WHO DRUG INFORMATION

VOLUME 7 • NUMBER 3 • 1993

RECOMMENDED INN LIST 33 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL 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.

WHO Drug Information is published 4 times a year and can be ordered from: Distribution and Sales, World Health Organization, 1211 Geneva 27, Switzerland.

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©World Health Organization 1993

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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. WHO Drug Information

Contents

General Policy Topics Regulatory Matters Role of the International Conference of Drug Antihyperlipidaemic agents: paraesthesia and Regulatory Authorities 97 neuropathy 123 Atovaquone as an alternative treatment for Pneumocystis pneumonia 123 Personal Perspectives Bovine brain gangliosides: marketing Patient's rights and the therapeutic dialogue 99 suspension recommended 124 Antiretroviral therapy: recommendations for use 124 Reports on Individual Drugs Short-acting hypnotics: a comparative Dapsone-pyrimethamine: dual therapy in HIV assessment 125 infection? 101 Identification codes for tablets and capsules 126 Diethylstilbestrol: a human carcinogen 103 Misoprostol: unsafe in pregnancy 126 Tacrine: a first step towards management of Propofol: adverse neurological events 127 Alzheimer's disease 104 Bismuth subsalicylate: association with Folic acid and spina bifida 106 Reye's syndrome 127 Poliovirus vaccines: the case for a Tacrine approved for the symptomatic relief supplemental dose 108 of Alzheimer's disease 127 Quality control of propylene glycol 127 General Information Essential Drugs Guillain-Barré syndrome: immunoglobulins or Viral hepatitis 128 steroids 110 Hepatitis B vaccine 130 Artemisinin and its derivatives: use as Hepatitis B immune globulin 131 antimalarials 111 Human immunoglobulin 132 Tuberculosis preventive therapy in HIV- Hepatitis A vaccine 132 infected individuals 113 Advertising in medical journals 115 Antiarrhythmic agents: the problems of clinical Recent Publications assessment 116 Quality control of essential drugs in developing Biological products and transmissible countries: standardized methods 134 pathogens 118 Sickle cell disease: a trend towards less Recommended International invasive management 120 Nonproprietary Names: List 33 135

General Policy Topics

Role of the International Conference • discuss contemporaneous issues of international relevance. of Drug Regulatory Authorities The objective is, above all, to offer practical support One of the primary functions of the World Health to decision-makers in drug regulatory authorities. Organization is to serve as the directing and The conferences have been looked upon with coordinating agency in international health work. benevolence by the governing bodies of WHO, and Among a wide range of technical functions, WHO's they have been actively supported by an increasing Constitution requires the secretariat to "develop, number of Member States that arrange to be establish and promote international standards for represented at the meetings. It is gratifying that the food, biological, pharmaceutical and similar conferences have now been formally recognized by products". In no other domain does the Organiza­ the World Health Assembly in which resolution tion work in such direct collaboration with the WHA45.28 defines WHO's role in intergovern­ governments of Member States. Currently, over mental harmonization of drug registration and 160 countries have designated a senior official to control. The resolution urges all Member States to be responsible for disseminating technical advice support and participate in sessions of the ICDRA received from WHO on the safety and efficacy of concerning the harmonization process. It also drugs, and who also arranges for WHO to be kept invites the pharmaceutical industry "to continue to informed of national drug regulatory decisions that collaborate with drug regulatory authorities and with are of international relevance and concern. It is this WHO, where appropriate, in order to ensure that initiative that has established WHO as the inter­ the advantages of harmonization benefit all national focus for drug regulatory affairs and has concerned". helped to establish and maintain the International Conferences of Drug Regulatory Authorities The ICDRA has helped to create a commitment (ICDRA). within drug regulatory authorities to address international responsibilities. Certain obligations The first of these conferences was convened in towards collaboration are manifest. They include Annapolis in the USA in 1980, as a joint initiative of the need to exorcise trade in counterfeit, spurious the WHO Secretariat and officials of the US Food and substandard products; to assure broad and Drug Administration. For the first time within a international respect for good manfacturing global context, representatives of drug regulatory practices in all circumstances; to establish efficient authorities in both developed and developing approaches to drug registration and other aspects countries were provided with a forum for debate. of control in all countries; and to sensitize law Conferences have since been held biennially, each enforcement and customs authorities to their role in one being sponsored by the Ministry of Health of a control mechanisms. host country and the agenda is proposed by a regionally-representