to virus binding and entry subunit recombinant proteins have usually failed to (the V3 loop) was shown to protect chimpanzees protect monkeys against postvaccination viral from homologous HIV challenge both prior to and challenge, although they have reduced the initial after exposure (43, 44). This highly immunogenic virus burden after infection (56). More effective site is also highly variable and labile and the protection against SIV infection has been conferred neutralizing antibodies that it induces are com­ by inoculation of closely-related live HIV-2 virus. parably strain specific. However, it has recently This has not resulted in sterilizing immunity. been claimed that extensive in vitro cross- Seroconversion followed challenge with SIV, but neutralization has been demonstrated between viral replication has since been greatly restricted strains belonging to different genetic subtypes (45). and the animals are reported to have remained Other studies indicate that anti-V3 and antibodies to asymptomatic for over 5 years — long after other loci within gp120 may act synergistically with unvaccinated controls died of AIDS (57). The one another in virus neutralization (44, 46). histopathology and immune status of these animals is claimed to be strikingly similar to that of long-term At least 17 candidate vaccines, most of them human survivors with nonprogressive HIV-1 containing subunit recombinant envelope glyco­ infection (10, 11). Whereas sterilizing immunity proteins (47), have been tested in phase 1 human must always be the aim of vaccination, it has been trials since 1987. A recent review (45) concludes pointed out that the live virus vaccines currently that these are well tolerated, and also that they used to protect against yellow fever, adenovirus, induce neutralizing antibodies efficiently against poliomyelitis, measles and rubella all operate by homologous strains and, less efficiently, against suppressing rather than preventing infection (58). other strains from the same genetic subgroup. It cautions, however, that most of these data have Very recently, sterilizing immunity has been been generated using highly passaged laboratory reported in macaques against challenge with an strains of HIV-1, and that current monomeric gp120 uncloned pathogenic strain of SIV following vaccines are considerably less effective in vaccination with a live attenuated molecular clone neutralizing clinical isolates containing primary of SIV (59). No evidence of replication of the strains in which the CD4-receptor binding site may challenge virus could be detected in the vaccinated be less accessible (48-53). One monoclonal animals either by searching for proviral DNA antibody to a complex gp120 epitope near the sequences or by testing for anamnestic antibody

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responses to SIV envelope peptides. Protection proportion of vaccinated subjects; it should was conferred against both intracellular and free stimulate both the cellular and antibody com­ virus whether the challenge was administered ponents of the immune system; it should protect either intravenously or mucosally; when it was against different retroviral subtypes and variants delayed for as long as 2 years after vaccination; now circulating in different geographic regions of and when the envelope antigens of the challenge the world; it should induce long-lasting protection; it virus were distantly related to the vaccine strain. should induce local immunity in the mucosa of the The protection was consequently unlikely to have genital tract and rectum; it should be effective when been mediated by antibodies. Indeed, the titres of administered in a practicable regimen of immu­ neutralizing and other antibodies induced by the nizations; and it should be made available at a cost attenuated virus were considerably lower than that can assure worldwide availability. those reported to have been induced by ineffective recombinant vaccines (60), or to have been used in Complementary guidelines have been developed unsuccessful attempts to achieve passive immuni­ under the aegis of WHO for the conduct of clinical zation (61). It seems likely that protection was con­ trials of candidate vaccines (68). Their aim is to ferred by cellular immunity, but since CT-lympho¬ assist those involved in planning to assess whether cyte activity was not measured, this remains un¬ local conditions permit a trial of a given scale to be proven. These latter results provide a landmark in carried out efficiently, safely and in accordance with attempts to develop a protective HIV vaccine, not internationally-operative ethical precepts. least because the possibility of preventing infection by intracellular virus had long been held in question New avenues of research (62). Meanwhile, realization of the complexities of the processes that result in HIV replication, of the As yet, however, attenuated virus holds little direct resilience of the retrovirus to subunit vaccines, and prospect of protecting persons already infected with of the hazards inherent in attenuated vaccines, has HIV: predictably, in the macaque model, pre-exist­ resulted in a concerted call from the scientific ing SIV infection establishes resistance to infection establishment for a more equitable balance in the with vaccine virus (63). Moreover, whether this funding of applied and basic research (52, 69-71) approach can ever provide the basis for developing and the setting-up in the USA of the Strategic an acceptably safe vaccine remains unresolved. Programme for Innovative Research on AIDS (72). The attenuated SIV virus used with success in the macaque study differed from a related virulent These new areas of research are diverse. Some clone only in a few deletions or substitutions of involve inserting genetic material into target located principally in the nef gene lymphocytes (gene therapy) intended to render (changes similar to those associated with attenu­ them resistant to HIV infection (73-75). Others aim ated HIV disease in man) (11, 64). Its reversion in to revitalize the immune system. Yet others are vivo to a virulent form that gives rise to disease has directed to developing novel forms of vaccine. apparently already been reported (63), while other versions of attenuated SIV have been reported to result in symptomatic infection in neonatal monkeys The potential of gene therapy HIV replication has been successfully suppressed (65). in mature human CD4 cells in vitro in various ways by inserting genes that express: A re-evaluation of strategy Many promising options now exist for further re­ • sequences of RNA that either bind HIV regulatory search, but clinical studies of existing vaccines in proteins competitively (76) or cleave and inacti­ man have reached an apparent impasse. In 1994, vate viral RNA (77, 78); an advisory committee to the US National Institute of Allergy and Infectious Diseases concluded that it • mutant, incompetent forms of HIV regulatory was premature to take two HIV recombinant subunit proteins that bind competitively with viral RNA, vaccines into large-scale clinical trials (66). Guid­ and frustrate its intracellular transport and ance provided to US pharmaceutical companies processing (79, 80); with ongoing HIV vaccine development pro­ grammes (67) set out a series of basic criteria to be • intracellular antibodies specific to key loci in the satisfied in an ideal vaccine: it should be safe; it HIV virus, such as gp160 (81) or one of the should elicit a protective immune response in a high regulatory proteins (82); and even

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• intracellular toxins encoded by genes regulated more effective than currently used regimens of exclusively by HIV proteins which programme the antiviral drugs in raising the CD4 count (95). It is death of newly-infected target cells (83, 84). possible that a more efficient response can be obtained by promoting the expression of this and Fundamental technical difficulties remain to be other cytokines in immune competent cells. surmounted before any of these approaches can Ambitious efforts are now in hand to embrace provide a viable form of therapy. Vectors need to be immune modulation within planned gene therapy developed to ensure efficient delivery of these projects involving reinfusion into the HIV-infected antiviral genes to patients. Attenuated, non­ patient of selected T-cell populations that have pathogenic HIV variants are an obvious resort been modified by antiviral genes and cytokine because they target susceptible cells even when genes to alter or enhance immune mechanisms they are not dividing (85, 86), but the risk of (96). reversion is dissuasive. Ultimately, it is hoped, ways will be found to use liposomes and other non-viral Rapid progress with nucleic acid vaccines particles as vectors that will efficiently target T- Even more ambitious are strategies to develop lymphocytes (87). Even so, the possibility of vaccines against HIV and other infections by insertional mutagenesis may remain, although it delivering gene sequences that express selected may be ameliorated if means can be developed of viral antigens (73, 97). Such sequences were first precisely targeting the insertion of proviral DNA into successfully inserted, unintegrated, into muscle specific sequences within chromosomes (89, 89). cells in mice simply by using plasmid DNA as a Crucially, protracted gene therapy awaits not only vector (98). The potential importance of gene the development of techniques for transducing therapy in vaccine development was established by puripotent haemopoietic stems cells, rather than demonstration that DNA encoding either the mature CD4 lymphocytes, but also demonstration nucleoprotein or the haemagglutinin of influenza A that the transduced anti-HIV gene is conserved protects against challenge with different strains of indefinitely in an active form within the progeny of the virus (99). An analogous finding has since been these cells: ideally, the protective effect should be obtained in several animal models following intra­ maintained throughout the anticipated life-span of muscular injection of a non-replicating retroviral the recipient (75). At this stage, whether these vector containing HIV genes coding for gp160 and aims are practicable, or even achievable, remains the Rev regulatory protein (100) which is inserted an open question. securely into host chromosomes. The cellular immune response is prolonged and cross-reactive Prospects for immune restitution with isolates from diverse HIV isolates (101). The The aim of immune restitution is to restore to HIV- technique appears to have wide implication since infected persons immune competent cell popu­ similar DNA-induced responses have also been lations. A variety of methods has been used induced with hepatitis B, herpes and rabies viruses including bone marrow transplantation or lympho­ (97). cyte transfer (90); infusion of immunomodulating agents such as ditiocarb sodium (91) or inosine A globally-relevant option? pranobex (92); and infusion of cytokines, such as The challenges in assuring the safety of such interferon alfa (93), interferon gamma (94) and products are complex: there is the ever-present risk interleukin-2 (95). In general, responses to of damaging the host's genome, and of generating conventional administration of these products have serious autoimmune reactions. The avoidance of been characterized by modest and transient immune tolerance and the targeting of puripotential increases in CD4 counts; patients with severely haemopoietic stem cells to assure prolonged impaired immune function have shown little protection may also pose major developmental reaction; and the extent of any clinical benefit problems. However, these discoveries have already remains uncertain. generated wide interest within the commercial sector, since the basic technology may have The precise method of administration of immuno­ application not only to the development of antiviral modulating substances is almost certainly an vaccines, but also to the therapy of cancer and important determinant of the clinical response. many other diseases. The pace of basic and Intermittent, repeated slow infusion of interleukin-2, applied research in this area is set to intensify. a T-cell derived cytokine with several immuno­ Already it is perceived as offering the first tangible modulating effects, has recently been found to be prospect of providing meaningful protection against

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HIV infection at a cost that less developed countries 13. Pan, L., Sheppard, H., Winkelstein, W., Levy, J. Lack might afford (97). of detection of human immunodeficiency virus in persistently seronegative homosexual men with high or References medium risks for infection. Journal of Infectious Diseases, 164: 962-964 (1991). 1. Levy, J. Pathogenesis of human immunodeficiency virus infection. Microbiological Reviews, 56: 183-263 14. Borkowsky, W., Krasinski, K., Moore, T., (1993). Papaevangelou, V. Lymphocyte proliferation responses to HIV-1 envelope and core antigens by infected and 2. Embretson, J., Zupanic, M., Ribas, J. et al. Massive uninfected adults and children. AIDS Research and covert infection of helper T lymphocytes and macro­ Human Retroviruses, 6: 673-678 (1990). phages by HIV during the incubation period of AIDS. Nature, 362: 359-362 (1993). 15. Borkowsky, W., Krasinski, K., Paul, D. et al. Human immunodeficiency virus type 1 antigenemia in children. 3. Panteleo, G., Graziosi, C, Demarest, J. et al. HIV Journal of Pediatrics, 114: 940-945 (1989). infection is active and progressive during the clinically latent stage of disease. Nature, 362: 355-358 (1993). 16. De Rossi, A., Ades, A., Mammano, F. et al. Antigen detection, virus culture, polymerase chain reaction, and in 4. Cheynier, R., Henrichwark, S., Hadida, F. et al. HIV and vitro antibody production in the diagnosis of vertically T cell expansion in splenic white pulps is accompanied by transmitted HIV-1 infection. AIDS, 5: 15-20 (1991). infiltration of HIV-specific cytotoxic T lymphocytes. Cell, 78: 373-387 (1994). 17. Bryson, Y., Pang, S., Wei, L. et al. Clearance of HIV infection in a perinatally infected infant. New England 5. Zinkernadel, R., Hengartner, H. T-cell-mediated Journal of Medicine, 332: 833-838 (1995). immunopathology versus direct cytolysis by virus: implications for HIV and AIDS. Immunology Today, 15: 18. Clerici, M., Berzofsky, J., Schearer, G., Tacket, C. 262-268 (1994). Exposure to human immunodeficiency virus (HIV) type 1 indicated by HIV-specific T helper cell responses before 6. Wain-Hobson, S. Virological mayhem. Nature, 373: 102 detection of infection by polymerase chain reaction and (1995). serum antibodies. Journal of Infectious Diseases, 164: 178-182 (1991). [Erratum, idem, 164: 832 (1991).]. 7. Rutherford, G., Lifson, A., Hessol, N. et al. Course of HIV-1 infection in a cohort of homosexual men: an 11-year 19. Clerici, M., Giorgi, J., Chou, C. et al. Cell-mediated follow-up study. British Medical Journal, 301: 1183-1188 immune response to human immunodeficiency virus (HIV) (1990). type 1 in seronegative homosexual men with recent sexual exposure to HIV-1. Journal of Infectious Diseases, 8. Buchbinder, S., Katz, M., Hessol, N. et al. Long-term 165: 1012-1019 (1992). HIV-1 infection without immunologic progression. AIDS, 8: 1123-1128 (1994). 20. Shearer, G., Sision, A., Rakusan, T. et al. In vitro T cell immunity to HIV synthetic peptides and other antigens 9. Cao, Y., Qion, L., Zhang, L. et al. Virologic and by peripheral blood leukocytes from HIV-infected women immunologic characterization of long-term survivors of and by cord blood from their offspring. Journal of Cellular human immunodeficiency virus type 1 infection. New Biochemistry, 112 (suppl): 16E (1992). England Journal of Medicine, 332: 209-216 (1995). 21. Clerici, M., Levin, J., Kessler, H. et al. HIV-specific T- 10. Pantaleo, G., Menzo, S., Vaccarezza, M. et al. Studies helper activity in seronegative health care workers in subjects with long-term nonprogressive human exposed to contaminated blood. Journal of the American immunodeficiency virus infection. New England Journal of Medical Association, 271: 42-46 (1994). Medicine, 332: 209-216 (1995). 22. Rowland-Jones, S., Sutton, J., Ariyoshi, K. et al. HIV- 11. Kirchhoff, F., Greenough, T., Brettler, D. et al. specific cytotoxic T-cells in HIV-exposed but uninfected Absence of intact nef sequences in a long-term survivor Gambian women. Nature Medicine, 1: 59-64 (1995). with nonprogressive HIV-1 infection. New England Journal of Medicine, 332: 228-232 (1995). 23. Farzadegan, H., Polis, M., Wolinsky, S. et al. Loss of human immunodeficiency virus type 1 (HIV-1) antibodies 12. Baltimore, D. Lessons from people with nonprogres­ with evidence of viral infection in asymptomatic homo­ sive HIV infection. New England Journal of Medicine, 332: sexual men: a report from the multicenter AIDS Cohort 259-260 (1995). Study. Annals of Internal Medicine, 108: 785-790 (1988).

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50. Sullivan, N., Sun, Y., Hofmann, W., Sodrosky, J. 62. Sabin, A. Improbability of effective vaccination against Replicative function and neutralization sensitivity of human immunodeficiency virus because of its intracellular envelope glycoproteins from primary and T-cell line- transmission and rectal port of entry. Proceedings of the passaged human immunodeficiency virus type 1 isolates. National Academy of Sciences, USA, 89: 8852-8855 Journal of Virology, 69: 4413-4422 (1995). (1992).

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Reports on Individual Drugs

Acetylsalicylic acid: a protective The available information clearly establishes the potential of acetylsalicylic acid as a means of effect against colorectal cancer protecting patients at high risk against colorectal cancer (27). However, until a minimum effective Within the past five years the results of several dosage is defined and an indication is obtained of case-control studies conducted in the United States the time-scale over which risk declines during have suggested that regular use of acetylsalicylic treatment, no satisfactory basis for devising a acid reduces the risk of both colorectal cancer (1-5) preventive clinical regimen exists. Much of the and colorectal adenomas (5-7). Whereas no such necessary information has now been obtained association has been found in two prospective within the context of the Nurses' Health Study studies (8, 9), the results of three others support the cohort. This was established in the United States in hypothesis (10-12). 1976 when over 120 000 nurses then aged Other clinical studies have not only provided cir­ between 30 and 35 years returned a mailed cumstantial support for the hypothesis: they have questionnaire relating to known or suspected risk indicated that the same protective effect may be factors for breast cancer and cardiovascular shared by other nonsteroidal anti-inflammatory disease (28). Every second year since this time, agents (NSAIDs). The incidence of tumours of the follow-up questionnaires have been issued, and stomach and colon seems to be reduced among these were extended in 1980 to provide an assess­ patients with rheumatoid arthritis who have taken ment of diet and patterns of use of acetylsalicylic acetylsalicylic acid or other NSAIDs over many acid. Each respondent was asked how many years (13, 14). Sulfasalazine — which is metabo­ tablets she was taking each week and when she lized in the colon to sulfapyridine and mesalazine had first started to take them. (5-amino-salicylic acid) — has been claimed on the This information has enabled rates of colorectal basis of a case-control study to reduce the risk of cancer to be determined according to the number of colorectal cancer among patients with ulcerative consecutive years of regular use of acetylsalicylic colitis (15). Sulindac — a prodrug which is revers¬ acid (29). From 1984 to 1992, 331 new cases of ibly reduced to a sulfide metabolite that inhibits colorectal cancer were reported within the cohort. prostaglandin synthesis — has been reported to Overall, regular use of two or more tablets each induce regression of familial adenomatous poly­ week had no discernible protective effect. However, posis (16). Analogous activity has been demon­ the relative risk decreased inversely with the period strated in animal models. Acetylsalicylic acid (17- of use. The effect became statistically significant 18), indometacin (19, 20), piroxicam (21, 22) and among women who had consistently used sulindac (23) have each been shown to inhibit acetylsalicylic acid for 20 years or more (relative chemical induction of tumours in the rat colon. risk, 0.56; 95% confidence interval, 0.36 to 0.90; p Exactly how NSAIDs exert their anticarcinogenic for trend = 0.008). Controlling for diet and other action remains speculative. Some of the data ob­ known risk factors for colorectal cancer did not tained from animal models suggest that they are change the results; nor could the difference be active only during the earliest stages of tumour for­ accounted for by possible earlier diagnosis or mation (17, 24). All of these substances interfere removal of colorectal adenomas among the women with the normal cellular metabolism of arachidonic taking acetylsalicylic acid. acid by acetylating and inhibiting the action of the Maximum benefit appeared to result from use of 4 cyclo-oxygenase enzymes that convert arachí¬ or more tablets each week, but the authors do not donate to eicosanoids (substances including rule out the possibility that the lower doses effective thromboxane, prostacyclin, and prostaglandins in coronary artery disease (30) are also sufficient to active in haemostasis and thrombus formation) provide substantial protection against colorectal (25). In this situation, arachidonic acid is dominantly cancer. They note, in particular, that such a dose transformed by lipoxygenases into hydroxy fatty (80 mg acetylsalicylic acid daily) has been found to acids, some of which may regulate cell proliferation reduce rectal epithelial concentrations of prosta­ and contribute to the protective effect against glandins (31). colorectal cancer (26).

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A commentary accompanying this article concludes 11. Schreinemachers, D., Everson, R. Aspirin use and with a firm recommendation that persons at risk for lung, colon, and breast cancer incidence in a prospective colorectal cancer — those with inflammatory bowel study. Epidemiology, 5: 138-146 (1994). disease; breast, ovarian, or endometrial cancer; a 12. Thun, M., Namboodiri, M., Heath, C. Aspirin use and previous adenoma or large bowel cancer; or a reduced risk of fatal colon cancer. New England Journal of family history of colorectal cancer or adenoma — Medicine, 325: 1593-1596 (1991). should start taking a single 325 mg tablet of acetyl¬ salicylic acid on alternate days, unless they have a 13. Gridley, G., McLaughlin, J., Ekbom, A. et al. Incidence condition that contraindicates use of the drug (32). of cancer among patients with rheumatoid arthritis. Colorectal cancer is a common condition. Its Journal of the National Cancer Institute. 85: 307-311 ravages, it is emphasized, far exceed the possible (1993). complications of long-term therapy with acetyl¬ salicylic acid. 14. Laakso, M., Mutru, O., Isomaki, H., Koota, K. Cancer mortality in patients with rheumatoid arthritis. Journal of References Rheumatology, 13: 522-526 (1986).

1. Kune, G., Kune, S., Watson, L. Colorectal cancer risk, 15. Pinczowski, D., Ekbom, A., Baron, J. et al. Risk factors chronic illnesses, operations, and : case- for colorectal cancer in patients with ulcerative colitis: a control results from the Melbourne Colorectal Cancer case-control study. Gastroenterology, 107: 117-120 Study. Cancer Research, 48: 4399-4404 (1988). (1994). 2. Rosenberg, L, Palmer, J., Zauber, A. et al. A hypo­ thesis: nonsteroidal anti-inflammatory drugs reduce the 16. Giardiello, F., Hamilton, S., Krush, A. et al. Treatment incidence of large-bowel cancer. Journal of the National of colonic and rectal adenomas with sulindac in familial Cancer Institute, 83: 355-358 (1991). adenomatous polyposis. New England Journal of Medicine, 328: 1313-1316 (1993). 3. Muscat, J., Stellman, S., Wynder, E. Nonsteroidal anti­ inflammatory drugs and colorectal cancer. Cancer, 74: 17. Craven, P., DeRubertis, F. Effects of aspirin on 1, 2- 1847-1854 (1994). dimethylhydrazine-induced colonic carcinogenesis. Carcinogenesis, 13: 541-546 (1992). 4. Peleg, I., Maibach, H., Brown, S., Wilcox, C. Aspirin and nonsteroidal anti-inflammatory drug use and the risk 18. Reddy, B., Rao, C, Rivenson, A., Kelloff, G. Inhibitory of subsequent colorectal cancer. Archives of Internal effect of aspirin on azoxymethane-induced colon Medicine, 154: 394-399 (1994). carcinogenesis in F344 rats. Carcinogenesis, 14: 1493- 5. Suh, O., Mettlin, C, Petrelli, N. Aspirin use, cancer, and 1497 (1993). polyps of the large bowel. Cancer, 72: 1171-1177 (1993). 19. Pollard, M., Luckert, P. Effect of indomethacin on 6. Greenberg, E., Baron, J., Freeman, D. et al. Reduced intestinal tumors induced in rats by the acetate derivative risk of large bowel adenomas among aspirin users. of dimethylnitrosamine. Science, 214: 558-559 (1981). Journal of the National Cancer Institute, 85: 912-916 (1993). 20. Narisawa, T., Sato, M., Tani, M. et al. Inhibition of development of methylnitrosourea-induced rat colon 7. Logan, R., Little, J., Hawtin, P., Hardcastle, J. Effect of tumors by indometacin treatment. Cancer Research, 41 : aspirin and nonsteroidal anti-inflammatory drugs on 1954-1957 (1981). colorectal adenomas: case-control study of subjects participating in the Nottingham faecal occult blood 21. Reddy, B., Maruyama, H., Kelloff, G. Dose-related screening programme. British Medical Journal, 307: 285- inhibition of colon carcinogenesis by dietary piroxicam, a 289 (1993). nonsteroidal anti-inflammatory drug, during different stages of rat colon tumor development. Cancer Research, 8. Paganini-Hill, A., Chao, A., Ross, R., Henderson, B. 47: 5340-5346 (1987). Aspirin use and chronic diseases: a cohort study of the elderly. British Medical Journal, 299: 1247-1250 (1989). 22. Pollard, M., Luckert, P. Indomethacin treatment of rats 9. Gann, P., Manson, J., Glynn, R. et al. Low-dose aspirin with dimethylhydrazine-induced intestinal tumors. Cancer and incidence of colorectal tumors in a randomized trial. Treatment Reports, 64: 1323-1327 (1980). Journal of the National Cancer Institute, 85: 1220-1224 (1993). 23. Morghen, M., Ince, P., Finney, K. et al. A protective effect of sulindac against chemically induced primary 10. Giovannucci, E., Rimm, E., Stampfer, M. et al. Aspirin colonic tumours in mice. Journal of Pathology, 156: 341- use and the risk for colorectal cancer and adenoma in 347 (1988). male health professionals. Annals of Internal Medicine, 121: 241-246 (1994).

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24. Mereto, E., Frencia, L, Ghia, M. Effect of aspirin on Ultimately, it may be feasible to bring the disease incidence and growth of aberrant crypt foci induced in the largely under control with the vaccines that have rat colon by 1, 2-dimethylhydrazine. Cancer Letter, 76: 5-9 already been developed (1). Meanwhile, there are (1994). some 200-300 million carriers of the virus through­ 25. al-Mondhiry, H., Marcus, A., Spaet, T. On the out the world. Each year, in the United States mechanism of platelet function inhibition by acetylsalicylic alone, it is estimated that some 200 000 people acid. Proceedings of the Society of Experimental Biology become primarily infected and 5000 die from the and Medicine, 133: 632-636 (1970). complications of chronic infection (2). 26. Marnett, L. Aspirin and the potential role of prostaglandins in colon cancer. Cancer Research, 52: For those already infected, antiviral therapy offers 5575-5589 (1992). the only prospect of benefit. Recombinant interferon alfa-2b has been available for this purpose in the 27. Health, C, Thun, M., Greenberg, E. et al. Nonsteroidal United States and some other developed countries anti-inflammatory drugs and human cancer: report of an for several years, but it is of limited practical value. interdisciplinary research workshop. Cancer, 74: 2885- 2888 (1994). It is extremely costly; it has to be given parenterally over a period of four to six months; adverse effects 28. Willett, W., Stampfer, M., Colditz, G. et al. Dietary fat are often troublesome; and little more than one- and the risk of breast cancer. New England Journal of third of the patients are estimated to gain a Medicine, 316: 22-28 (1987). protracted remission (3-6). 29. Giovannucci, E., Egan, K., Hunter, D. et al. Aspirin and the risk of colorectal cancer in women. New England Experience with other antiviral agents, particularly Journal of Medicine, 333: 609-614 (1995). nucleoside analogues, has been largely dis­ appointing. Clinical studies of , aciclovir, 30. Patrono, C. Aspirin as an antiplatelet drug. New zidovudine, zalcitabine, didanosine, and ribavirin England Journal of Medicine, 330: 1287-1294 (1994). have shown them to be either largely ineffective in chronic hepatitis or too toxic for prolonged use (7- 31. Ruffin, M., Krishnan, K., Kraus, E. et al. Aspirin as a 11). Interest in these agents has been maintained, chemopreventive agent for colorectal cancer: lowest dose however, because several more recently-developed of aspirin to suppress rectal mucosal prostaglandins nucleoside analogues, lamivudine, famciclovir and (abstract). Proceedings of the American Association of Cancer Research, 36: 600 (1995). fialuridine have been shown, in vitro, to be potent as inhibitors of the hepatitis B virus (12). 32. Marcus, A. Aspirin as prophylaxis against colorectal cancer. New England Journal of Medicine, 333: 656-657 In phase 1 clinical studies, one of these compounds (1995). — fialuridine, a nucleoside analogue — was shown to be highly effective in temporarily reducing circulating levels of viral DNA when Nucleoside analogues: administered by mouth to chronic carriers of premonitory experience in hepatitis B virus at doses that were well tolerated over periods of 14 to 28 days (13-15). These therapy of viral hepatitis results were considered encouraging enough to justify a trial of more prolonged treatment (16). Effective control of hepatitis B infections remains a Fifteen patients known to have chronic HBV primary public health objective in both developed infection for periods ranging from 1 to 12 years, but and developing countries. The greatest need is in with no evidence of hepatic decompensation or sub-Saharan Africa and south-east Asia where other serious illnesses, were randomly assigned to many children infected during the first few years of receive fialuridine orally at a total dose of either life become chronic carriers of the virus and are at 0.10 or 0.25 mg/kg daily. Most of these subjects high risk of ultimate death from chronic hepatitis, had participated uneventfully in the preliminary 4- cirrhosis or primary hepatocellular carcinoma. In week study. However, after the study had run for 13 developed countries infection is usually acquired weeks it was abandoned when one of the patients later in life, either through sexual contact, or as a lapsed into shock with hepatic failure and lactic result of transfusion or accidental inoculation of acidosis. At this stage, the therapeutic response contaminated blood. Typically these infections was highly promising: viral DNA had become cause severe and sometimes fulminating acute undetectable in six of ten patients who had hepatitis, and survivors are at risk of chronic completed eight weeks or more of treatment. disease.

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Although all treatment was immediately dis­ mitochondrial DNA by locking into the ends of continued, seven other patients who had received nucleic acid chains and preventing their elongation cumulative doses ranging from 550 to 1750 mg (21-23). This action has been held responsible for fialuridine developed rapidly progressive hepatic at least some of the relatively uncommon toxic and pancreatic insufficiency. Most complained of effects of these substances, including myopathy prodromal symptoms of fatigue, nausea, constip­ (23, 24), lactic acidosis (24, 25), fatty infiltration of ation, and abdominal pain for some two weeks the liver (26-29), and pancreatitis (30). before deepening jaundice and worsening liver failure supervened. None was responsive to Fialuridine, in contrast, does not deplete mito­ attempts to reverse the effects of fialuridine by chondrial DNA (31). It is thus not a chain termin­ intravenous infusions of thymidine (17), or to ator, but it does insert itself into nascent DNA replenish intracellular stores with oral chains in both cellular and mitochondrial DNA (32- (18). Emergency liver transplantation was 34). The facility with which mitochondrial poly­ successful in two instances. The remaining five merases, in particular, incorporate fialuridine patients all died within seven weeks of discon­ monophosphate instead of deoxythymidine mono­ tinuing fialuridine. Serial liver biopsy specimens phosphate into DNA provides a persuasive but as confirmed the diagnosis of chronic hepatitis in all yet hypothetical explanation of the toxicity of the seven patients and showed that cirrhotic changes compound (35-36). had occurred in three prior to the study. Marked accumulation of intravesicular fat in hepatocytes The tragic outcome of the development of fialur­ and striking mitochondrial changes evident from idine has prompted a reappraisal of the criteria by electron microscopy, including marked swelling, which the safety of new drugs are assessed and loss of cristae, matrix dissolution, and scattered monitored as they pass into the early stages of vesicular inclusions were the only histological clinical investigation (15). For nucleoside-like drugs changes found to be associated with exposure to this reappraisal has several implications. Firstly, fialuridine (19). No intensification of inflammation or considerably more data will be required from animal necrosis was recorded and no substantial rises in experiments and cell-culture lines during the serum aminotransferase levels were noted during preclinical phases of development to establish their treatment. effects on both genomic and mitochondrial DNA. Secondly, all patients involved in pre-registration Three other patients who were treated for similar trials of these substances will need to be monitored periods, and who received cumulative doses of carefully for at least several months after com­ fialuridine in the same range, developed mild pleting the treatment. Thirdly, the outcome of this clinical signs of hepatic dysfunction within two to monitoring must be fully assessed before consi­ three weeks of stopping treatment, but these signs deration can be given to proceeding to the next resolved completely within 4 to 12 weeks. Five phase of clinical testing. other patients who received fialuridine for less than four weeks showed no sign of drug-related toxicity. The long-term aim must be to develop nucleoside- However, follow-up of 67 patients treated in the like drugs with greater specificity for viral DNA. The pilot studies (13, 14) has shown that three of these feasibility of achieving this might well be held in patients died from liver disease and one from question, were it not for some striking properties pancreatitis within six months of taking fialuridine. now accredited to the recently-developed nucleo­ In one case microvesicular fat was demonstrated in side analogue, lamivudine, which differs from the liver post mortem. The possibility that some of zalcitabine (2',3'-dideoxycytidine) only by the these events were drug-related could not be substitution of a sulfur atom for a methylene group excluded (20). in the 3' position of the ring (37). It is a potent inhibitor of isolates of HIV-1, HIV-2 and human Fialuridine, like all nucleoside analogues, exerts its hepatitis B virus, yet it is only weakly toxic in vitro to antiviral effect by becoming incorporated into viral human bone marrow progenitor cells, and it is a DNA and arresting its replication. All the nucleoside weak inhibitor of human DNA polymerases (38). analogues developed thus far are also incorporated to a greater or lesser extent into the genomic and Lamivudine has now been administered to several mitochondrial DNA of the host. The first generation thousands of patients with HIV infection for periods of these analogues — zidovudine, didanosine and ranging up to one year without evidence of bone- zalcitabine — are "chain terminators" which deplete marrow depression or any other dose-limiting

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adverse effect being identified (36, 39, 40). It is 10. Janssen, H., Berk, L., Heijtink, R. et al. Interferon- reputed not to be incorporated into mitochondria alpha and zidovudine combination therapy for chronic (36). Preliminary information on a recently hepatitis B: results of a randomized, placebo-controlled completed trial involving patients with chronic trial. Hepatology, 17: 383-388 (1993). hepatitis B virus infections indicates that, given 11. Fried, M., Fong, T-L., Swain, M. et al. Therapy of orally for 12 weeks, it completely cleared circulating chronic hepatitis B with a 6-month course of ribavirin. viral DNA from the plasma and that this loss was Journal of Hepatology, 21: 145-150 (1994). sustained in some 20% of the patients (36). These are among the most encouraging results yet 12. Korba, B., Gerin, J. Use of a standardized cell culture obtained with a nucleoside analogue. It is propitious assay to assess activities of nucleoside analogs against that they have been generated at a time when hepatitis B virus replication. Antiviral Research, 19: 55-75 confidence in the potential value of these drugs was (1992). seriously at issue. 13. Paar, D., Hooten, T., Smiles, K. et al. The effect of FIAU on chronic hepatitis B virus (HBV) infection in HIV- References infected subjects. In Program and Abstracts of the 32nd Interscience Conference on Antimicrobial Agents and 1. Hepatitis B vaccines: immunogenicity reappraised. Chemotherapy, (Abstract). American Society for WHO Drug Information, 8: 52-54 (1995). Microbiology, Anaheim, 1992, p. 264. 2. Robinson, W. Hepatitis B virus and hepatitis D virus. In: 14. Fried, M., Di Bisceglie, A., Straus, E. et al. FIAU, a Principles and practice of infectious diseases, 4th edition. new, oral antiviral agent, profoundly inhibits HBV DNA in Bennett, J., Dolin, R. eds. Churchill Livingstone, New patients with chronic hepatitis B. Hepatology, 16: 127A York, 1995, pp.1406-1439 (1992). (Abstract) 3. Hoofnangle, J., Peters, M., Mullen, K. et al. 15. Institute of Medicine. Review of fialuridine (FIAU) Randomized, controlled trial of recombinant human alpha- clinical trials. National Academy Press, Washington, DC, interferon in patients with chronic hepatitis B. Gastro­ 1995. enterology, 95: 1318-1325 (1988). 16. McKenzie, R., Fried, M., Sallie, R. et al. Hepatic failure 4. Perrillo, R., Schiff, E., Davis, G. et al. A randomized, and lactic acidosis due to fialuridine (FIAU), an investiga­ controlled trial of interferon alfa-2b alone and after tional nucleoside analogue for chronic hepatitis B. New prednisone withdrawal for the treatment of chronic England Journal of Medicine, 333: 1099-1105 (1995). hepatitis B. New England Journal of Medicine, 323: 295- 301 (1990). 17. Grem, J., King, S., Sorensen, J., Christian, M. Clinical use of thymidine as a rescue agent from methotrexate 5. Lok, A., Wu, P-C., Lai, C-l. et al. A controlled trial of toxicity. Investigational New Drugs, 9: 281-290 (1991). interferon with or without prednisone priming for chronic hepatitis B. Gastroenterology, 102: 2091-2097 (1992). 18. Seiter, K., Kemeny, N., Martin, D. et al. Uridine allows dose escalation of 5-fluorouracil when given with N- 6. Wong, D., Cheung, A., O'Rourke, K. et al. Effect of phosphonacetyl-L-aspartate, methotrexate, and alpha-interferon treatment in patients with hepatitis B: a leucovorin. Cancer, 71: 1975-1881 (1993). meta-analysis. Annals of Internal Medicine, 119: 312-323 (1993). 19. Stevenson, W., Gaffey, M., Ishitani, M. et al. Clinical course of four patients receiving the experimental antiviral 7. Garcia, G., Smith, C, Weissberg, J. et al. agent fialuridine for the treatment of chronic hepatitis B arabinoside monophosphate (vidarabine phosphate) in infection. Transplantation Proceedings, 27: 1219-1221 combination with human leukocyte interferon in the (1995). treatment of chronic hepatitis B: a randomized, double- blind, placebo-controlled trial. Annals of Internal Medicine, 20. Manning, F., Swartz, M. eds. Review of the fialuridine 107: 278-285 (1987). (FIAU) clinical trials. National Academy Press, Washington, DC, 1995. 8. Alexander, G., Fagan, E., Hegarty, J. et al. Controlled clinical trial of aciclovir in chronic hepatitis B infection. 21. Chen. C, Vasquez-Padua, M., Cheng, Y-C. Effect of Journal of Medical Virology, 21: 81-87 (1987). anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed 9. Fried, M., Korenman, J., DiBisceglie, A. et al. A pilot toxicity. Molecular Pharmacology, 39: 625-628 (1991). study of 2', 3'-dideoxyinosine for the treatment of chronic hepatitis B. Hepatology, 16: 861-864 (1992).

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22. Lewis, L, Hamzeh, F., Leitman, P. Ultrastructural 34. Cui, L., Yoon, S., Schinazi, R., Sommadossi, J. changes associated with reduced mitochondrial DNA and Cellular and molecular events leading to mitochondrial impaired mitochondrial function in presence of 2',3'- toxicity of 1-(2-deoxy-2-fluoro-1-beta-D-arabino- dideoxycytidine. Antimicrobial Agents and Chemotherapy, furanosyl)-5-iodouracil in human liver cells. Journal of 36: 2061-2065 (1992). Clinical Investigation, 95: 555-563 (1995).

23. Arnaudo, E., Dalakas, M., Shanske, S. et al. Depletion 35. Lewis, W., Meyer, R., Simpson, J. et al. Mammalian of muscle mitochondrial DNA in AIDS patients with DNA polymerases, alpha, beta, gamma, delta and epsilon zidovudine-induced myopathy. Lancet, 337: 508-510 incorporate fialuridine (FIAU) monophosphate into DNA (1991). and are inhibited competitively by FIAU triphosphate. Biochemistry, 33: 14620-14624 (1994). 24. Gopinath, R., Hutcheon, M., Cheema-Dhadli, Halperin, M. Chronic lactic acidosis in a patient with acquired 36. Swartz, M. Mitochondrial toxicity — new adverse drug immunodeficiency syndrome and mitochondrial myopathy: effects. New England Journal of Medicine, 333: 1146- biochemical studies. Journal of the American Society of 1148 (1995). Nephrology, 3: 1212-1219 (1992). 37. Génu-Dellac, C, Gosselin, G., Aubertin, A. et al. 3'- 25. Chattha, G., Arieff, A., Cummimgs, C, Tierney, L. substituted alpha-L-nucleoside derivatives as Lactic acidosis complicating the acquired immuno­ potential antiviral agents: synthesis and biological deficiency syndrome. Annals of Internal Medicine, 118: evaluation. Antiviral Chemistry and Chemotherapy, 2: 83- 37-39 (1993). 92 (1991).

26. Gradon, J., Chapnick, E., Sepkowitz, D. Zidovudine- 38. Chang, C, Doong, S., Zhou, J. et al. induced hepatitis. Journal of Internal Medicine, 231: 317- deaminase-resistant stereo-isomer is the active form of 318 (1992). (+/-)-2, 3'-dideoxy-3'-thiacytidine in the inhibition of hepatitis B virus replication. Journal of Biological 27. Freiman, J., Helfert, K., Harwell, M., Stein, D. Chemistry, 267: 13938-13942 (1992). Hepatomegaly with severe steatosis in HIV-seropositive patients. AIDS, 7: 379-385 (1993). 39. van Leeuwen, R., Katlama, C, Kitchen, V. et al. Evaluation of safety and efficacy of 3TC (lamivudine) in 28. Lai, K., Gang, D., Zawacki, K., Cooley, T. Fulminant patients with asymptomatic or mildly symptomatic human hepatic failure associated with 2',3'-dideoxyinosine (ddl). immunodeficiency virus: a phase l/ll study. Journal of Annals of Internal Medicine, 118: 283-284 (1991). Infectious Diseases, 171: 1166-1171 (1995).

29. Bissuel, F., Bruneel, F., Habersetzer, F. et al. 40. Pluda, J., Cooley, T., Montaner, J. et al. A phase l/ll Fulminant hepatitis with severe lactate acidosis in HIV- study of 2'-deoxy-3'-thiacytidine (lamivudine) in patients infected patients on didanosine therapy. Journal of with advanced human immunodeficiency virus infection. Internal Medicine, 235: 367-371 (1994). Journal of Infectious Diseases, 171: 1438-1447 (1995).

30. Maxon, C, Greenfield, S., Turner, J. Acute pancreatitis as a complication of 2',3'-dideoxyinosine therapy in the acquired immunodeficiency syndrome. Amphotericin: a candidate for American Journal of Gastroenterology, 87: 708-713 (1992). first-line treatment of visceral

31. Colasino, J., Malcolm, S., Jaskunas, S. Effect of leishmaniasis? fialuridine on replication of mitochondrial DNA in CEM The pentavalent antimony compounds, meglumine cells and human hepatoblastoma cells in culture. Antimicrobial Agents and Chemotherapy, 38: 1997-2002 antimonate and sodium stibogluconate, have long (1994). been used as first-line treatment for visceral leishmaniasis (or kala-azar). In recent years, 32. Klecker, R., Katki, K., Collins, J. Toxicity, metabolism, however, there has been a tendency to increase DNA incorporation with lack of repair, and lactate pro­ the dose and to extend the period of treatment in duction for 1-(2'-fluoro, 2'-deoxy-beta-D-arabinofuranosyl)- the belief that the protozoal parasite is becoming 5-iodouracil in U-937 and MOLT-4 cells. Molecular less susceptible to these compounds (1, 2). Sodium Pharmacology, 46: 1204-1209 (1994). stibogluconate is now commonly administered for 20 days — and 40 days in the event of relapse — 33. Richardson, F., Engelhardt, J., Bowsher, R. Fialuridine at a dose of some 20 mg/kg daily. This provides accumulates in DNA of dogs, monkeys and rats following long-term administration. Proceedings of the National more than twice the dose that was generally Academy of Sciences, USA, 91: 12003-12007 (1994). regarded as curative in the early 1980s (3).

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The possibility has been raised that, in part, thera­ in other settings, far surpass expectation of an peutic failure may be a consequence of widespread antimicrobial that is generally reserved for patients use of antileishmanial drugs (including the second- with potentially fatal fungal infections and who are line drug, pentamidine, as well as the pentavalent hospitalized or under close medical supervision. antimony compounds) in subtherapeutic dosage by unqualified practitioners (4). This ineffectual use The investigators concede that use of amphotericin may have contributed directly to the apparent is relatively expensive, not least because of the emergence of antimicrobial resistance and, absolute necessity to admit patients to hospital for indirectly — as a result of increased dosage — to a treatment. However, given the outcome of their greater incidence of drug-induced toxic effects study, they express confidence that much of the (including arthralgia, nephrotoxicity, and potentially additional cost would be defrayed by a substantial fatal cardiotoxicity) (5-7). reduction in treatment failure. They create optimism that a disease apparently escaping from control can Within the north-east Indian state of Bihar where again be effectively treated, and they have paved visceral leishmaniasis is hyperendemic in some the way for comparable studies of the newer formu­ regions, and where relapse rates following primary lations of amphotericin that have been developed treatment are rising, the feasibility of selecting specifically to reduce the toxicity of the parent amphotericin as a treatment of first resort has been compound. under consideration. Amphotericin is the only polyene antibiotic which can be administered References parenterally. In the systemic treatment of fungal 1. Thakur, C, Kumar, M., Pandey, A. Evaluation of diseases — in dosages ranging from 0.25 to efficacy of longer durations of therapy in fresh cases of 1.5 mg/kg daily — it is acknowledged to cause a kala-azar with sodium stibogluconate. Indian Journal of broad spectrum of serious systemic effects Medical Research, 93: 103-110 (1991). involving, in particular, acute dose-related damage 2. Jha, T., Singh, N., Jha, S. Therapeutic use of sodium to the liver, kidneys, the bone marrow, the heart stibogluconate on kala-azar from some hyperendemic and the nervous system. However, it has been districts of N. Bihar, India. Journal of the Association of reported that schedules based on doses towards Physicians of India, 42: 868 (1992). the lower end of this range are sufficient to cure many cases of visceral leishmaniasis with little risk 3. World Health Organization. The leishmaniases: report of a WHO Expert Committee. WHO Technical Report of serious toxicity (8, 9). Series, 701, 1984, pp. 99-109.

A prospective, open, randomized trial has now 4. Sundar, S., Thakur, B., Tandon, N. et al. Clinico- been completed in which sodium stibogluconate (20 epidemiological study of drug resistance in Indian kala- mg/kg daily in two divided doses for 40 days) and azar. British Medical Journal, 308: 307 (1993). amphotericin (14 infusions of 0.5 mg/kg on alter­ 5. Berman, J. Chemotherapy for leishmaniasis: biochemi­ nate days preceded by preliminary incremental cal mechanisms, clinical efficacy and future strategy. doses) were compared in the primary treatment of Reviews of Infectious Diseases, 10: 560-586 (1988). visceral leishmaniasis (10). None of 40 patients 6. Herwaldt, B., Berman, J. Recommendations for treating randomized to amphotericin developed signs or leishmaniasis with sodium stibogluconate (Pentostam) symptoms attributable to infection within the and review of pertinent clinical studies. American Journal following 12 months: all were regarded as cured. In of Tropical Medicine and Hygiene, 46: 296-306 (1992). contrast, 12 of 40 patients who received sodium stibogluconate failed to respond adequately — 7. Chunge, C, Gachihi, G., Chulay, J., Spencer, H. either clinically or parasitologically — to treatment. Complications of kala-azar and its treatment in Kenya. East African Medical Journal, 61: 120-127 (1984). Each of these patients was subsequently cured by amphotericin. 8. Mishra, M., Singh, M., Choudhury, D. et al. Amphoter­ icin B for second-line treatment of kala-azar. Lancet, 337: Fevers and chills, which responded to paracetamol, 926 (1991). were common during infusion of amphotericin. 9. Mishra, M., Biswas, U., Jha, D., Khan, A. Amphotericin Otherwise, no serious adverse effects were versus pentamidine in antimony-unresponsive kala-azar. attributed to either drug throughout the study, and Lancet, 340:1256-1257 (1992). no patient required corticosteroid therapy. These 10. Mishra, M., Biswas, U., Jha, D., Khan, A. Amphotericin results, and particularly the apparent freedom from versus sodium stibogluconate in first-line treatment of many of the adverse effects considered inevitable Indian kala-azar. Lancet, 344: 1599-1600 (1994).

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General Information

Polypharmacy, parenteral References treatment, and blood-borne 1. World Health Organization. Ebola haemorrhagic fever in Zaire, 1976: report of an International Commission. infection Bulletin of the World Health Organization, 56: 271-293 (1978). Parenteral transmission of viral disease is largely associated in the medical literature with blood 2. Hersh, B., Popovici, F., Apetrei, R. et al. Acquired transfusion. In less developed countries risk of immunodeficiency syndrome in Romania. Lancet, 338: accidental inoculation has been implicated in 645-649 (1991). hospital-centred outbreaks of various conditions, including Ebola fever and HIV infection (1, 2). 3. Fisher-Hoch, S., Tmori, O., Nasidi, A. et al. Review of cases of nosocomial Lassa fever in Nigeria: the high price Circumstantial evidence has recently been of poor medical practice. Lancet, 311: 857-859 (1995). presented in the Lancet to show that two recent outbreaks of Lassa fever in small hospitals in rural 4. Carey, D., Kemp, G., White, H. et al. Lassa fever. Nigeria were fuelled by reuse of disposable Epidemiological aspects of the 1970 epidemic, Jos, syringes during parenteral drug rounds conducted Nigeria. Transactions of the Royal Society of Tropical by inadequately trained and supervised staff (3). Medicine and Hygiene, 66: 402-408 (1972).

Lassa fever, which is now endemic in most of West 5. Fabiyi, A., Tomori, O., Pinneo, P. Lassa fever antibodies in hospital personnel in the Plateau State of Africa, is caused by an arenavirus that infects a Nigeria. Nigerian Medical Journal, 9: 23-25 (1979). locally prevalent rodent, Mastomys natelensis. It was first documented in man in 1969 following a hospital-associated outbreak in northern Nigeria. Increasing concerns about Since then, patients with Lassa fever have been admitted sporadically to local hospitals. Close pneumococcal drug resistance contact with severely ill patients and accidental inoculation have long been recognized as risk Reports of penicillin-resistant pneumococci (Streptococcus pneumoniae) first began to appear factors for transmission of the infection within in the mid-1970s. Substantial prevalence was hospitals (4, 5). Investigation of the recent subsequently reported from Spain, Hungary, South outbreaks, which was undertaken at the request of Africa, and South American countries (1). Given the Nigerian Ministry of Health in collaboration with that these countries are widely scattered, and given staff from the US Centers for Disease Control, has the scale on which penicillins are used around the provided the first clearly documented evidence of world, there was every reason to assume that these needle transmission. strains would spread widely and increase in prevalence. The resulting report reveals that "rampant poly­ pharmacy and widespread use of parenteral treatment often for trivial indications is driven by Trends over the past decade have shown these patients who believe that injections have superior apprehensions to be justified. One clone alone, therapeutic value and by practitioners to generate which has spread extensively in the United States, revenue." "The conditions observed are rooted in has been recovered in four continents (2). The rate systems where there is poor education, little at which resistant strains have taken hold in the US attention to safety, no surveillance, no rules, and no is remarkable. In a nationwide surveillance programme conducted between 1979 and 1987, safeguards " It concludes that "efforts of the only 0.02% of pneumococcal isolates were highly World Health Organization to develop such resistant to penicillin (3). By 1992, this proportion guidelines and to assist developing countries in had risen to 1.3% (4). Several subsequent spot devising an effective way of promulgating them and estimates have placed this proportion considerably enforcing them must be supported. Failure to do so higher. Most recently, 7% of isolates taken from will have far-reaching and costly consequences." patients with invasive pneumococcal disease in

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acute care hospitals in Atlanta were highly resistant impending need to undertake antimicrobial- to penicillin (MIC > 2 µg/ml), while 25% were mod­ susceptibity testing of all invasive pneumococcal erately resistant (5). These proportions were even isolates from both children and adults, and for higher among isolates taken from children under 6 community-based programmes of surveillance for years. Moreover, many were also resistant to drug-resistant strains will add substantially to these cefotaxime, trimethoprim/sulfamethoxazole, eryth­ costs (5). romycin or tetracycline. Some 10% of all isolates were resistant to three or more antimicrobials. Strategies of this nature are simply too costly for most countries to contemplate. The first imperative The assumption must be that this trend will render is to curb excessive and inappropriate use of therapy of invasive pneumococcal disease more antibiotics for community infections where this is difficult and result in increasing numbers of treat­ known to be a problem (18, 19). The second is to ment failures. Such failures have already been promote the development of novel antimicrobial reported in the management of pneumococcal agents: it has already been observed that "the meningeal infections resistant to penicillins or shortage of available chemotherapeutic agents cefalosporins (6, 7), and it has been proposed that begins to resemble the situation with multidrug a third-generation cefalosporin or vancomycin resistant Staphylococcus aureus" (16, 20). The third should be used for meningeal infections when the is to strive to make the existing pneumococcal MIC for penicillin exceeds 0.12 µg/ml (8, 9). vaccines more widely available, to administer them Fortunately, there is little evidence thus far from earlier in life than is currently practised, and to countries with effective microbiological services that develop new vaccines better suited for adminstra¬ the emergence of resistant strains has increased tion to children (21). the mortality associated with non-meningeal pneumococcal bacteraemias (10, 11). It is widely References agreed that, used in high dosages, penicillins or 1. Applebaum, P. Antimicrobial resistance in Strepto­ cefalosporins remain effective in these infections coccus pneumoniae: an overview. Clinics of Infectious provided the MIC for penicillin does not exceed Diseases, 15: 77-83 (1992). some 2 µg/ml (12-14). 2. Munoz, R., Coffey, T., Daniels, M. et al. Intercontinental However, the portents are sombre. First, it has spread of a multiresistant clone of serotype 23F Strepto­ been suggested that the fast and extensive dis­ coccus pneumoniae. Journal of Infectious Diseases, 164: 302-306 (1994). persal of some multidrug-resistant clones may indicate that traits conferring antibiotic resistance 3. Spika, J., Facklam, R., Plikaytis, B., Oxtoby, M. Anti­ have become associated with some traits related to microbial resistance of Streptococcus pneumoniae in the virulence (15, 16). Second, although routine United States, 1979-1987. Journal of Infectious Diseases, penicillin regimens provide peak serum levels well 163: 1273-1278 (1991). in excess of the MICs of most existing resistant strains, these MICs may be expected to rise further 4. Breiman, R., Butler, J., Tenover, F. et al. Emergence of (11, 16): isolates resistant to penicillin concentra­ drug-resistant pneumococcal infections in the United tions ranging up to 16 µg/ml have already been States. Journal of the American Medical Association, 271 : identified in Eastern Europe (1). 1831-1835 (1994). 5. Hofmann, J., Cetron, M., Farley, M. et al. The preva­ This is a dire situation. Streptococcus pneumoniae lence of drug-resistant Streptococcus pneumoniae in is a ubiquitous organism that is responsible, Atlanta. New England Journal of Medicine, 333: 481-486 globally, for a substantial proportion of cases of (1995). acute invasive bacterial disease, including pneu­ monia, meningitis, bactaeremia, sinusitis and otitis 6. Viladrich, P., Gudiol, F., Liñares, J. et al. Characteristics media. It attacks both adults and children, and it is and antibiotic therapy of adult meningitis due to penicillin- a major cause of both chronic morbidity and resistant pneumococci. American Journal of Medicine, 84: mortality. Pneumococcal pneumonia and bacte­ 839-846 (1988). remia have repeatedly been associated with death 7. John, C. Treatment failure with use of a third-genera­ rates of some 25% (11). The annual cost of treating tion cephalosporin for penicillin-resistant pneumococcal all these infections in the United States alone may meningitis: case report and review. Clinics of Infectious already exceed US$ 4000 million (17). The Diseases, 18: 188-193 (1992).

218 WHO Drug Information Vol. 9, No. 4, 1995 General Information

8. Viladrich, P., Gudiol, F., Liñares, J. et al. Evaluation of 15. Soares, S., Kristinsson, K., Musser, J., Tomasz, A. vancomycin for therapy of adult pneumococcal meningitis. Evidence for the introduction of a multi-resistant clone of Antimicrobial Agents and Chemotherapy, 35: 2467-2472 serotype 6B Streptococcus pneumoniae from Spain to (1991). Iceland in the late 1980s. Journal of Infectious Diseases, 168: 158-163 (1993). 9. Friedland, I., McCracken, G. Management of infections caused by antibiotic resistant Streptococcus pneumoniae. 16. Tomasz, A. The pneumococcus at the gates. New New England Journal of Medicine, 331: 337-382 (1994). England Journal of Medicine, 333: 514-515 (1995). 10. Kramer, M., Rudensky, B., Hadas-Halperin, I. et al. Pneumococcal bacteremia — no change in mortality in 30 17. Gable, C, Holzer, S., Englehart, L. et al. Pneumo­ years: analysis of 104 cases and review of the literature. coccal vaccine: efficacy and associated cost savings. Israeli Journal of Medical Science, 23: 174-180 (1987). Journal of the American Medical Association, 264: 2910- 2915 (1990). 11. Pallares, R., Liñares, J., Vadillo, M. et al. Resistance to penicillin and cephalosporin and mortality from severe 18. Melnick, S., Sprafka, J., Laitinen, D. et al. Antibiotic pneumococcal pneumonia in Barcelona, Spain. New- use in urban whites and blacks: the Minnesota Heart England Journal of Medicine, 333: 474-480 (1995). Survey. Annals of Pharmacotherapy, 26: 1292-1295 (1992). 12. Pallares, R., Gudiol, F., Liñares, J. et al. Risk factors and response to antibiotic therapy in adults with 19. McCaig, L., Hughes, J. Trends in antimicrobial drug bacteremic pneumonia caused by penicillin-resistant prescribing among office-based physicians in the United pneumococci. New England Journal of Medicine, 317: 18- States. Journal of the American Medical Association, 273: 22 (1987). 214-219 (1995).

13. Garcia-Leoni, M., Cercenado, E., Rodeña, P. et al. 20. Tomasz, A. Multiple-antibiotic-resistant pathogenic Susceptibility of Streptococcus pneumoniae to penicillin: a bacteria — a report on the Rockefeller University work­ prospective microbiological and clinical study. Clinical shop. New England Journal of Medicine, 330: 1247-1251 Infectious Diseases, 14: 427-435 (1992). (1994). 14. Tan, T., Mason, E., Kaplan, S. Systemic infections due to Streptococcus pneumoniae relatively resistant to 21. Austrian, R. Confronting drug-resistant pneumococci. penicillin in a children's hospital: clinical management and Annals of Internal Medicine, 121: 807-809 (1994). outcome. Pediatrics, 90: 928-933 (1992).

219 WHO Drug Information Vol. 9, No. 4, 1995

Regulatory Matters

Nifedipine: danger of groups of hypertensive patients who received either a beta-adrenergic blocking agent; a short-acting short-acting formulations formulation of a calcium channel blocking agent (nifedipine, verapamil, or diltiazem); a diuretic United States of America — The National Heart, alone; or a diuretic in combination with a calcium Lung and Blood Institute has issued a statement channel blocking agent (3). An overall increase in based on the recommendations of an Ad Hoc risk of some 60% was registered among patients Committee on Calcium Channel Blockers warning treated with a regimen containing one of the doctors that short-acting formulations of nifedipine calcium channel blocking agents. However, a should be used "with great caution (if at all), similar study involving hypertensive patients that is especially at higher doses, in the treatment of shortly to be published (4) associates a statistically hypertension, angina, and myocardial infarction" significant increase in mortality with nifedipine, but (1). The committee was convened to review several not with diltiazem or verapamil. recent publications which conclude that such use of nifedipine — and possibly of other calcium channel The Committee considers several possible blocking agents — is associated with an increased mechanisms that might account for this adverse and dose-dependent risk of death from myocardial effect. In particular, it notes that in the presence of infarction. advanced coronary disease, the vasodilatation produced by calcium channel blocking agents — Particularly persuasive is a meta-analysis of 16 and by nifedipine in particular — may shunt blood placebo-controlled clinical trials involving over 8000 away from ischaemic areas of the myocardium by patients with symptomatic coronary heart disease selectively dilating relatively healthy collateral (2). The mortality risk ratio (RR) rose progressively vessels. This possibility has long been acknow­ from RR=1.06 (95% confidence interval, 0.89 to ledged in product information issued by manu­ 1.27) for patients receiving 30-50 mg nifedipine facturers. Some product data sheets warn explicitly daily, to RR=1.18 (0.96 to 1.50) for 60 mg daily, and that nifedipine has invoked ischaemic pain shortly to RR=2.83 (1.35 to 5.93) for 80 mg daily. after its administration in a small minority of patients (5). They advise that short-acting nifedipine should The common pharmacological characteristic of be prescribed at a starting dose of 10 mg three calcium channel blocking agents is that they inhibit times daily which may be raised exceptionally to a the cellular influx of calcium ions into the smooth maximum of 20 mg three times daily. Doses of up muscle of blood vessels and into myocardial cells. to 90 mg daily are recommended only for delayed- In consequence, they reduce myocardial contract­ release formulations. The US data have confirmed ility, impair the generation and propagation of the that the excess mortality associated with use of conduction impulse, and decrease vascular tone nifedipine is sharply dose-related and the trend is within the coronary arteries. The range of marketed evident even at a total dose of 60 mg daily. products, however, is far from homogeneous. The three most widely used products differ in both their In conclusion, the Committee reminds doctors that chemical configurations and their pharmacological whereas certain beta-adrenergic blocking agents profiles. Most importantly, nifedipine (a dihydro¬ have been shown to reduce mortality and re- pyridine) acts predominantly on vascular smooth infarction in the post-infarction period, "controlled muscle and dilates coronary and peripheral trials of adequate size with calcium channel arteries; while both nifedipine and diltiazem (a blocking agents have not revealed such a benefit, benzothiazepine) depress the myocardium to a and there is no reason to use them in the post­ lesser degree than verapamil (a phenyl alkylamine). infarction setting except to treat symptoms". Equally tellingly, it notes that "diuretics and beta-blockers As yet, it is unclear whether treatment with vera­ have reduced major cardiovascular events and pamil or diltiazem is associated with the hazard mortality in well-controlled trials in hypertension, now attributed to nifedipine. One recently published while other agents have not been adequately study compared the risk of myocardial infarction in tested". It also acknowledges, however, that the

220 WHO Drug Information Vol. 9, No. 4, 1995 Regulatory Matters

excess mortality is attributed to short-acting formu­ • data to be submitted on the incidence of myo­ lations of nifedipine and that the conclusions drawn cardial infarction associated with these various from these studies do not necessarily apply to products within the cohorts already studied; and longer-acting dosage forms of nifedipine, longer- acting dihydropyridines, or other classes of calcium • additional data to be presented by interested channel blocking agents. manufacturers. Sources In the interim, the Committee has advised that doctors and users should be reminded that: 1. US National Heart, Lung, and Blood Institute, State­ ment issued 1 September 1995. • the contraindications of combined oral contra­ ceptive products include the presence of, or a 2. Furberg, C. Psaty, B., Meyer, J.V. Nifedipine: dose- history of, venous thromboembolic, cerebro­ related increase in mortality in patients with coronary heart vascular or cardiovascular disease; disease. Circulation, 92: 1326-1330 (1995). • the known risk factors for venous thrombo­ 3. Psaty, B., Heckbert, S., Koepsell, T. et al. The risk of embolism include obesity (defined as a body/mass myocardial infarction associated with antihypertensive index greater than 30 when measured in kg/m2), drug therapies. Journal of the American Medical Association, 274: 620-625 (1995). varicose veins, or a family history of venous thrombosis; 4. Pahor, M., Guralnik, J.M., Corti, M.C. et al. Long-term • the risk of venous thromboembolic events survival and use of antihypertensive medications in older persons. Journal of the American Geriatrics Society, 43: associated with all types of combined contra­ 1191-1197 (1995). ceptives is substantially less than that associated with pregnancy. 5. in: ABPI Data Sheet Compendium, 1994-1995, Datapharm Publications, London, 1994, pp. 158 & 478. The World Health Organization, which has Also in: British National Formulary, Number 29. British coordinated one of the three studies now under Medical Association/Royal Pharmaceutical Society of discussion, has issued an independent statement Great Britain, London, 1995, pp. 90 & 92. based on its own findings (2). This confirms the apparent differences in risk of venous thrombosis associated with low-dose estrogen contraceptive Oral contraceptives and products containing different progestogens. It also thromboembolism discloses that no such difference has been detected in the risk of either myocardial infarction or The Committee for Proprietary Medicinal Products stroke among women receiving one or another of (CPMP) is an advisory body to the national these products. regulatory bodies serving the member states of the European Union. At a meeting in October 1995, the An advisory committee to WHO does not exclude Committee was apprised by its British and German the possibility that these results, taken in isolation, members of data obtained in three independent may have been determined by chance or bias epidemiological studies — as yet unpublished — rather than by other factors. It concludes, none the indicating that the incidence of venous thrombo­ less, that "current users of oral contraceptives embolism is some twofold higher among women containing desogestrol or gestodene appear to be who take combined, low-estrogen (less than 50 µg) at higher risk of venous thromboembolism com­ oral contraceptive products containing the pared to users of pills containing levonorgestrel or progestogens desogestrel or gestodene than norethindrone" and that "until further information among women who take analogous products becomes available, low-dose estrogen oral contra­ containing either levonorgestrel or norethindrone. ceptives containing progestogens other than deso­ gestrel and gestodene may be preferred." In In a subsequent assessment of benefits and risks, lending perspective to this conclusion, however, it based on a report prepared by an ad hoc Expert emphasizes that "the new information should be Working Group, the CPMP concluded that it would interpreted in the light of evidence that the inci­ be inappropriate to withdraw combined oral contra­ dence of venous thromboembolism in women of ceptives containing gestodene or desogestrol on reproductive age throughout the world is low, and the basis of currently available information (1). The any excess risk from using combined oral contra­ committee undertook to review the position within ceptives affects a relatively small number of the following six months on the basis of: women."

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Statements have also been issued by the regula­ 3. Federal Institute for Medicines and Medicinal Products. tory authorities in Germany (3) and in the United Increased risk of venous thrombosis associated with Kingdom (4). The stance of the UK's Committee on contraceptive products containing gestodene and Safety of Medicines is uncompromising: it con­ desogestrel. Press release, 20 October 1995 (in German). cludes that combined preparations containing 4. Committee on Safety of Medicines. Combined oral desogestrol or gestodene "should be used only by contraceptives and thromboembolism. Open letter to all women who are intolerant of other combined oral doctors and pharmacists. London,18 October 1995. contraceptives and prepared to accept an increased risk of thromboembolism." Naftidrofuryl infusion withdrawn External commentary on the evidence at issue will become possible only after publication of the three United Kingdom — Intravenous naftidrofuryl, a studies which were used as a basis for regulatory product previously approved for the treatment of decisions. severe peripheral vascular disease, has been withdrawn from the UK market on the advice of the Sources: Committee on Safety of Medicines. A review 1. European Agency for the Evaluation of Medicinal conducted within several European countries has Products. Position statement of the CPMP on oral shown that risks of cardiac and neurological toxicity contraceptives containing gestodene or desogestrel. outweigh the benefits of treatment. The oral form of London, 27 October 1995. naftidrofuryl (100 mg capsules) remains available 2. UNDP/UNFPA/WHO/World Bank Special Programme for the treatment of less severe degrees of of Research, Development and Research Training in peripheral vascular disease in accordance with the Human Reproduction. Oral contraceptives and venous original terms of the product licence. thromboembolism. WHO News Release, Geneva, 23 October 1995. Source: Committee on Safety of Medicines. Current Problems in Pharmacovigilance, No. 21 (1995).

222 WHO Drug Information Vol. 9, No. 4, 1995

Essential Drugs

WHO Model List: revised in December 1995

Section 1 : Anaesthetics injection, 1%, 2% (hydrochloride) 1.1 GENERAL ANAESTHETICS AND OXYGEN + epinephrine 1:200 000 in vial injection for spinal anaesthesia, ether, anaesthetic (2) inhalation 5% (hydrochloride) in 2-ml ampoule halothane (2) inhalation to be mixed with 7.5% glucose solution ketamine (2) injection, 50 mg (as hydro- topical forms, 2 - 4% (hydrochloride) chloride)/ml in 10-ml vial dental cartridge, 2% (hydrochloride) + epinephrine 1:80 000 nitrous oxide (2) inhalation oxygen inhalation (medicinal gas) 1.3 PREOPERATIVE MEDICATION & SEDATION *thiopental (2) powder for injection, 0.5 g, 1.0 g FOR SHORT-TERM PROCEDURES (sodium salt) in ampoule atropine injection, 1 mg (sulfate) 1.2 LOCAL ANAESTHETICS in 1-ml ampoule chloral hydrate syrup, 200 mg/5 ml *bupivacaine (2, 9) injection, 0.25%, 0.5% (hydrochloride) in vial *diazepam (1b) injection, 5 mg/ml injection for spinal anaesthesia, in 2-ml ampoule tablets, 5 mg 0.5% (hydrochloride) in 4-ml ampoule to be mixed with 7.5% glucose solution *morphine (1a) injection, 10 mg (sulfate or *lidocaine injection, 1%, 2% hydrochloride) in 1 -ml ampoule (hydrochloride) in vial *promethazine elixir or syrup, 5 mg (hydrochloride)/5 ml

Explanatory Notes

When the strength of a drug is specified in terms of a (4) In renal insufficiency, contraindicated or dosage selected salt or ester, this is mentioned in brackets; adjustments necessary; when it refers to the active moiety, the name of the salt (5) To improve compliance; or ester in brackets is preceded by the word "as". (6) Special pharmacokinetic properties; (7) Adverse effects diminish benefit/risk ratio; * Example of a therapeutic group. Various drugs can (8) Limited indications or narrow spectrum of activity; serve as alternatives. (9) For epidural anaesthesia; (10) Sustained release preparations are available. The Numbers, in parentheses, following the drug names fact of proper sustained release of the dosage form indicate: should be documented. (1) Drugs subject to international control under (a) the Single Convention on Narcotic Drugs (1961); (b) the Letters in parentheses following the drug names indicate Convention on Psychotropic Substances (1971); and (c) the reasons for the inclusion of complementary drugs: the Convention on Illicit Traffic in Narcotic Drugs and (A) When drugs in the main list cannot be made Psychotropic Substances (1988); available; (2) Specific expertise, diagnostic precision, individualiza­ (B) When drugs in the main list are known to be tion of dosage or special equipment required for proper ineffective or inappropriate for a given individual; use; (C) For use in rare disorders or in exceptional circum­ (3) Greater potency or efficacy; stances.

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Section 2: Analgesics, Antipyretics, Section 4: Antidotes and Other Nonsteroidal Anti-inflammatory Substances Used in Poisonings Drugs and Drugs Used to Treat 4.1 NON-SPECIFIC Gout *charcoal, activated powder ipecacuanha syrup, containing 0.14% ipecacuanha 2.1 NON-OPIOIDS alkaloids calculated as emetine acetylsalicylic acid tablet, 100-500 mg 4.2 SPECIFIC suppository, 50 -150 mg atropine injection, 1 mg (sulfate) allopurinol (4) tablet, 100 mg in 1-ml ampoule colchicine (7) tablet, 500 µg deferoxamine powder for injection, 500 mg (mesilate) in vial *ibuprofen tablet, 200 mg, 400 mg dimercaprol (2) injection in oil, 50 mg/ml paracetamol tablet, 100-500 mg in 2-ml ampoule suppository, 100 mg *methionine tablet, 250 mg (racemate) syrup, 125 mg/5 ml methylthioninium chloride injection, 10 mg/ml (methylene blue) in 10-ml ampoule 2.2 OPIOID ANALGESICS naloxone injection, 400 µg (hydrochloride) *codeine (1a) tablet, 30 mg (phosphate) in 1-ml ampoule *morphine (1a) injection, 10 mg (sulfate or penicillamine (2) capsule or tablet, 250 mg hydrochloride) in 1-ml ampoule potassium ferric hexacyano- powder for oral ferrate(ll)2H O (Prussian blue) administration oral solution, 10 mg (hydrochloride 2 or sulfate))/5 ml sodium calcium edetate (2) injection, 200 mg/ml in 5-ml ampoule tablet, 10 mg (sulfate) sodium nitrite injection, 30 mg/ml Complementary drug in10-ml ampoule *pethidine (A) (1a, 4) injection, 50 mg sodium thiosulfate injection, 250 mg/ml (hydrochloride) in 1-ml ampoule in 50-ml ampoule tablet, 50 mg, 100 mg (hydrochloride) Section 5: Anticonvulsants Section 3: Antiallergics carbamazepine (10) scored tablet, 100 mg, 200 mg and Drugs Used in Anaphylaxis *diazepam (1b) injection, 5 mg/ml in 2-ml ampoule (intravenous or rectal) *chlorphenamine tablet, 4 mg (hydrogen maleate) ethosuximide capsule, 250 mg injection, 10 mg (hydrogen syrup, 250 mg/5 ml maleate) in 1-ml ampoule magnesium sulfate 500 mg/ml in 2-ml ampoule *dexamethasone tablet, 500 µg, 4 mg phenobarbital (1b) tablet, 15-100 mg injection, 4 mg (as sodium elixir, 15 mg/5 ml phosphate) in 1-ml ampoule phenytoin capsule or tablet, epinephrine injection, 1 mg (as hydro­ 25 mg, 50 mg, 100 mg (sodium salt) chloride or hydrogen tartrate) in 1-ml ampoule injection, 50 mg (sodium salt)/ml in 5-ml vial hydrocortisone powder for injection, 100 mg enteric coated tablet, (as sodium succinate) in vial valproic acid (7) 200 mg, 500 mg (sodium salt) *prednisolone tablet, 5 mg Complementary drug *clonazepam scored tablets, 500 µg

* Example of a therapeutic group. Various drugs can serve as alternatives.

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Section 6: Anti-infective Drugs powder for injection, 500 mg (as sodium salt) in vial 6.1 ANTHELMINTICS phenoxymethylpenicillin tablet, 250 mg 6.1.1 INTESTINAL ANTIHELMINTHICS (as potassium salt) albendazole chewable tablet, 400 mg powder for oral suspension, 250 mg (as potassium salt)/5 ml levamisole (8) tablet, 50 mg, 150 mg procaine benzylpenicillin powder for injection, (as hydrochloride) 1 g (= 1 million IU), 3 g (= 3 million IU) *mebendazole chewable tablet, 100 mg, 500 mg 6.2.2 OTHER ANTIBACTERIALS niclosamide chewable tablet, 500 mg praziquantel tablet, 150 mg, 600 mg *ciprofloxacin tablet, 250 mg (as hydrochloride) pyrantel chewable tablet, 250 mg (as embonate) *chloramphenicol (7) capsule, 250 mg oral suspension, 50 mg oral suspension, 150 mg (as embonate)/ml (as palmitate salt)/5 ml 6.1.2 ANTIFILARIALS powder for injection, 1 g (as sodium succinate) in vial diethylcarbamazine tablet, 50 mg (dihydrogen citrate) *doxycycline (5, 6) capsule or tablet, ivermectin scored tablet, 6 mg 100 mg (as hyclate) Complementary drug *erythromycin capsule or tablet, 250 mg (as stearate or ethyl succinate) suramin sodium (B) (2, 7) powder for injection, 1 g in vial powder for oral suspension, 125 mg (as stearate or ethyl succinate) 6.1.3 ANTISCHISTOSOMALS powder for injection, 500 mg metrifonate tablet, 100 mg (as lactobionate) in vial oxamniquine capsule, 250 mg *gentamicin (2, 4, 7) injection, 10 mg, 40 mg syrup, 250 mg/5 ml (as sulfate)/ml in 2-ml vial praziquantel tablet, 600 mg *metronidazole tablet, 200 - 500 mg injection, 500 mg in 100-ml vial 6.2 ANTIBACTERIALS suppository, 500 mg, 1 g 6.2.1 PENICILLINS oral suspension, 200 mg *amoxicillin (4) capsule or tablet, 250 mg, (as benzoate)/5 ml 500 mg (anhydrous) nalidixic acid (8) tablet, 250 mg, 500 mg powder for oral suspension, 125 mg (anhydrous)/5 ml nitrofurantoin (4, 7 8) tablet, 100 mg ampicillin (4) powder for injection, 500 mg spectinomycin (8) powder for injection, 2 g (as sodium salt) in vial (as hydrochloride) in vial benzathine powder for injection, *sulfadimidine (4) tablet, 500 mg benzylpenicillin 1.44 g benzylpenicillin oral suspension, 500 mg/5 ml (= 2.4 million IU) in 5-ml vial injection, 1 g (sodium salt) benzylpenicillin powder for injection, in 3-ml ampoule 600 mg (= 1 million IU), 3 g (= 5 million IU) *sulfamethoxazole + tablet, 100mg + 20 mg, (as sodium or potassium salt) in vial trimethoprim (4) 400 mg + 80 mg *cloxacillin capsule, 500 mg (as sodium salt) oral suspension, 200 mg + 40 mg/5 ml powder for oral solution, 125 mg (as sodium salt)/5 ml trimethoprim (8) tablet, 100 mg, 200 mg

* Example of a therapeutic group. Various drugs can serve as alternatives.

225 Essential Drugs WHO Drug Information Vol. 9, No. 4, 1995

Complementary drugs Complementary drug chloramphenicol injection 0.5g (as sodium flucytosine (B) (4, 8) capsule, 250 mg oily suspension (C) succinate)/ ml in 2-ml ampoule infusion, 2.5 g in 250 ml clindamycin (B) injection, 150 mg potassium iodide (A) saturated solution (as phosphate)/ml 6.4 ANTIPROTOZOAL DRUGS Restricted indications ceftriaxone powder for injection, 250 mg (as 6.4.1 ANTIAMOEBIC AND ANTIGIARDIASIS sodium salt) in vial DRUGS ceftazidime powder for injection, 250 mg (as *diloxanide tablet, 500 mg (furoate) pentahydrate) in vial *metronidazole tablet, 200 - 500 mg vancomycin powder for injection 250 mg (as injection, 500 mg in 100-ml vial hydrochloride) in vial oral suspension, 200 mg (as benzoate)/5 ml 6.2.3 ANTILEPROSY DRUGS clofazimine capsule, 50 mg, 100 mg 6.4.2 ANTILEISHMANIASIS DRUGS dapsone tablet, 50 mg, 100 mg *meglumine antimoniate injection, rifampicin capsule or tablet, 150 mg, 300 mg 30%, equivalent to approx. 8.5% antimony, in 5-ml ampoule 6.2.4 ANTITUBERCULOSIS DRUGS pentamidine (5) powder for injection, 200 mg (isetionate) in vial ethambutol (4) tablet, 100 - 400 mg Complementary drug (hydrochloride) amphotericin B (4) (B) powder for injection, isoniazid tablet, 100-300 mg 50 mg in vial pyrazinamide tablet, 400 mg 6.4.3 ANTIMALARIAL DRUGS rifampicin capsule or tablet, 150 mg, 300 mg rifampicin + tablet, 150 mg + 75 mg, (a) FOR CURATIVE TREATMENT isoniazid 300 mg + 150 mg, 150 mg + 150 mg *chloroquine tablet, 100 mg, 150 mg streptomycin (4) powder for injection, (as phosphate or sulfate) 1 g (as sulfate) in vial syrup, 50 mg rifampicin tablet, 150 mg + 75 mg + 400 mg, (as phosphate or sulfate)/5 ml + isoniazid 150 mg + 150 mg + 500 mg injection, 40 mg (as hydro­ + pyrazinamide chloride phosphate or sulfate)/ml in 5-ml ampoule isoniazid + ethambutol tablet, 400 mg + 150 mg primaquine tablet, 7.5 mg, 15 mg Complementary drug (as diphosphate) thioacetazone + tablet, 50 mg + 100 mg, isoniazid (A) (7) 150 mg + 300 mg quinine tablet, 300 mg (as bisulfate or sulfate) injection, 300 mg (as dihydrochloride)ml 6.3 ANTIFUNGAL DRUGS in 2-ml ampoule amphotericin B (4) powder for injection, 50 mg in vial Complementary drugs griseofulvin (8) capsule or tablet, 125 mg, 250 mg mefloquine (B) tablet, 250 mg (as hydrochloride) *sulfadoxine + tablet, 500 mg + 25 mg *ketoconazole (2) tablet, 200 mg pyrimethamine (B) oral suspension, 100 mg/5 ml *doxycycline (B)1 capsule or tablet, nystatin tablet, 100 000, 500 000 IU 100 mg (hyclate) lozenge 100 000 IU Restricted indications artemether injection, 80 mg/ml pessary, 100 000 IU in 1-ml ampoule * Example of a therapeutic group. Various drugs can serve as alternatives. 1 For use only with quinine.

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(b) FOR PROPHYLAXIS ciclosporin (2)3 capsule, 25 mg chloroquine tablet, 150 mg concentrate for injection (as phosphate or sulfate) 50 mg/ml in 1-ml ampoule syrup, 50 mg (as phosphate 8.2 CYTOTOXIC DRUGS or sulfate)/5 ml asparaginase (2) powder for injection mefloquine tablet, 250 mg (as hydrochloride) 10 000 IU in vial 2 proguanil tablet, 100 mg (hydrochloride) bleomycin (2) powder for injection, 15 mg (as sulfate) in vial 6.4.4 ANTITRYPANOSOMAL DRUGS calcium folinate (2) tablet, 15 mg (a) AFRICAN TRYPANOSOMIASIS injection, 3 mg/ml melarsoprol (5) injection, 3.6% solution in 10-ml ampoule pentamidine (5) powder for injection, 200 mg chlormethine (2) powder for injection 10 mg (isetionate) in vial (hydrochloride) in vial suramin sodium (7) powder for injection, 1 g in vial cisplatin (2) powder for injection, Complementary drug 10 mg, 50 mg in vial eflornithine (C) injection, 200 mg (hydro- cyclophosphamide (2) tablet, 25 mg chloride)/ml in 100 ml bottles powder for injection, 500 mg in vial (b) AMERICAN TRYPANOSOMIASIS benznidazole (7) tablet, 100 mg cytarabine (2) powder for injection, 100 mg in vial nifurtimox (2, 8) tablet, 30 mg, 120 mg, 250 mg dacarbazine (2) powder for injection, 6.5 INSECT REPELLENTS 100 mg in vial diethyltoluamide topical solution, 50%, 75% dactinomycin (2) powder for injection, 500 µg in vial *doxorubicin (2) powder for injection, 10 mg, Section 7: Antimigraine Drugs 50 mg (hydrochloride) in vial

7.1 FOR TREATMENT OF ACUTE ATTACK etoposide (2) capsule, 100 mg acetylsalicylic acid tablet, 300 - 500 mg injection, 20 mg/ml in 5-ml ampoule ergotamine (7) tablet, 1 mg (tartrate) fluorouracil (2) injection, 50 mg/ml in 5-ml ampoule paracetamol tablet, 300 - 500 mg levamisole (2) tablet, 50 mg 7.2 FOR PROPHYLAXIS (as hydrochloride) *propranolol tablet, 20 mg, 40 mg (hydrochloride) mercaptopurine (2) tablet, 50 mg methotrexate (2) tablet, 2.5 mg (as sodium salt) powder for injection, 50 mg Section 8: Antineoplastics, (as sodium salt) in vial Immunosuppressives and Drugs procarbazine capsule, 50 mg (as hydrochloride) Used in Palliative Care vinblastine (2) powder for injection, 10 mg (sulfate) in vial 8.1 IMMUNOSUPPRESSIVE DRUGS vincristine (2) powder for injection, *azathioprine (2) tablet, 50 mg 1 mg, 5 mg (sulfate) in vial powder for injection, 100 mg (as sodium salt) in vial

* Example of a therapeutic group. Various drugs can serve as alternatives. 2 For use only in combination with chloroquine. 3 For organ transplantation.

227 Essential Drugs WHO Drug Information Vol. 9, No. 4, 1995

8.3 HORMONES AND ANTIHORMONES heparin sodium injection, 1000 IU/ml, 5000 lU/ml, 20 000 lU/ml *prednisolone tablet, 5 mg in 1-ml ampoule powder for injection, 20 mg, phytomenadione injection, 10 mg/ml 25 mg, (as sodium phosphate or in 5-ml ampoule sodium succinate) in vial tablet, 10 mg tamoxifen tablet, 10 mg, 20 mg (as citrate) protamine sulfate injection, 10 mg/ml 8.4 DRUGS USED IN PALLIATIVE CARE in 5-ml ampoule The Committee recommended that all the drugs *warfarin (2, 6) tablet, 1, 2 and 5 mg mentioned in the WHO publication Cancer Pain Relief (sodium salt) be considered essential. The drugs are included in the relevant section of the model list, according to their therapeutic use, e.g. analgesics. Section 11 : Blood Products and Plasma Substitutes Section 9: Antiparkinsonism Drugs 11.1 PLASMA SUBSTITUTES

*biperiden tablet, 2 mg (hydrochloride) *dextran 70 injectable solution, 6% injection, 5 mg (lactate) *polygeline injectable solution, 3.5% in 1-ml ampoule 5 levodopa + tablet, 100 mg + 10 mg, 11.2 PLASMA FRACTIONS FOR SPECIFIC USE *carbidopa (5, 6) 250 mg + 25 mg *albumin, human (2, 8) injectable solution, 5%, 25%

Complementary drugs Section 10: Blood, Drugs *factor VIII concentrate (C) (2, 8) (dried) affecting the *factor IX complex (coagulation (dried) factors II, VII, IX, X) concentrate (C) (2, 8) 10.1 ANTIANAEMIA DRUGS ferrous salt tablet, equivalent to 60 mg iron Section 12: Cardiovascular Drugs oral solution, equivalent to 12.1 ANTIANGINAL DRUGS 25 mg iron (as sulfate)/1 ml *atenolol tablet, 50 mg, 100 mg ferrous salt + folic acid 4 tablet, 60 mg + 250 µg glyceryl trinitrate tablet (sublingual), 500 µg folic acid (2) tablet, 1 mg, 5 mg injection, 1 mg (as sodium salt) * tablet (sublingual), 5 mg in 1-ml ampoule *verapamil (10) tablet, 40 mg, 80 mg hydroxocobalamin (2) injection, 1 mg (hydrochloride) in 1-ml ampoule Complementary drug 72.2 ANTIDYSRHYTHMIC DRUGS *iron dextran (B) (5) injection, equivalent *atenolol tablet, 50 mg, 100 mg to 50 mg iron/ml in 2-ml ampoule lidocaine injection, 20 mg 10.2 DRUGS AFFECTING COAGULATION (hydrochloride)/ml in 5-ml ampoule desmopressin (8) injection, 4 µg (acetate)/ml verapamil (8) (10) tablet, 40 mg, in 1-ml ampoule 80 mg (hydrochloride) nasal spray 10 µg (acetate)/ injection, 2.5 mg (hydrochloride)/ml metered dose in 2-ml ampoule

* Example of a therapeutic group. Various drugs can serve as alternatives. 4 Nutritional supplement for use during pregnancy. 5 All plasma fractions should comply with the WHO requirements for the collection, processing and quality control of blood, blood components, and plasma derivatives (Revised 1992). In: WHO Technical Report Series, No. 840, 1994, Annex 2.

228 WHO Drug Information Vol. 9, No. 4, 1995 Essential Drugs

Complementary drug Section 13: isoprenaline (C) injection 1 mg (hydrochloride)/ml Dermatological Drugs (topical) *procainamide (B) tablet, 250 mg, 13.1 ANTIFUNGAL DRUGS 500 mg (hydrochloride) benzoic acid + salicylic acid ointment or injection, 100 mg (hydrochloride)/ml in 10-ml ampoule cream, 6% + 3% *miconazole ointment or cream, 2% (nitrate) *quinidine (A) (7) tablet, 200 mg (sulfate) sodium thiosulfate solution, 15% 12.3 ANTIHYPERTENSIVE DRUGS Complementary drug *atenolol (B) tablet, 50 mg, 100 mg selenium sulfide (C) detergent-based suspension, 2% *captopril (B) scored tablet, 25 mg 73.2 ANTI-INFECTIVE DRUGS *hydralazine tablet, 25 mg, 50 mg (hydrochloride) *methylrosanilinium chloride aqueous solution, 0.5% powder for injection, 20 mg (gentian violet) tincture, 0.5% (hydrochloride) in ampoule potassium permanganate aqueous solution, 1:10 000 *hydrochlorothiazide scored tablet, 25 mg neomycin +/- *bacitracin ointment, *nifedipine (10) capsule or tablet, 10 mg 5 mg neomycin sulfate + 500 IU bacitracin zinc/g Complementary drugs silver sulfadiazine cream, 1%, in 500-g container doxazosin mesilate (B) tablet, 1 mg, 2 mg, 4 mg methyldopa (B) (7) tablet, 250 mg 13.3 ANTI-INFLAMMATORY AND ANTIPRURITIC DRUGS *reserpine (A) tablet, 100 µg, 250 µg *betamethasone (3) ointment or cream, injection, 1 mg in 1-ml ampoule 0.1% (as valerate) *sodium nitroprusside powder for preparing *calamine lotion lotion (C) (2, 8) infusion, 50 mg in ampoule *hydrocortisone ointment or cream, 1 % (acetate) 12.4 CARDIAC GLYCOSIDES 13.4 ASTRINGENT DRUGS digoxin (4) tablet, 62.5 µg, 250 µg aluminium diacetate solution, 13% for dilution oral solution, 50 (µg/ml injection, 250 µg/ml in 2-ml ampoule 13.5 KERATOPLASTIC AND KERATOLYTIC AGENTS Complementary drug benzoyl peroxide lotion or cream, 5% digitoxin (B) (6) tablet, 50 µg, 100 µg coal tar solution, 5% injection, 200 µg in 1-ml ampoule dithranol ointment, 0.1 -2% 12.5 DRUGS USED IN VASCULAR SHOCK fluorouracil ointment, 5% dopamine injection, 40 mg *podophyllum resin (7) solution, 10 - 25% (hydrochloride)/ml in 5-ml vial salicylic acid solution, topical 5% 12.6 ANTITHROMBOTIC DRUGS urea ointment or cream, 10% acetylsalicylic acid tablet. 100 mg 13.6 SCABICIDES AND PEDICULICIDES Complementary drug benzyl benzoate lotion, 25% streptokinase (C) powder for injection, 100 000 IU, 750 000 IU in vial permethrin cream, 1%, 5%

* Example of a therapeutic group. Various drugs can serve as alternatives.

229 Essential Drugs WHO Drug Information Vol. 9, No. 4, 1995

13.7 ULTRAVIOLET BLOCKING AGENTS *hydrochlorothiazide tablet, 25 mg, 50 mg Complementary drugs Complementary drugs *benzophenones, SPF 15(C) cream, lotion or gel *mannitol (C) injectable solution, 10%, 20% *zinc oxide (C) cream, ointment spironolactone (C) tablet, 25 mg

Section 14: Diagnostic Agents Section 17: Gastrointestinal Drugs

14.1 OPHTHALMIC DRUGS 17.1 ANTACIDS AND OTHER ANTIULCER fluorescein eye drops, 1% (sodium salt) DRUGS *tropicamide eye drops, 0.5% aluminium hydroxide tablet, 500 mg oral suspension, 320 mg/5 ml 14.2 RADIOCONTRAST MEDIA *cimetidine tablet, 200 mg *amidotrizoate injection, 140 - 420 mg iodine (as sodium or meglumine injection, 200 mg in 2-ml ampoule salts)/ml in 20-ml ampoule magnesium hydroxide oral suspension, 550 mg barium sulfate aqueous suspension magnesium oxide/10 ml *iopanoic acid tablet, 500 mg 17.2 ANTIEMETIC DRUGS *propyliodone oily suspension, 500-600 mg/ml in 20-ml ampoule 6 metoclopramide tablet, 10 mg (as hydrochloride) injection, 5 mg (as hydrochloride)/ml Complementary drug in 2-ml ampoule *meglumine iotroxate (C) solution, 5 - 8 g iodine *promethazine tablet, 10 mg, in 100-250 ml 25 mg (hydrochloride) elixir or syrup, 5 mg Section 15: (hydrochloride)/5 ml Disinfectants and Antiseptics injection, 25 mg (hydrochloride)/ml in 2-ml ampoule 15.1 ANTISEPTICS *chlorhexidine solution, 5% (digluconate) 17.3 ANTIHAEMORRHOIDAL DRUGS concentrate for dilution *local anaesthetic, astringent ointment hydrogen peroxide solution, 3% and anti-inflammatory drug or suppository *polyvidone iodine solution, 10% 17.4 ANTI-INFLAMMATORY DRUGS 15.2 DISINFECTANTS hydrocortisone suppositories, 25 mg (acetate) *calcium hypochlorite powder for solution *sulfasalazine (2) tablet, 500 mg glutaral solution, 2% 17.5 ANTISPASMODIC DRUGS solution *phenolic *atropine tablet, 1 mg (sulfate) injection, 1 mg (sulfate) Section 16: Diuretics in 1-ml ampoule 17.6 CATHARTIC DRUGS *amiloride (4, 7, 8) tablet, 5 mg (hydrochloride) *senna tablet, 7.5 mg (sennosides) *furosemide tablet, 40 mg (or traditional dosage forms) injection, 10 mg/ml in 2-ml ampoule

* Example of a therapeutic group. Various drugs can serve as alternatives. 6 This suspension is for administration only into the bronchial tree.

230 WHO Drug Information Vol. 9, No. 4, 1995 Essential Drugs

17.7 DIARRHOEA, DRUGS USED IN Complementary drugs medroxy­ depot injection 17.7.1 ORAL REHYDRATION progesterone 150 mg/ml in 1-ml, oral rehydration salts (for glucose/ acetate (B) (7, 8) 50 mg/ml in 1-ml vial electrolyte solution) powder, 27.9 g/l *levonorgestrel (B) tablet 30 µg Components to reconstitute 1 litre of g/l norethisterone oily solution, 200 mg/ml in glucose/electrolyte solution: enantate (B) (7, 8) 1-ml ampoule

sodium chloride 3.5 *ethinylestradiol + 50 µg + 250 µg (pack of four) trisodium citrate dihydrate 7 2.9 *levonorgestrel (C) potassium chloride 1.5 glucose 20.0 18.3.2 INTRAUTERINE DEVICES copper-containing device

17.7.2 ANTIDIARRHOEAL (SYMPTOMATIC) 18.3.3 BARRIER METHODS DRUGS condoms with or without spermicide (nonoxinol) *codeine (1a) tablet, 30 mg (phosphate) diaphragms with spermicide (non.oxinol)

Section 18: Hormones, other Endo­ 18.4 ESTROGENS crine Drugs and Contraceptives *ethinylestradiol tablet, 50 µg, 10 µg

18.1 ADRENAL HORMONES AND 18.5 AND OTHER ANTIDIABETIC SYNTHETIC SUBSTITUTES AGENTS *dexamethasone tablet, 500 µg, 4 mg insulin injection (soluble) injection, 40 lU/ml in 10-ml vial, injection, 4 mg (as sodium 80 lU/ml in 10-ml vial, phosphate) in 1-ml ampoule 100 IU/ml in 10-ml vial hydrocortisone powder for injection, 100 mg intermediate-acting insulin injection, (as sodium succinate) in vial 40 IU/ml in 10-ml vial, *prednisolone tablet, 1 mg, 5 mg 80 lU/ml in 10-ml vial, 100 IU/ml in 10-ml vial Complementary drug (as compound insulin zinc suspension or isophane insulin) fludrocortisone (C) tablet, 100 µg (acetate) *tolbutamide tablet, 500 mg 18.2 ANDROGENS Complementary drug 18.6 OVULATION INDUCERS *clomifene (2, 8) tablet, 50 mg (citrate) (C) (2) injection, 200 mg (enantate) in 1-ml ampoule 18.7 PROGESTOGENS 18.3 CONTRACEPTIVES norethisterone tablet, 5 mg 18.3.1 HORMONAL CONTRACEPTIVES Complementary drug *ethinylestradiol + tablet, 30 µg + 150 µg, medroxyprogesterone acetate (B) tablet, 5 mg *levonorgestrel 30 µg + 250 µg *ethinylestradiol + tablet, 35 µg + 1.0 mg *norethisterone

* Example of a therapeutic group. Various drugs can serve as alternatives. 7 Trisodium citrate dihydrate may be replaced by sodium bicarbonate (sodium hydrogen carbonate) 2.5 g/litre. However, as the stability of this latter formulation is very poor under tropical conditions, it is only recommended when manufactured for immediate use.

231 Essential Drugs WHO Drug Information Vol. 9, No. 4, 1995

18.8 THYROID HORMONES AND 19.3.2 FOR SPECIFIC GROUPS OF INDIVIDUALS ANTITHYROID DRUGS influenza vaccine injection levothyroxine tablet, 50 µg, 100 µg meningococcal vaccine injection (sodium salt) rabies vaccine injection (in cell culture) potassium iodide tablet, 60 mg rubella vaccine injection *propylthiouracil tablet, 50 mg typhoid vaccine injection yellow fever vaccine injection Section 19: Immunologicals 19.1 DIAGNOSTIC AGENTS Section 20: tuberculin,8 injection purified protein derivative (PPD) Muscle Relaxants (peripherally act­ ing) and Cholinesterase Inhibitors 19.2 SERA AND IMMUNOGLOBULINS9 *alcuronium chloride (2) injection, 5 mg/ml anti-D immunoglobulin, injection, 250 µg in in 2-ml ampoule (human) single-dose vial antiscorpion sera injection *neostigmine bromide tablet, 15 mg *antitetanus immunoglobulin, injection, 500 IU injection, 500 µg, 2.5 mg human in vial (metilsulfate) in 1-ml ampoule antivenom serum Injection pyridostigmine bromide (2, 8) tablet, 60 mg injection, 1 mg diphtheria antitoxin injection, 10 000 IU, 20 000 IU in vial in 1-ml ampoule immunoglobulin, suxamethonium (2) injection, 50 mg/ml injection (intramuscular) human normal (2) chloride in 2-ml ampoule immunoglobulin, powder for injection injection (intravenous) human normal (2, 8) Complementary drug *rabies immunoglobulin injection, 150 lU/ml vecuronium bromide (C) powder for injection, 10 mg in vial 19.3 VACCINES 10 19.3.1 FOR UNIVERSAL IMMUNIZATION Section 21 : BCG vaccine (dried) injection Ophthalmological Preparations diphtheria-pertussis-tetanus injection vaccine 21.1 ANTI-INFECTIVE AGENTS diphtheria-tetanus vaccine injection *gentamicin solution (eye drops), 0.3% hepatitis B vaccine injection *idoxuridine solution (eye drops), 0.1% measles-mumps-rubella vaccine injection eye ointment, 0.2% measles vaccine injection silver nitrate solution (eye drops), 1% poliomyelitis vaccine oral solution (live attenuated) *tetracycline eye ointment, 1% (hydrochloride) poliomyelitis vaccine (inactivated) injection 21.2 ANTI-INFLAMMATORY AGENTS tetanus vaccine injection *prednisolone eye drops, 0.5% tetanus-diphtheria (Td) injection

* Example of a therapeutic group. Various drugs can serve as alternatives. 8 All tuberculins should comply with the WHO requirements for tuberculins (Revised 1985). WHO Technical Report Series, No. 745, 1987. Annex 1. 9 All plasma fractions should comply with the WHO requirements for the collection, processing and quality control of blood, blood components and plasma deriviatives (Revised 1992). In: WHO Technical Report Series, No. 840, 1994, Annex 2. 10 All vaccines should comply with the WHO requirements for biological substances.

232 WHO Drug Information Vol. 9, No. 4, 1995 Essential Drugs

21.3 LOCAL ANAESTHETICS *fluphenazine (5) injection, 25 mg (decanoate or enantate) *tetracaine solution (eye drops), 0.5% in 1-ml ampoule (hydrochloride) *haloperidol tablet, 2 mg, 5 mg 21.4 MIOTICS AND ANTIGLAUCOMA DRUGS injection, 5 mg in 1-ml ampoule acetazolamide tablet, 250 mg 24.2 DRUGS USED IN MOOD DISORDERS *pilocarpine solution (eye drops), 2%, 4% (hydrochloride or nitrate) * tablet, 25 mg (hydrochloride) *timolol solution (eye drops), 0.25%, 0.5% lithium carbonate (2, 4) capsule or tablet, 300 mg (maleate) 24.3 DRUGS USED FOR SEDATION AND 21.5 MYDRIATICS GENERALIZED ANXIETY DISORDERS atropine solution (eye drops), *diazepam (1b) scored tablet, 2 mg, 5 mg 0.1%, 0.5%, 1% (sulfate) Complementary drug 24.4 DRUGS USED FOR OBSESSIVE epinephrine (A) solution (eye drops), 2% COMPULSIVE DISORDERS AND (as hydrochloride) PANIC ATTACKS clomipramine capsules, 10 mg, 25 mg Section 22: (hydrochloride) Oxytocics and Antioxytocics Section 25: Drugs Acting on 22.1 OXYTOCICS the Respiratory Tract *ergometrine tablet, 200 µg (hydrogen maleate) injection, 200 µg (hydrogen maleate) 25.1 ANTIASTHMATIC DRUGS in 1-ml ampoule *aminophylline (2) injection, 25 mg/ml oxytocin injection, 10 IU in 1-ml ampoule in 10-ml ampoule

22.2 ANTIOXYTOCICS theophylline (10) tablet, 100 mg, 200 mg *beclometasone inhalation (aerosol), 50 µg *salbutamol (2) tablet, 4 mg (as sulfate) (dipropionate) per dose injection, 50 µg (as sulfate)/ml in 5-ml ampoule *epinephrine injection, 1 mg (as hydrochloride or hydrogen tartrate) in 1 -ml ampoule Section 23: Peritoneal *salbutamol tablet, 2 mg, 4 mg (as sulfate) Dialysis Solution inhalation (aerosol), 100 µg (as sulfate) per dose intraperitoneal dialysis solution parenteral solution (of appropriate composition) syrup, 2 mg (as sulfate)/5 ml injection, 50 µg (as sulfate)/ml in 5-ml ampoule Section 24: respirator solution for use in nebulizers, Psychotherapeutic Drugs 5 mg (as sulfate)/ml Complementary drugs 24.1 DRUGS USED IN PSYCHOTIC DISORDERS *cromoglicic acid (B) inhalation (cartridge), *chlorpromazine tablet, 100 mg (hydrochloride) 20 mg (sodium salt) per dose syrup, 25 mg (hydrochloride)/5 ml 25.2 ANTITUSSIVES injection, 25 mg (hydrochloride)/ml in 2-ml ampoule *codeine (1a) tablet, 10 mg (phosphate)

* Example of a therapeutic group. Various drugs can serve as alternatives.

233 Essential Drugs WHO Drug Information Vol. 9, No. 4, 1995

Section 26: Section 27: Vitamins and Minerals

Solutions correcting Water, Electro¬ ascorbic acid tablet, 50 mg lyte and Acid-base Disturbances *ergocalciferol capsule or tablet, 1.25 mg (50 000 IU) 26.1 ORAL oral solution, oral rehydration salts (for glucose/ see section 250 µg/ml (10 000 IU/ml) electrolyte solution) 17.7.1 potassium chloride powder for solution iodine (8) iodized oil, 1 ml (480 mg iodine), 0.5 ml (240 mg iodine) in 26.2 PARENTERAL ampoule (oral or injectable) *compound solution injectable solution iodized oil, 0.57 ml of sodium lactate (308 mg iodine) in dispenser bottle glucose injectable solution, capsule, 200 mg 5% isotonic, 50% hypertonic *nicotinamide tablet, 50 mg glucose with injectable solution, 4% pyridoxine tablet, 25 mg (hydrochloride) sodium chloride glucose, 0.18% sodium chloride (equivalent to Na+ 30 mmol/l *retinol sugar-coated tablet, 10 000 IU CI- 30 mmol/l ) (as palmitate) (5.5 mg) potassium chloride (2) 11.2% solution in capsule, 200 000 IU (as 20-ml ampoule, (equivalent to palmitate) (110 mg) K+ 1.5 mmol/ml, Cl- 1.5 mmol/ml) oral oily solution, 100 000 lU/ml in multidose sodium chloride injectable solution, 0.9% dispenser (as palmitate) isotonic (equivalent to Na+ 154 mmol/l, CL- 154 mmol/l) water-miscible injection, 100 000 IU (as palmitate) sodium hydrogen injectable solution, 1.4% (55 mg) in 2-ml ampoule carbonate isotonic (equivalent to Na+ 167 - mmol/l, HCO3 167 mmol/l) riboflavin tablet, 5 mg 8.4% solution in 10-ml ampoule *sodium fluoride in any appropriate formulation (equivalent to Na* 1000 mmol/l, thiamine tablet, 50 mg (hydrochloride) HCO3- 1000 mmol/l) Complementary drug 26.3 MISCELLANEOUS calcium gluconate (C), (2, 8) injection, 100 mg/ml water for injection 2-ml, 5-ml, 10-ml ampoules in 10-ml ampoule

The following changes in the WHO Model List were approved by the WHO Expert Committee on the Use of Essential Drugs which met in December 1995. The report of the meeting will be published in the WHO Technical Report Series. Deletions: aminobenzoic acid, indometacin, norethisterone, piperazine, piperacillin, tetracycline (oral)

Additions: artemether levonorgestrel ceftazidime magnesium sulfate ceftriaxone potassium permanganate clonazepam rifampicin + isoniazid + pyrazinamide phenolic urea doxazosin mesilate vancomycin isoniazid + ethambutol

Example of a therapeutic group. Various drugs can serve as alternatives.

234 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

International Nonproprietary Names for Pharmaceutical Substances (INN)

Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances, the names given in the list on the following pages are under consideration by the World Health Organization as Proposed International Nonproprietary Names. The inclusion of a name in the lists of Proposed 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. The statements indicating action and use are based largely on information supplied by the manufacturer. This information is merely meant to provide an indication of the potential use of new substances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors will neither be revised nor included in the Cumulative Lists of INNs.

Dénominations communes internationales des Substances pharmaceutiques (DCI) Il est notifié que, conformément aux dispositions de l'article 3 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques 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. Les mentions indiquant les propriétés et les indications des substances sont fondées sur les renseignements communiqués par le fabricant. Elles ne visent qu'à donner une idée de l'utilisation potentielle des nouvelles substances au moment où elles sont l'objet de propositions de DCI. L'OMS n'est pas en mesure de confirmer ces déclarations ni de faire de commentaires sur l'efficacité du mode d'action ainsi décrit. En raison de leur caractère provisoire, ces informations ne figureront pas dans les listes récapitulatives de DCI.

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI) De conformidad con lo que dispone el párrafo 3 del "Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas", se comunica por el presente anuncio que las denominaciones detalladas en las páginas siguientes están sometidas a estudio por la Organización Mundial de La Salud como Denominaciones Comunes Internacionales Propuestas. La inclusión de una denominación en las listas de las DCI Propuestas 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. Las indicaciones sobre acción y uso que aparecen se basan principalmente en la información facilitada por los fabricantes. Esta información tiene por objeto dar una idea únicamente de las posibilidades de aplicación de las nuevas sustancias a las que se asigna una DCI Propuesta. La OMS no está facultada para respaldar esas indicaciones ni para formular comentarios sobre la eficacia de la acción que se atribuye al producto. Debido a su carácter provisional, esos datos descriptivos no deben incluirse en las listas recapitulativas de DCI.

235 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

Proposed International Nonproprietary Names: List 74 Comments on, or formal objections to, the proposed names may be forwarded by any person to the INN Programme of the World Health Organization within four months of the date of their publication in WHO Drug Information, i.e., for List 74 Proposed INN not later than 30 June 1996.

Dénominations communes internationales proposées: Liste 74 Des observations ou des objections formelles à l'égard des dénominations proposées peuvent être adressées par toute personne au Programme des Dénominations communes internationales de l'Organisation mondiale de la Santé dans un délai de quatre mois à compter de la date de leur publication dans WHO Drug Information, c'est à dire pour la Liste 74 de DCI Proposées le 30 juin 1996 au plus tard.

Denominaciones Comunes Internacionales Propuestas: Lista 74 Cualquier persona puede dirigir observaciones u objeciones respecto de las denominaciones propuestas, al Programa de Denominaciones Comunes Internacionales de la Organización Mundial de la Salud, en un plazo de cuatro meses, contados desde la fecha de su publicación en WHO Drug Information, es decir, para la Lista 74 de DCI Propuestas el 30 de junio de 1996 a más tardar.

Proposed INN Chemical name or description: Action and use: Molecular formula (Latin, English, French, Spanish) Chemical Abstracts Service (CAS)* registry number: Graphic formula

DCI Proposée Nom chimique ou description: Propriétés et indications: Formule brute Numéro dans le registre du CAS*: Formule développée

DCI Propuesta Nombre químico o descripción: Acción y uso: Fórmula empírica Número de registro del CAS*: Fórmula desarrollada

abafunginum abafungin hexahydro-2-[[4-[o-(2,4-xylyloxy)phenyl]-2-thiazolyl]imino]pyrimidine antibacterial, antifungal [4-[2-(2,4-diméthylphénoxy)phényl]thiazol-2-yl](tétrahydropyrimidin- abafungine 2(1 H)-ylidène)amine antibactérien, antifongique hexahidro-2-[[4-[o-(2,4-xililoxi)fenil]-2-tiazolil]imino]pirimidina abafungina antibacteriano, antifúngico

C21H22N4OS 129639-79-8

* Please note that effective September 5, 1995, CAS discontinued the explicit registration of racemates. A compter du 5 septembre 1995 le CAS n'enregistre plus les racémates en tant que tel. A partir de 5 Septiembre, 1995, CAS no registrará las formas racemato. WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

abirateronum 17-(3-pyridyl)androsta-5,16-dien-3β-ol abiraterone antiandrogen 17-(3-pyridyl)androsta-5,16-dién-3β-ol abiratérone antiandrogène 17-(3-piridil)androsta-5,16-dien-3β-ol abiraterona antiandrógeno

C24H31NO 154229-19-3

acidum ranelicum 5-[bis(carboxymethyl)amino]-2-carboxy-4-cyano-3-thiopheneacetic acid ranelic acid calcium regulator (for strontium salt) acide [5-carboxy-4-(carboxyméthyl)-3-cyano-2-thiényl]iminodiacétique acide ranélique régulateur calcique (pour le sel de strontium) àcido 5-[bis(carboximetil)amino]-2-carboxi-4-cìano-3-tiofenoacético ácido ranélico regulador del calcio (para la sal de estróntio)

C12H10N2O8S 135459-87-9

alinastinum alinastine 2-[1 -(p-tert-butylphenethyl)-4-piperidyl]-1 -(2-ethoxyethyl)benzimidazole antihistaminic, antiallergic alinastine 2-[1-[2-[4-(1,1-diméthyléthyl)phényl]éthyl]pipéridin-4-yl]-1-(2-éthoxyéthyl)- 1 H-benzimidazole antihistaminique, antiallergique alinastina 2-[1-(p-terc-butilfenetil)-4-piperidil]-1-(2-etoxietil)benzimidazol antihistamínico, antialérgico

237 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

C28H39N3O 154541-72-7

almurtidum almurtide 2-acetamido-3-O[[[(1 S)-1 -[[(1 R)-1-carbamoyl-3-carboxypropyl]carbamoyl] = ethyl]carbamoyl]metrtyl]-2-deoxy-D-glucopyranose immunostimulant almurtide acide (4R)-5-amino-4-[[(2S)-2-[[2-[[2-(acétylamino)-2-désoxy- D-glucopyranos-3-yl]oxy]acétyl]amino]propanoyl]amino]-5-oxopentanoïque immunostimulant almurtida 2-acetamido-3-O[[[(1 S)-1 -[[(1 R)-1 -carbamoil-3-carboxipropil]carbamoil]etil]= carbamoil]metil]-2-desoxi-D-glucopiranosa inmunoestimulante

C18H30N4O11 61136-12-7

amelometasonum amelometasone (+)-9-fluoro-11β,17-dihydroxy-21-methoxy-16β-methylpregna-1,4-diene- 3,20-dione 17-propionate corticosteroid amélométasone (+)-17-propanoate de 9-fluoro-11β,17-dihydroxy-21-méthoxy- 16β-méthylprégna-1,4-diène-3,20-dione corticostéroïde amelometasona 17-propionato de (+)-9-fluoro-11 β,17-dihidroxi-21-metoxi-16β-metilpregna- 1,4-dien-3,20-diona corticosteroide

238 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

C26H35FO6 123013-22-9

apadolinum apadoline (+)-10-[1-methyl-2-(1-pyrrolidinyl)ethyl]-N-propylphenothiazine- 2-carboxamide analgesic apadoline (+)-10-[(1R)-1-métriyl-2-(pyrrolidin-1-yl)éthyl]-N-propyl-10H-phénothiazine- 2-carboxamide analgésique apadolina (+)-10-[1-metil-2-(1-pirrolidinil)etil]-N-propilfenotiazina-2-carboxamida analgésico

C23H29N3OS 135003-30-4

arcitumomabum arcitumomab immunoglobulin G 1 (mouse monoclonal IMMU-4 Fab' fragment γ-chain anti- human antigen CEA), disulfide with mouse monoclonal IMMU-4 light chain diagnostic agent arcitumomab immunoglobuline G 1 (chaîne γ du fragment Fab' de l'anticorps monoclonal de souris IMMU-4 anti-antigène CEA humain), disulfure avec la chaîne légère de l'anticorps monoclonal de souris IMMU-4 produit à usage diagnostique arcitumomab inmunoglobulina G 1 (cadena y del fragmento Fab' del anticuerpo mono­ clonal de ratón IMMU-4 anti-antigeno CEA humano) disulfuro con la cadena ligera del anticuerpo monoclonal de ratón IMMU-4 agente de diagnóstico 154361-48-5

239 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

asimadolinum asimadoline N-[(aS)-a-[[(3S)-3-hydroxy-1-pyrrolidinyl]methyl]benzyl]-N-methyl- 2,2-diphenylacetamide analgesic asimadoline N-[(1 S)-2-[(3S)-3-hydroxypyrrolidin-1 -yl]-1 -phényléthyl]-N-méthyl- 2,2-diphénylacétamide analgésique asimadolina N-[(aS)-a-[[(3S)-3-hidroxi-1-pirrolidinil]metil]bencil]-N-metil- 2,2-difenilacetamida analgésico

C27H30N2O2 153205-46-0

atizoramum atizoram tetrahydro-5-[4-methoxy-3-[(1S,2S,4R)-2-norbornyloxy]phenyl]- 2(1 H)-pyrimidinone antipsoriatic atizoram 5-[3-[[(1S,2S,4R)-bicyclo[2.2.1]hept-2-yl]oxy]-4-méthoxyphényl]= tétrahydropyrimidin-2(1 H)-one antipsoriasique atizoram tetrahidro-5-[4-metoxi-3-[(1S,2S,4R)-2-norborniloxi]fenil]-2(1H)-pirimidinona antipsoriásico

C18H24N2O3 135637-46-6

atliprofenum (±)-p-3-thienylhydratropic acid atliprofen non-steroidal anti-inflammatory acide (RS)-2-[4-(3-thiényl)phényl]propanoïque atliprofène anti-inflammatoire non stéroïdien ácido (±)-p-3-tienilhidratropico atliprofeno antiinflamatorio no esteroideo

240 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

C13H12O2S

and enantiomer et énantiomère y enantiómero

avorelinum avorelin 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-2-methyl-D-tryptophyl- L-leucyl-L-arginyl-N-ethyl-L-prolinamide luteinizing hormone-releasing-hormone (LHRH) agonist avoréline (5-oxo-L-prolyl)-L-histidyl-L-tryptophyl-L-séryl-L-tyrosyl-(2-méthyl-D-tryptophyl)- L-leucyl-L-arginyl-(N-éthyl-L-prolinamtde) agoniste de l'hormone de libération de la lutéostimuline avorelina 5-oxo-L-prolil-L-histidil-L-triptofil-L-seril-L-tirosil-2-metil-o-triptofil-L-leucil- L-arginil-N-etil-L-prolinamida agonista de la hormona de liberación de hormona luteinizante

C65H85N17O12 140703-49-7

becaplerminum recombinant human platelet-derived B platelet derived growth factor bécaplermine facteur de croissance B d'origine plaquettaire humain obtenu par génie génétique facteur de croissance d'origine plaquettaire becaplermina factor B de crecimiento derivado de plaquetas (humano recombinante) factor de crecimiento derivado de plaquetas

165101-51-9

241 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

cariporidum N-(diaminomethylene)-4-isopropyl-3-(methylsulfonyl)benzamide + + cariporide Na /H antiport inhibitor N-(diarninométhylène)-4-(1-méthyléthyl)-3-(méthylsulfonyl)benzamide + + cariporide inhibiteur de l'échange Na /H N-(diaminometilen)-4-isopropil-3-(metilsulfonil)benzamida + + cariporida inhibidor del transporte activo Na /H

C12H17N3O3S 159138-80-4

cerivastatinum cerivastatin (3R,5S,6E)-7-[4-(p-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)- 3-pyridyl]-3,5-dihydroxy-6-heptenoic acid antihyperlipidaemic cérivastatine acide (6E)-(3R,5S)-7-[4-(4-fluorophényl)-5-(méthoxyméthyl)- 2,6-bis(1-méthyléthyl)-3-pyridyl]-3,5-dihydroxyhept-6-énoïque antihyperlipidémiant cerivastatina ácido (3R,5S,6E)-7-[4-(p-fluorofenil)-2,6-diisopropil-5-(metoximetil)- 3-piridil]-3,5-dihidroxi-6-heptenoico antihiperlipémico

C26H34FNO5 145599-86-6

ceterminum cetermin transforming growth factor β2 (human) transforming growth factor cétermine facteur de croissance "transformant" β2 (humain) facteur de croissance "transformant"

242 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

cetermina factor de crecimiento transformador β2 (humano) factor de crecimiento transformador

C1132H1716N298O330S20 157238-32-9

ciaftalanum zincum (SP-4-1)-[phthalocyaninato(2-)-N29, N30, N31, N32]zinc ciaftalan zinc photosensitizing agent (SP-4-1)-[29H,31H-phtalocyaninato(2-)-N29,N30,N31,N32]zinc ciaftalane zinc photosensibilisant (SP-4-1)-[ftalocianinato(2-)-N29, N30, N31, N32]zinc ciaftalan zinc agente fotosensibilizante

C32H16N8Zn 14320-04-8

dabelotinum (±)-1,2,3,4-tetrahydro-1-methyl-8-(2-morpholinylmethoxy)quinoline dabelotine nootropic agent (±)-1-méthyl-8[(2RS)-morpholin-2-yl]méthoxy]-1,2,3,4-tétrahydroquinoléine dabélotine nootrope (±)-1,2,3,4-tetrahidro-1-metil-8-(2-morfolinilmetoxi)quinolina dabelotina nootrópico

243 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

C15H22N2O2 118976-38-8

and enantiomer et énantiomère y enantiómero

danaparoidum natricum danaparoid sodium mixture of: mucopolysaccarides derived from hog intestinal mucosa consisting of sodium salts of heparan sulfate (major component), dermatan sulfate, and chondroitin sulfate antithrombotic danaparoïde sodique mélange de: mucopolysaccharides extraits de la muqueuse intestinale de porc, constitué par les sels de sodium du sulfate d'héparan (principal composant), du sulfate de dermatan et du sulfate de chondroïtine antithrombotique danaparoide sódico mezcla de: mucopolisacaridos de mucosa intestinal de cerdo consistentes en sales sodicas de haparan sulfato (componente principal), dermatan sulfato y condroitin sulfato) antitrombótico

dapitantum dapitant (3aS,4S,7aS)-hexahydro-2-[(αS)-o-methoxyhydratropoyl]- 4-(omethoxyphenyl)-7,7-diphenyl-4-isoindolinol tachykinin receptor antagonist dapitant (3aS,4S,7aS)-4-hydroxy-4-(2-méthoxyphényl)-2-[(2S)-2-(2-méthoxyphényl)= propanoyl]-7,7-diphényloctahydro-1H-isoindole antagoniste de récepteurs de la tachykinine dapitant (3aS,4S,7aS)-hexahidro-2-[(αS)-o-metoxihidratropoil]-4-(o-rnetoxifenil)- 7,7-difenil-4-isoindolinol antagonista del receptor de taquiquinina

C37H39NO4 153438-49-4

244 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

dexsotalolum dexsotalol (+)-(S)-4'-[1-hydroxy-2-(isopropylamino)ethyl]methanesulfonanilide antiarrhythmic dexsotalol (+)-N-[4-[(1S)-1-hydroxy-2-[(1-méthyléthyl)amino]éthyl]phényl]= méthanesulfonamide antiarythmique dexsotalol (+)-(S)-4'-[1-hidroxi-2-(isopropilamino)etil]metanosulfonanilida antiarrítmico

C12H20N2O3S 30236-32-9

droxinavirum droxinavir 3-tert-butyl-1-[(2R,3S)-3-[(2S)-3,3-dimethyl-2-[2-(methylamino)acetamido]= butyramido]-2-hydroxy-4-phenylbutyl]-1-isopentylurea antiviral droxinavir 3-(1,1-diméthyléthyl)-1-[(2R,3S)-3-[[(2S)-3,3-diméthyl-2-[[(méthylamino)= acétyl]amino]butanoyl]amino]-2-hydroxy-4-phénylbutyl]-1-(3-méthylbutyl)urée antiviral droxinavir 3-terc-butil-1-[(2R,3S)-3-[(2S)-3,3-dimetil-2-[2-(metilamino)acetamido]= butiramido]-2-hidroxi-4-fenilbutil]-1-isopentilurea antiviral

C29H51N5O4 159910-86-8

245 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

edaravonum 3-methyl-1-phenyl-2-pyrazolin-5-one edaravone free radical scavenger 5-méthyl-2-phényl-2,4-dihydro-3H-pyrazol-3-one édaravone piégeur de radicaux libres 3-metil-1-fenil-2-pirazolin-5-ona edaravona secuestrador de radicales libres

C10H10N2O 89-25-8

edrecolomabum edrecolomab immunoglobulin G 2a (mouse monoclonal 17-1A γ-chain anti-human colon cancer tumor-associated antigen), disulfide with mouse monoclonal 17-1A light chain, dimer immunomodulator édrécolomab immunoglobulin G 2a (chaîne γ de l'anticorps monoclonal de souris 17-1A anti-antigène tumoral associé au cancer du colon humain), dimère du disulfure avec la chaîne légère de l'anticorps monoclonal de souris 17-1A immunomodulateur edrecolomab inmunoglobulina G 2a (cadena y del anticuerpo monoclonal de ratón 17-1A anti-antigeno tumoral asociado al cáncer de colon humano), dimero del disulfuro con la cadena ligera del anticuerpo monoclonal de ratón 17-1A inmunomodulador 156586-89-9

eletriptanum 3-[[(R)-1-methyl-2-pyrrolidinyl]methyl]-5-[2-(phenylsulfonyl)ethyl]indole eletriptan antimigraine, serotonin receptor agonist 3-[(2R)-(1-méthylpyrrolidin-2-yl)méthyl]-5-[2-(phénylsulfonyl)éthyl]-1H-indole élétriptan antimigraineux, agoniste de récepteurs de la sérotonine 3-[[(R)-1-metil-2-pirrolidinil]metil]-5-[2-(fenilsulfonil)etil]indol eletriptán antimigrañoso, agonista de los receptores de la serotonina

C22H26N2O2S 143322-58-1

246 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

emoctakinum interleukin 8 (human) emoctakin immunomodulator interleukin 8 humaine émoctakine immunomodulateur interleuquina 8 humana producida por ingenieria genetica emoctakin inmunomodulador

C372H600N106O106S4 142298-00-8

fabesetronum fabesetron (+)-(R)-8,9-dihydro-10-methyl-7-[(5-methylimidazol-4-yl)methyl]pyrido= [1,2-a]indol-6(7H)-one serotonin receptor antagonist fabésétron (+)-(7R)-10-méthyl-7-[(5-méthyl-1 H-imidazol-4-yl)méthyl]- 8,9-dihydropyrido[1,2-a]indol-6(7H)-one antagoniste de récepteurs de la sérotonine fabesetron (+)-(R)-8,9-dihidro-10-metil-7-[(5-metilimidazol-4-il)metil]pirido= [1,2-a]indol-6(7H)-ona antagonista de los receptores de la serotonina

C18H19N3O 129300-27-2

fasidotrilum fasidotril N-[(S)-α-(mercaptomethyl)-3,4-(methylenedioxy)hydrocinnamoyl]-L-alanine, benzyl ester, acetate (ester) antihypertensive fasidotril (2S)-2-[[(2S)-2-[(acétylsulfanyl)méthyl]-3-(1,3-benzodioxol- 5-yl)propanoyl]amino]propanoate de benzyle antihypertenseur fasidotril N-[(S)-α-(mercaptometil)-3,4-(metilenodioxi)hidrocinamoil]-L-alanina, éster bencílico, acetato (éster) antihipertensivo

247 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

C23H25NO6S 135038-57-2

fexofenadinum fexofenadine (±)-p-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidino]butyl]- α-methylhydratropic acid antihistaminic fexofénadine acide 2-[4-[(1RS)-1-hydroxy-4-[4-(hydroxydiphénylméthyl)pipéridin- 1-yl]butyl]phényl]-2-méthylpropanoïque antihistaminique fexofenadina ácido (±)-p-[1-hidroxi-4-[4-(hidroxidifenilmetil)piperidino]butil]- α-metilhidratropico antihistamínico

C32H39NO4 138452-21-8

and enanliomer et l'énantiomère y enantiómero

forasartanum forasartan 5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-(o-1H-tetrazol- 5-ylphenyl)pyridine angiotensin II receptor antagonist forasartan 5-[(3,5-dibutyl-1 H-1,2,4-triazol-1 -yl)méthyl]-2-[2-(1 H-tétrazol- 5-yl)phényl]pyridine antagoniste du récepteur de l'angiotensine II forasartan 5-[(3,5-dibutil-1H-1,2,4-triazol-1-il)metil]-2-(o-1H-tetrazol-5-ilfenil)piridine antagonista del receptor de angiotensina II

248 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

C23H28N8 145216-43-9

furominum furomine 4,4'-[ethylenebis(iminomethylidyne)]bis[dihydro-2,2,5,5-tetramethyl- 3(2H)-furanone] diagnostic agent furomine 4,4'-[éthylènebis(iminométhylidyne)]bis[2,2,5,5-tétraméthyl-4,5-dihydrofuran- 3(2H)-one] produit à usage diagnostique furomina 4,4'-[etilenbis(iminometilidino)]bis[dihidro-2,2,5,5-tetrametil-3(2H)-furanona] agente de diagnóstico

C20H32N2O4 142996-66-5

gatifloxacinum gatifloxacin (±)-1 -cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1 -piperazinyl)- 4-oxo-3-quinolinecarboxylic acid antibacterial gatifloxacine acide 1 -cyclopropyl-6-fluoro-8-méthoxy-7-[(3RS)-3-méthylpipérazin-1 -yl]- 4-oxo-1,4-dihydroquinoléine-3-carboxylique antibactérien gatifloxacino ácido (±)-1 -ciclopropil-6-fluoro-1,4-dihidro-8-metoxi-7-(3-metil-1 -piperazinil)- 4-oxo-3-quinolinacarboxílico antibacteriano

C19H22FN3O4 160738-57-8

and enantiomer et l'énantiomère y el enantiómero

249 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

glaspimodum glaspimod N2,N2'-[(2S,7S)-2,7-bis[(2S)-3-carboxy-2-[(2S)-4-carboxy-2-[(2S)-5-oxo- 2-pyrrolidinecarboxamido]butyramido]propionamido]octanedioyl]di-L-lysine immunomodulator glaspimod N2,N2'-[(2S,7S)-2,7-bis[[(5-oxo-L-prolyl)-L-glutamyl-L-aspartyl]amino]= octanedioyl]di-L-lysine immunomodulateur glaspimod N2,N2'-[(2S,7S)-2,7-bis[(2S)-3-carboxi-2-[(2S)-4-carboxi-2-[(2S)-5-oxo- 2-pirrolidinacarboxamido]butiramido]propionamido]octanodioil]di-L-lisina inmunomodulador

C48H74N12O22 134143-28-5

igovomabum igovomab immunoglobulin G 1 (mouse monoclonal OC125 F(ab')2 fragment anti- human ovarian cancer antigen CA 125), disulfide with mouse monoclonal OC125 F(ab')2 light chain diagnostic agent igovomab fragment F(ab')2 de l'anticorps monoclonal OC 125 anti-antigène CA 125 associé à certaines tumeurs ovariennes produit à usage diagnostique igovomab fragmento F(ab')2 del anticuerpo monoclonal OC 125 anti-antígeno CA 125 asociado a ciertos tumores ováricos agente de diagnóstico

indinavirum indinavir (αR,γS,2S)-α-benzyl-2-(tert-butylcarbamoyl)-γ-hydroxy-N-[(1S,2R)- 2-hydroxy-1-indanyl]-4-(3-pyridylmethyl)-1-piperazinevaleramide antiviral indinavir (2R,4S)-2-benzyl-5-[(2S)-2-[(1,1-diméthyléthyl)carbamoyl]-4-(3-pyridyl= méthyl)pipérazin-1-yl]-4-hydroxy-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-indén- 1-yl]pentanamide antiviral

250 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

indinavir (αR,γS,2S)-α-bencil-2-(terc-butilcarbamoil)-γ-hidroxi-N-[(1S,2R)-2-hidroxi- 1 -indanil]-4-(3-piridilmetil)-1 -piperazinavaleramida antiviral

C36H47N5O4 150378-17-9

iroplactum N-L-methionylblood platelet factor 4 (human subunit) immunomodulator iroplact N-L-méthionylfacteur plaquétaire 4 sanguin (sous-unité humaine) immunomodulateur iroplact N-L-metionilfactor plaquetario 4 (subunidad humana) iroplact inmunomodulador

C346H585N97O102S5 154248-96-1

levobupivacainum (S)-1-butyl-2',6'-pipecoloxylidide levobupivacaine anaesthetic (2S)-1-butyl-N-(2,6-diméthylphényl)pipéridine-2-carboxamide anesthésique lévobupivacaïne (S)-1-butil-2',6'-pipecoloxilidida levobupivacaina anestésico

251 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

C18H28N2O 27262-47-1

linetastinum linetastine (2E,4E)-N-[2-[4-(diphenylmethoxy)piperidino]ethyl]-5-(4-hydroxy- 3-methoxyphenyl)-2,4-pentadienamide ethyl carbonate (ester) antiallergic linétastine carbonate de 4-[(1E,3E)-5-[[2-[4-(diphénylméthoxy)pipéridin- 1-yl]éthyl]amino]-5-oxopenta-1,3-diényl]-2-méthoxyphényle et d'éthyle antiallergique linetastina etilcarbonato de (2E,4E)-N-[2-[4-(difenilmetoxi)piperidino]etil]-5-(4-hidroxi- 3-metoxifenil)-2,4-pentadienamida. antialérgico

C35H40N2O6 159776-68-8

lintitriptum 2-[[4-(o-chlorophenyl)-2-thiazolyl]carbamoyl]indole-1-acetic acid lintitript cholecystokinin receptor antagonist acide 2-[2-[[4-(2-chlorophényl)thiazol-2-yl]carbamoyl]-1 H-indol-1 -yl]acétique lintitript antagoniste du récepteur de la cholécystokinine ácido 2-[[4-(o-clorofenil)-2-tiazolil]carbamoil]indol-1-acético lintitript antagonista del receptor de la colecistoquinina

C20H14CIN3O3S 136381-85-6

252 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

lirexapridum lirexapride 4-amino-5-chloro-α-cyclopropyl-N-[(1R,2R)-2-[(4-methylpiperidino)methyl]= cyciohexyl]-o-anisamide serotonin receptor agonist lirexapride 4-amino-5-chloro-2-(cyclopropylméthoxy)-N-[(1R,2R)-2-[(4-méthylpipéridin- 1-yl)méthyl]cyclohexyl]benzamide agoniste de récepteurs de la sérotonine lirexaprida 4-amino-5-cloro-α-ciclopropil-N-[(1R,2R)-2-[(4-metilpiperidino)metil]= ciclohexil]-o-anisamida agonista de los receptores de la serotonina

C24H36CIN3O2 145414-12-6

lurtotecanum lurtotecan (8S)-8-ethyl-2,3-dihydro-8-hydroxy-15-[(4-methyl-1-piperazinyl)methyl]-11H- p-dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H,14H)-dione antineoplastic lurtotécan (8S)-8-éthyl-8-hydroxy-15-[(4-méthylpipérazin-1-yl)méthyl]- 2,3,11,14-tétrahydro-12H-1,4-dioxino[2,3-g]pyrano[3',4':6,7]indolizino= [1,2-b]quinoléin-9,12(8H)-dione antinéoplasique lurtotecán (8S)-8-etil-2,3-dihidro-8-hidroxi-15-[(4-metil-1-piperazinil)metil]-11H- p-dioxino[2,3-g]pirano[3',4':6,7]indolizino[1,2-b]quinolina-9,12(8H,14H)-diona antineoplásico

C28H30N4O6 149882-10-0

253 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

melagatranum melagatran N-[(R)-[[(2S)-2-[(p-amidinobenzyl)carbarnoyl]-1-azetidinyl]carbonyl]= cyclohexylmethyl]glycine thrombin inhibitor mélagatran acide 2-[[(1 R)-2-[(2S)-2-[(4-carbamimidoylbenzyl)carbamoyl]azétidin-1 -yl]- 1-cyclohexyl-2-oxoéthyI]amino]acétique inhibiteur de la thrombine melagatrán N-[(R)-[[(2S)-2-[(p-amidinobencil)carbamoil]-1-azetidinil]carbonil]= ciclohexilmetil]glicina inhibidor de la trombina

C22H31N5O4 159776-70-2

milamelinum 1,2,5,6-tetrahydro-1-methylnicotinaldehyde (E)-O-methyloxime milameline nootropic agent (E)-1 -méthyl-1,2,5,6-tétrahydropyridine-3-carbaldéhyde O-méthyloxime milaméline nootrope 1,2,5,6-tetrahidro-1 -metilnicotinaldehide (E)-O-metiloxima milamelina nootrópico

C8H14N2O 139886-32-1

milodistimum milodistim 23-L-leucine-27-L-aspartic acid-39-L-glutamic acidcolony-stimulating factor 2 (human clone pHG25 protein moiety reduced), (127 9')-protein with 9-glycine-10-glycine-11 -glycine-12-glycine-13-L-serine-14-glycine-15-glycine- 16-glycine-18-glycine-19-L-serine-34-L-aspartic acid-89-L-aspartic acid- 9-152-interleukin 3 (human clone D11 precursor protein moiety reduced) immunomodulator

254 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

milodistim [23-L-leucine-27-acide L-aspartique-39-acide L-glutamique]facteur 2 de stimulation des colonies (clone humain pHG25, partie protéique réduite), (127 9')-protéine avec la [9-glycine-10-glycine-11-glycine-12-glycine-13- L-sérine-14-glycine-15-glycine-16-glycine-18-glycine-19-L-sérine-34-acide L-aspartique-89-acide L-aspartique]-9-152-interleukin 3 (clone humain D11 précurseur de la partie protéique réduite) immunomodulateur milodistim 23-L-leucina-27-ácido L-aspártico-39-ácido L-glutámico-factor 2 estimulante de colonias (clon humano pHG25 fraccion proteica reducida), (127 9')- proteina con 9-glicina-10-glicina-11 -glicina-12-glicina-13-L-serina-14-glicina- 15-glicina-16-glicina-18-glicina-19-L-serina-34-ácido L-aspártico-89-ácido L-aspártico-9-152-interleuquina 3 (clon humano D11 precursor de la fracción proteica reducida) inmunomodulador

C1336H2116N362O410S13 137463-76-4

APARSPSPST QPWEHVNAIQ EALRLLDLSR DTAAEMNEEV EVISEMFDLQ EPTCLQTRLE LYKQGLRGSL TKLKGPLTMM ASHYKQHCPP TPETSCATQI ITFESFKENL KDFLLVIPFD CWEPVQEGGG GSGGGGGSAD MTQTTPLKTS WVDCSNMIDE IITHLKQPPL PLLDFNNLNG EDQDILMENN LRRPNLEAFN RAVKSLQDAS AIESILKNLL PCLPLATAAP TRHPIHIKDG DWNEFRRKLT FYLKTLENAQ AQQTTLSLAI F

miproxifenum miproxifene (Z)-a-[p-[2-(dimethylamino)ethoxy]phenyl]-α'-ethyl-4'-isopropyl-4-stilbenol antineoplastic miproxifène 4-[(1Z)-1 -[4-[2-(diméthylamino)éthoxy]phényl]-2-[4-(1 -méthyléthyl)phényl]but- 1-ényl]phénol antinéoplasique (Z)-α-[p-[2-(dimetilamino)etoxi]fenil]-α'-etil-4'-isopropil-4-estilbenol miproxifeno antineoplásico

C29H35NO2 129612-87-9

255 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

nepaprazolum nepaprazole (±)-(9R*)-9-[(SS*)-2-benzimidazolylsulfinyl]-6,7,8,9-tetrahydro-4-methoxy- 5H-cyclohepta[b]pyridine antiulcer agent népaprazole (9RS)-9-[(SR)-1H-benzimidazol-2-ylsulfinyl]-4-méthoxy-6,7,8,9-tétrahydro- 5H-cyclohepta[b]pyridine antiulcéreux nepaprazol (±)-(9R*)-9-[(SS*)-2-benzimidazolilsulfinil]-6,7,8,9-tetrahidro-4-metoxi- 5H-ciclohepta[b]piridina antiulceroso

C18H19N3O2S 156601-79-5

and enantiomer et l'énantiomère y enantiómero

osanetantum osanetant N-[1-[3-[(S)-1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidyl]propyl]-4-phenyl- 4-piperidyl]- N-methylacetamide tachykinin receptor antagonist osanétant N-[1-[3-[(3S)-1-benzoyl-3-(3,4-dichlorophényl)pipéridin-3-yl]propyl]- 4-phénylpipéridin-4-yl]-N-méthylacétamide antagoniste de récepteurs de la tachykinine osanetant N-[1-[3-[(S)-1-bencil-3-(3,4-diclorofenil)-3-piperidil]propil]-4-fenil-4-piperidil]- N-metilacetamida antagoniste de los receptores de taquiquinina

C36H41CI2N3O2 160492-56-8

pagoclonum pagoclone (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)phthalimidine anxiolytic pagoclone (+)-2-(7-chloro-1,8-naphtyridin-2-yl)-3-(5-méthyl-2-oxohexyl)-2,3-dihydro- 1H-isoindol-1-one anxiolytique

256 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

pagoclona (+)-2-(7-cloro-1,8-naftiridin-2-il)-3-(5-metil-2-oxohexil)ftalimidina ansiolítico

C23H22CIN3O2 133737-32-3

palinavirum palinavir N-[(1 S)-1-[[(1S,2R)-1-benzyl-3-[(2S,4R)-2-(tert-butylcarbamoyl)- 4-(4-pyridylmethoxy)piperidino]-2-hydroxypropyl]carbamoyl]- 2-methylpropyl]quinaldamide antiviral palinavir N-[(1S)-1-[[(1S,2R)-1-benzyl-3-[(2S,4R)-2-[(1,1-diméthyléthyl)carbamoyl]- 4-(4-pyridylméthoxy)pipéridin-1-yl]-2-hydoxypropyl]carbamoyl]-2-méthyl= propyl]quinoléine-2-carboxamide antiviral palinavir N-[(1 S)-1 -[[(1 S,2R)-1 -bencil-3-[(2S,4R)-2-(terc-butilcarbamoil)- 4-(4-piridilmetoxi)piperidino]-2-hidroxipropil]carbamoil]- 2-metilpropil]quinaldamida antiviral

C41H52N6O5 154612-39-2

palonosetronum palonosetron 2,4,5,6-tetrahydro-2-[(3S)-3-quinuclidinyl]-1H-benz[de]isoquinolin-1-one antiemetic palonosétron 2-[(3S)-1-azabicyclo[2.2.2]oct-3-yll-2,4,5,6-tétrahydro- 1 H-benzo[de]isoquinoléin-1-one antiémétique palonosetron 2,4,5,6-tetrahidro-2-[(3S)-3-quinuclidinil]-1H-benz[de]isoquinolin-1-ona antiemético

257 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

C19H22N2O 135729-56-5

pamaquesidum pamaqueside 11-oxo-(25R)-5α-spirostan-3β-yl 4-O-β-D-glucopyranosyl- β-D-glucopyranoside antihyperlipidaemic pamaquéside 3β-((4-O-β-D-glucopyranosyl-β-D-glucopyranosyl)oxy]-(25R)-5α-spirostan- 11-one antihyperlipidémiant pamaquesida 11-oxo-(25R)-5α-espirostan-3β-il 4-O-β-D-glucopiranosil-p-D-glucopiranósido antihiperlipémico

C39H62O14 150332-35-7

peldesinum 2-amino-3,5-dihydro-7-(3-pyridylmethyl)-4H-pyrrolo[3,2-d]pyrimidin-4-one peldesine antineoplastic 2-amino-7-(3-pyridylméthyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one peldésine antinéoplasique 2-amino-3,5-dihidro-7-(3-piridilmetil)-4H-pirrolo[3,2-d]pirimidin-4-ona peldesina antiplásico

258 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

C12H11N5O 133432-71-0

pramlintidum pramlintide L-lysyl-L-cysteinyl-L-asparaginyl-L-threonyl-u-alanyl-L-threonyl-L-cysteinyl- L-alanyl-L-threonyl-L-glutaminyl-L-arginyl-L-leucyl-L-alanyl-L-asparaginyl- L-phenylalanyl-L-leucyl-L-valyl-L-histidyl-L-seryl-L-seryl-L-asparaginyl- L-asparaginyl-L-phenylalanylglycyl-L-prolyl-L-isoleucyl-L-leucyl-L-prolyl-L-prolyl- L-threonyl-L-asparaginyl-L-valylglycyl-L-seryl-L-asparaginyl-L-threonyl- L-tyrosinamide, cyclic (2 7)-disulfide antidiabetic pramlintide (2 7)-disufure cyclique de L-lysyl-L-cystéinyl-L-asparaginyl-L-thréonyl- L-alanyl-L-thréonyl-L-cystéinyl-L-alanyl-L-thréonyl-L-glutaminyl-L-arginyl- L-leucyl-L-alanyl-L-asparaginyl-L-phénylalanyl-L-leucyl-L-valyl-L-histidyl-L-séryl- L-séryl-L-asparaginyl-L-asparaginyl-L-phénylalanyl-glycyl-L-prolyl-L-isoleucyl- L-leucyl-L-prolyl-L-prolyl-L-thréonyl-L-asparaginyl-L-valyl-glycyl-L-séryl- L-asparaginyl-L-thréonyl-L-tyrosinamide antidiabétique pramlintida (2 7)-disulfuro cíclico de L-lisil-L-cisteinil-L-asparaginil-L-treonil-L-alanil- L-treonil-L-cisteinil-L-alanil-L-treonil-L-glutaminil-L-arginil-L-leucil-L-alanil- L-asparaginil-L-fenilalanil-L-leucil-L-valil-L-histidil-L-seril-L-seril-L-asparaginil- L-asparaginil-L-fenilalanilglicil-L-prolil-L-isoleucil-L-leucil-L-prolil-L-prolil- L-treonil-L-asparaginil-L-valilglicil-L-seril-L-asparaginil-L-treonil-L-tirosinamida antidiabético

C171H267N51O53S2 151126-32-8

quetiapinum 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]ethanol quetiapine hypnotic, anxiolytic 2-[2-[4-(dibenzo[b,f][1,4]thiazépin-11-yl)pipérazin-1-yl]éthoxy]éthanol quétiapine hypnotique, anxiolytique 2-[2-(4-dibenzo[b,f ][1,4]tiazepin-11 -il-1 -piperazinil)etoxi]etanol quetiapina hipnótico, ansiolítico

259 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

C21H25N3O2S 111974-69-7

raltitrexedum raltitrexed N-[5-[[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]- 2-thenoyl]-L-glutamic acid antineoplastic raltitrexed acide (2S)-2-[[[5-[méthyl[(2-méthyl-4-oxo-3,4-dlhydroquinazolin- 6-yl)méthyl]amino]-2-thiényl]carbonyl]amino]pentanedioïque antinéoplasique raltitrexed ácido N-[5-[[(3,4-dihidro-2-metil-4-oxo-6-quinazolinil)metil]metilamino]- 2-tenoil]-L-glutámico antineoplásico

C21H22N4O6S 112887-68-0

resocortolum 11 β,17α-dihydroxy-17-propionylandrost-4-en-3-one resocortol corticosteroid 11β,17α-dihydroxy-17-propanoylandrost-4-én-3-one résocortol corticostéroïde 11 β,17α-dihidroxi-17-propionilandrost-4-en-3-ona resocortol corticosteroide

C22H32O4 76675-97-3

260 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

revatropatum revatropate (R)-3-quinuclidinyl (S)-β-hydroxy-α-[2-(R)-methylsulfinyl]ethyl]hydratropate bronchodilatator

révatropate (2S)-2-(hydroxyméthyl)-4-[(R)-méthylsulfinyl]-2-phénylbutanoate de (3R)-1-azabicyclo[2.2.2]oct-3-yle bronchodilatateur revatropato (2S)-2-(hidroximetil)-4-[(R)-metilsulfinil]-2-fenilbutanoato de (3R)-1-azabiciclo[2.2.2]oct-3-ilo broncodilatador

C19H27NO4S 149926-91-0

rismorelinum rismorelin 1 -(p-methylhippuric acid)-9-L-asparagine-12-L-arginine-15-L-threonine- 21 -L-arginine-27-L-leucine-51 -L-leucine-56-L-arginine- 58-L-leucineprosomatoliberin (pig) growth hormone release stimulating peptide rismoréline [1-[N-(4-méthylbenzoyl)glycine]-9-L-asparag¡ne-12-L-arginine-15-L-thréonine- 21-L-arginine-27-L-leucine-51-L-leucine-56-L-arginine- 58-L-leucine]prosomatolibérine (de porc) peptide stimulant la libération de l'hormone de croissance rismorelina 1-(ácido p-metilhipúrico)-9-L-asparagina-12-L-arginina-15-L-treonina- 21 -L-arginina-27-L-leucina-51 -L-leucina-56-L-arginina- 58-L-leucinaprosomatoliberina (cerdo) péptído estimulante de la liberación de la hormona del crecimiento

C379H623N127O118 146706-68-5

261 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

sildenafilum sildenafil 1 -[[3-(6,7-dihydro-1 -methyl-7-oxo-3-propyl-1 H-pyrazolo[4,3-d)pyrimidin-5-yl)- 4-ethoxyphenyl]sulfonyl]-4-methylpiperazine vasodilator sildénafil 1 -méthyl-4-[[4-éthoxy-3-[1 -méthyl-7-oxo-3-propyl-6,7-dihydro-1 H- pyrazolo[4,3-d|pyrimidin-5-yl]phenyl]sulfonyl]p¡pérazine vasodilatateur sildenafilo 1 -[[3-(6,7-dihidro-1 -metil-7-oxo-3-propil-1 H-pirazolo[4,3-d]pirimidin-5-il)- 4-etoxifenil]sulfonil]-4- metilpiperazina vasodilatador

C22H30N6O4S 139755-83-2

sinitrodilum 2,3-dihydro-3-(2-hydroxyethyl)-4H-1,3-benzoxazin-4-one nitrate (ester) sinitrodil vasodilatator nitrate de 2-[4-oxo-2H-1,3-benzoxazin-3(4H)-yl]éthyle sinitrodil vasodilatateur nitrato de 2-(4-oxo-2H-1,3-benzoxazin-3(4H)-il)etilo sinitrodil vasodilatador

C10H10N2O5 143248-63-9

sipatriginum 4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine sipatrigine nootropic agent [2-(4-méthylpipérazin-1-yl)-5-(2,3,5-trichlorophényl)pyrimidin-4-yl]amine sipatrigine nootrope 4-amino-2-(4-metil-1-piperazinil)-5-(2,3,5-triclorofenil)pirimidina sipatrigina nootrópico

264 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

C15H16CI3N5 130800-90-7

tilnoprofenum arbamelum tilnoprofen arbamel (±)-α,2-dimethyl-5H-[1]-benzopyrano[2,3-b]pyridine-7-acetic acid, ester with N,N-dimethylglycolamide non-steroidal anti-inflammatory tilnoprofène arbamel (2RS)-2-[2-méthyl-5H-[1]benzopyrano[2,3-b]pyridin-7-yl]propanoate de 2-(diméthylamíno)-2-oxoéthyle anti-inflammatoire non stéroïdien tilnoprofeno arbamel ácido (±)-α,2-dimetil-5H-[1]-benzopirano[2,3-b]piridina-7-acético, éster con N,N-dimetilglicolamida antiinflamatorio no esteroideo

C20H22N2O4 159098-79-0

and enantiomer et l'énantiomère y enantiómero

tivirapinum tivirapine (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo= [4,5,1 -jk][1,4]benzodiazepine-2(1 H)-thione antiviral tivirapine (-)-(5S)-8-chloro-5-méthyl-6-(3-méthylbut-2-ényl)-4,5,6,7-tétrahydro= imidazo[4,5,1 -jk][1,4]benzodiazépine-2(1 H)-thione antiviral tivirapina (S)-8-cloro-4,5,6,7-tetrahidro-5-metil-6-(3-metil-2-butenil)imidazo= [4,5,1-jk][1,4]benzodiazepina-2(1 H)-tiona antiviral

265 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

C16H20CIN3S 137332-54-8

traferminum trafermin 2-155-basic (human clone λKB7/λHFL1 precursor reduced fibrinoblast growth factor trafermine 2-155-facteur de croissance des fibroblastes basiques (forme réduite du précurseur issu du clone humain λKB7/λHFL1) facteur de croissance des fibroblastes trafermina 2-155-factor de crecimiento de los fibroblastos básicos (forma reducida del precursor procedente del clon humano λKB7/λHFL1) factor de crecimiento de fibroblastos

C764H1201N217O219S6 131094-16-1

trifosminum tris(3-methoxypropyl)phosphine trifosmin diagnostic agent tris(3-méthoxypropyl)phosphane trifosmine produit à usage diagnostique tris(3-metoxipropil)fosfina trifosmina agente de diagnóstico

C12H27O3P 83622-85-9

valnemulinum valnemulin [[2-[(R)-2-amino-3-methylbutyramido]-1,1 -dimethylethyl]thio]acetic acid, 8-ester with (3aS,4R,5S,6S,8R,9R,9aR,10R)-octahydro-5,8-dihydroxy- 4,6,9,10-tetramethyl-6-vinyl-3a,9-propano-3aH-cyclopentacycloocten-1(4H)- one antibiotic valnémuline 2-[[2-[[(2R)-2-amino-3-méthylbutanoyl]amino]-1,1-diméthyléthyl]= sulfanyl]acétate de (1 S,2R,3S,4S,6R,7R,8R,14R)-4-éthényl-3-hydroxy- 2,4,7,14-tétraméthyl-9-oxotricyclo[5.4.3.01,8]tétradéc-6-yle antibiotique

266 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

valnemulina ácido [[2-[(R)-2-amino-3-metilbutiramido]-1,1-dimetiletil]tio]acético, 8-éster con (3aS,4R,5S,6S,8R,9R,9aR,10R)-octahidro-5,8-dihidroxi- 4,6,9,10-tetrametil-6-vinil-3a,9-propano-3aH-ciclopentacicloocten-1(4H)-ona antibiótico

C31H52N2O5S 101312-92-9

xemilofibanum xemilofiban ethyl (3S)-3-[3-[(p-amidinophenyl)carbamoyl]propionamido]-4-pentynoate fibrinogen receptor antagonist xémilofiban (3S)-3-[[4-[(4-carbamimidoylphényl)amino]-4-oxobutanoyl]amino]pent- 4-ynoate d'éthyle antagoniste du récepteur du fibrinogène xemilofibán (3S)-3-[3-[(p-amidinofenil)carbamoil]propionamido]-4-pentinoato de etilo antagonista del receptor del fibrinógeno

C18H22N4O4 156586-91-3

zinostatinum stimalamerum zinostatin stimalamer substance produced by combining styrene-alt-maleic acid copolymer that is partially butyl esterized with zinostatin (neocarzinostatin) antineoplastic zinostatine stimalamère substance obtenue par combinaison d'un copolymère alterné de styrène et d'acide maléique partiellement estérifié par de l'alcool butylique avec la zinostatine (néocarzinostatine) antinéoplasique zinostatina estimalámero sustancia obtenida por combinación de zinostatina con un copolimero de estireno y ácido maleico, alternados, parcialmente esterificado con alcohol butílico antineoplásico 123760-07-6

267 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

zolmitriptanum (S)-4-[[3-[2-(dimethylamino)ethyl]indol-5-yl]methyl]-2-oxazolidinone zolmitriptan antimigraine, serotonin receptor agonist (4S)-4-[[3-[2-(diméthylamino)éthyl]-1H-indol-5-yl]méthyl]oxazolidin-2-one zolmitriptan antimigraineux, agoniste de récepteurs de la sérotonine (S)-4-[[3-[2-(dimetilamino)etil]indol-5-il]metil]-2-oxazolidinona zolmitriptán antimigrañoso, agonista de los receptores de la serotonina

C16H21N3O2 139264-17-8

AMENDMENTS TO PREVIOUS LISTS

Proposed International Nonproprietary Names (Prop. INN): List 1 (WHO Chronicle, Vol. 7, No. 10, 1953)

p.302 caicii pantothenas replace the entry by the following: calcium pantothenate calcium bis[(R)-N-(2,4-dihydroxy-3,3-dimethylbutyryl)-β-alaninate] vitamin B component (enzyme co-factor)

C18H32CaN2O10 137-08-6

268 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

Proposed International Nonproprietary Names (Prop. INN): List 40 (WHO Chronicle, Vol. 32, No. 9, 1978) p. 19 zinostatinum replace the description and graphic formula by the following: zinostatin (4S, 6R,11 R,12R)-11-[(α-D-2,6-dideoxy-2-methylaminogalactopyranosyl)oxy]- 12-[[(2-hydroxy-7-methoxy-5-methyl-1-naphtyl)carbonyl]oxy]-4-((4R)-2-oxo- 1,3-dioxolan-4-yl)-5-oxatricyclo[8.3.0.04,6]tridec-9,13-dien-2,7-diyne and apoprotein

AAPTATVTPS SGLSDGTWK VAGAGLQAGT AYDVGQCAWV DTGVLACNPA DFSSVTADAD GSASTSLTVR RSFEGFLFDG TRWGTVDCTT AACQVGLSDA AGNGPEGVAI SFN

Proposed International Nonproprietary Names (Prop. INN): List 54 (WHO Chronicle, Vol. 39, No. 4, 1985) p.18 sometribovum replace the molecular formula and CAS registry number by the following:

sometribove C978H1537N265O286S9 102744-97-8

Proposed International Nonproprietary Names (Prop. INN): List 55 (WHO Chronicle, Vol. 40, No. 1, 1986) p. 13 sometriporum replace the molecular formula and CAS registry number by the following:

sometripor C979H1527N265O287S8 102733-72-2

269 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

Proposed International Nonproprietary Names (Prop. INN): List 59 (WHO Drug Information, Vol. 2, No. 2, 1988) p. 18 somatropinum replace the chemical name and add the amino acid sequence: somatropin growth hormon (human), r-DNA derived

FPTIPLSRLF DNAMLRAHRL HQLAFDTYQE FEEAYIPKEQ KYSFLQNPQT SLCFSESIPT PSNREETQQK SNLELLRISL

LLIQSWLEPV QFLRSVFANS LVYGASDSNV YDLLKDLEEG IQTLMGRLED GSPRTGQIFK QTYSKFDTNS HNDDALLKNY GLLYCFRKDM DKVETFLRIV QCRSVEGSCG F

Proposed International Nonproprietary Names (Prop. INN): List 62 (WHO Drug Information, Vol. 3, No. 4, 1989) p. 4 ciclesonidum replace the chemical name, CAS registry number, and graphic formula by the following: ciclesonide (R)-11 β,16α,17,21 -tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17- acetal with cyclohexanecarboxaldehyde, 21-isobutyrate 141845-82-1

Proposed International Nonproprietary Names (Prop. INN): List 64 (WHO Drug Information, Vol. 4, No. 4, 1990) p.27 delete insert polyvidonum povidonum polyvidone povidone

Proposed International Nonproprietary Names (Prop. INN): List 67 (WHO Drug Information, Vol. 6, No. 2, 1992) p. 7 pegaldesleukinum replace the chemical name by the following: pegaldesleukin 125-L-serine-2-133-interleukin 2 (human reduced), reaction product with glutaric anhydride, esters with polyethylene glycol monomethyl ether

270 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

Proposed International Nonproprietary Names (Prop. INN): List 69 (WHO Drug Information, Vol. 7, No. 2, 1993)

p. 4 delete insert flocalcitriolum falecalcitriolum flocalcitriol falecalcitriol

Proposed International Nonproprietary Names (Prop. INN): List 70 (WHO Drug Information, Vol. 7, No. 4, 1993)

p. 14 delete insert dapropas daropas dapropate daropate

Proposed International Nonproprietary Names (Prop. INN): List 71 Dénominations communes internationales proposées (DCI Prop.): Liste 71 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 71 (WHO Drug Information, Vol. 8, No. 2, 1994) p. 8 delete /supprimer / suprímase insert/insérer / insértese colestimidum colestilanum colestimide colestilan colestimide colestilan colestimida colestilan

Proposed International Nonproprietary Names (Prop. INN): List 72 Dénominations communes internationales proposées (DCI Prop.): Liste 72 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 72 (WHO Drug Information, Vol. 8, No. 4, 1994) p.18 mangafodipirum mangafodipir sustituyase la descripción por la siguiente: hexahidrógeno (OC-6-13)-[[N,N '-etilenbis[N-[[3-hidroxi-5-(hidroximetil)- 2-metil-4-piridil]metil]glicina] 5,5'-bis(fosfato)](8-)]manganato(6-) p.19 delete / supprimer / suprímase insert /insérer / insértese marsidominum darsidominum marsidomíne darsidomine marsidomine darsidomine marsidomina darsidomina

271 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

p.21 muplestimum muplestim replace the description, molecular formula, and CAS registry number by the following: interleukin 3 (human protein moiety) muplestim remplacer la description, la formule brute et le numéro dans le registre du CAS par: interleukine 3 (partie protéique humaine) muplestim reemplácense la descripción, la fórmula empírica y el número de registro del CAS por: interleukina 3 (fracción proteica humana)

C670H1074N186O199S5 148641-02-5

Proposed International Nonproprietary Names (Prop. INN): List 73 Dénominations communes internationales proposées (DCI Prop.): Liste 73 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 73 (WHO Drug Information, Vol. 9, No. 2, 1995) p. 5 dimadectinum dimadectin replace the description by the following: mixture of: (2aE,4E,5'S,6S,6'R,7S,8E,11R,13R,15S,17aR,20R,20aR,20bS)-6'-(S)-sec- butyl-3',4',5',6,6',7,10,11,14,15,17a,20,20a,20b-tetradecahydro-20,20b- dihydroxy-7-[(2-methoxyethoxy)methoxy]-5', 6,8,19-tetramethylspiro[11,15- methano-2H,13H,17H-furo[4,3,2-pq][2,6]benzodioxacyclooctadecin-13,2'- [2H]pyran]-17-one (major component) and (2aE,4E,5'S,6S,6'R,7S,8E,11R,13R,15S,17aR,20R,20aR,20bS)- 3',4',5',6,6',7,10,11,14,15,17a,20,20a,20b-tetradecahydro-20,20b-dihydroxy- 6'-isopropyl-7-[(2-methoxyethoxy)methoxy]-5',6,8,19-tetramethylspiro[11, 15-methano-2H,13H,17H-furo[4,3,2-pq][2,6]benzodioxacyclooctadecin-13,2'- [2H]pyran]-17-one

p. 11 minolteparinum natricum minolteparin sodium delete CAS registry number minoltéparine sodique supprimer le numéro dans le registre de CAS minolteparina sodica suprímase el número de registro del CAS

272 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

MODIFICATIONS APPORTEES AUX LISTES ANTÉRIEURES

Dénominations communes internationales proposées (DCI Prop.): Liste 1 (WHO Chronicle, Vol. 7, No. 10, 1953) p.302 calcii pantothenas remplacer l'inscription et la formule developée par: pantothénate de calcium bis[3-[[(2R)-2,4-dihydroxy-3,3-diméthylbutanoyl]amino]propanoate] de calcium vitamine du groupe B (co-facteur d'enzyme)

C18H32CaN2O10 137-08-6

Dénominations communes internationales proposées (DCI Prop.): Liste 40 (Supplément à la Chronique OMS, Vol. 32 No.9, 1978) p. 19 zinostatinum remplacer la description et la formule developée par: zinostatin combinaison de: 2-hydroxy-7-méthoxy-5-méthylnaphtalène-1 -carboxylate de (4S,6R,11 R,12R)-11 -[[2-(méthylamino)-2,6-didésoxy-α-D- galactopyranosyl]oxy]-4-[(4R)-2-oxo-1,3-dioxolan-4-yl]-5- oxatricyclo[8.3.0.04,6]tridéca-1(13),9-diène-2,7-diyn-12-yle avec l'apoproptéine dont la structure suit.

AAPTATVTPS SGLSDGTWK VAGAGLQAGT AYDVGQCAWV DTGVLACNPA DFSSVTADAD GSASTSLTVR RSFEGFLFDG TRWGTVDCTT AACQVGLSDA AGNGPEGVAI SFN

273 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

Dénominations communes internationales proposées (OCI Prop.): Liste 54 (Supplément à la Chronique OMS, Vol. 39 No.4, 1985)

p.18 sometribovum remplacer la formule brute et le numéro dans le registre de CAS par:

sométribove C978H1537N265O286S9 102744-97-8

Dénominations communes internationales proposées (DCI Prop.): Liste 55 (Supplément à la Chronique OMS, Vol. 40 No.1, 1986)

p.13 sometriporum remplacer la formule brute et le numéro dans le registre de CAS par:

sométripor C979H1527N265O287S8 102733-72-2

Dénominations communes internationales proposées (DCI Prop.): Liste 59 (Informations pharmaceutiques OMS, Vol. 2, No. 2, 1988)

p.18 somatropinum remplacer la description et ajouter la formule développée: somatropine hormone de croissance (humaine), obtenue par génie génétique

Dénominations communes internationales proposées (DCI Prop.): Liste 62 (Informations pharmaceutiques OMS, Vol. 3, No. 4, 1989) p. 4 ciclesonidum remplacer le nom chimique, le numéro dans le registre du CAS et la formule développée par: ciclésonide 21 -(2-méthylpropanoate) de 16α,17-[[(R)-cyclohexylméthyléne]bis(oxy)]- 11 β, 21 -dihydroxyprégna-1,4-diéne-3,20-dione 141845-82-1

274 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

Dénominations communes internationales proposées (DCI Prop.): Liste 64 (Informations pharmaceutiques OMS, Vol. 4, No. 4, 1990)

p.28 supprimer insérer polyvidonum povidonum polyvidone povidone

Dénominations communes internationales proposées (DCI Prop.): Liste 69 (Informations pharmaceutiques OMS, Vol. 7, No. 2, 1993)

p. 4 supprimer insérer flocalcitriolum falecalcitriolum flocalcitriol falécalcitriol

Dénominations communes internationales proposées (DCI Prop.): Liste 70 (Informations pharmaceutiques OMS, Vol. 7, No. 4, 1993) p. 15 supprimer insérer dapropas daropas dapropate daropate

Pour toutes les modifications des Dénominations communes internationales proposées (DCI Prop.): Listes 71-73 voyez page 35 sous AMENDMENTS TO PREVIOUS LISTS.

MODIFICACIONES A LAS LISTAS ANTERIORES

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 1 (WHO Chronicle, Vol. 7, No. 10, 1953) p.302 calcii pantothenas reemplácense la formula desarrollada y la actividad por: pantotenato cálcico bis[3-[[(R)-N-(2,4-dihidroxi-3,3-dimetilbutiril)-β-alaninato]de calcio vitamina del grupo B (cofactor enzimatico)

275 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 40 (Suplemento de Crónica de la OMS, Vol. 32, No.9, 1978)

p. 19 zinostatinum sustituyanse la descripción y la fórmula desarrollada por las siguientes: zinostatina (4S, 6R,11 R,12R)-11 -[(α-D-2,6-didesoxi-2-metilaminogalactopiranosil)oxi]-12- [[(2-hidroxi-7-metoxi-5-metil-1-naftil)carbonil]oxi]-4-((4R)-2-oxo-1,3-dioxolan- 4-il)-5-oxatriciclo[8.3.0.04,6]tridec-9,13-dien-2,7-diine y apoproteina

AAPTATVTPS SGLSDGTWK VAGAGLQAGT AYDVGQCAWV DTGVLACNPA DFSSVTADAD GSASTSLTVR RSFEGFLFDG TRWGTVDCTT AACQVGLSDA AGNGPEGVAI SFN

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 54 (Suplemento de Crónica de la OMS, Vol. 39, No.4, 1985) p.17 sometribovum sustituyanse la fórmula molecular y el número de registro del CAS por los siguientes:

sometribovo C978H1537N265O286S9 102744-97-8

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 55 (Suplemento de Crónica de la OMS, Vol. 40, No.1, 1986) p.13 sometriporum sustituyanse la fórmula molecular y el número de registro del CAS por los siguientes:

sometripor C979H1527N265O287S8 102733-72-2

276 WHO Drug Information, Vol. 9, No. 4, 1995 Proposed INN: List 74

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 59 (Información Farmacéutica, OMS, Vol. 2, No. 2, 1988)

p.18 somatropinum sustituyase el nombre químico e insértese la fórmula desarrollada : somatropina hormona de crecimiento (humana), derivada de r-DNA

FPTIPLSRLF DNAMLRAHRL HQLAFDTYQE FEEAYIPKEQ KYSFLQNPQT SLCFSESIPT PSNREETQQK SNLELLRISL

LLIQSWLEPV QFLRSVFANS LVYGASDSNV YDLLKDLEEG IQTLMGRLED GSPRTGQIFK QTYSKFDTNS HNDDALLKNY GLLYCFRKDM DKVETFLRIV QCRSVEGSCG F J

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 62 (Información Farmacéutica, OMS, Vol. 3, No. 4, 1989) p. 4 ciclesonidum sustituyanse la fórmula empírica, el número de registro del CAS y la fórmula desarrollada por las siguientes: ciclesonida (R)-11 β,16α,17,21-tetrahidroxipregna-1,4-dieno-3,20-diona 16,17-acetal cíclico con cicloclohexanocarboxaldehído, 21-isobutirato

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 64 (Información Farmacéutica, OMS, Vol. 4, No. 4, 1990) p.27 suprímase insértese polyvidonum povidonum polyvidone povidone

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 67 (Información Farmacéutica, OMS, Vol. 6, No. 2, 1992) p. 7 pegaldesleukinum sustituyase la fórmula empírica por la siguiente: pegaldesleukina 125-L-serina-2-133-interleuquina 2 (humana reducida), producto de la reacción con anhídrido glutárico, esterificado con éter monometílico de polietilenglicol

277 Proposed INN: List 74 WHO Drug Information, Vol. 9, No. 4, 1995

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 69 (Información Farmacéutica, OMS, Vol. 7, No. 2, 1993) p. 4 suprímase insértese flocalcitriolum falecalcitriolum flocalcitriol falecalcitriol

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Liste 70 (Información Farmacéutica, OMS, Vol. 7, No. 4, 1993) p.15 suprímase insértese dapropas daropas dapropato daropato

Para cualquier modificación de las Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Listas 71-73 vease página 35, AMENDMENTS TO PREVIOUS LISTS.

Procedure and Guiding Principles / Procédure et Directives / Procedimientos y principios generales

The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharmaceutical Substances will be reproduced in uneven numbers of proposed INN lists only.

Les textes de la Procédure à suivre en vue de choix de dénominations communes internationales recommandées pour les substances pharmaceutiques et des Directives générales pour la formation de dénominations communes internationales applicables aux substances pharmaceutiques ont été publiés avec la liste 71 des DCI proposées et seront, à nouveau, publiés avec la prochaine liste.

El texto de los Procedimientos de selección de denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas y de los Principios generales de orientación para formar denominaciones comunes internacionales para sustancias farmacéuticas aparece solamente en los números impares de las listas de DCI propuestas.

278 SELECTED WHO PUBLICATIONS OF RELATED INTEREST

Price* (Sw. fr.) The use of essential drugs Sixth report of the WHO Expert Committee WHO Technical Report Series, No. 850 1995 (138 pages) 21.-

WHO model prescribing information: drugs used in anaesthesia 1989 (53 pages) 11 .-

WHO model prescribing information: drugs used in parasitic diseases, second edition 1995 (146 pages) 35-

WHO model prescribing information: drugs used in mycobacterial diseases 1991 (40 pages) 9-

WHO model prescribing information: drugs used in sexually transmitted diseases and HIV infection 1991 (97 pages) 25-

The International Pharmacopoeia, third edition Volume 1 : general methods of analysis. 1979 (223 pages) 24.- Volume 2: quality specifications. 1981 (342 pages) 36.- Volume 3: quality specifications. 1988 (407 pages) 64.- Volume 4: tests, methods and general requirements. 1994 (360 pages) 85.-

Basic tests for pharmaceutical substances 1986 (vi + 204 pages) 34.-

Basic tests for pharmaceutical dosage forms 1991 (v+ 129 pages) 24.-

International Nonproprietary Names (INN) for Pharmaceutical Substances, Cumulative List No. 8 1992 (xlvi + 692 pages) 140.-

Further information on these and other World Health Organization publications can be obtained from Distribution and Sales, World Health Organization, 1211 Geneva 27, Switzerland.

* Prices in developing countries are 70% of those listed here.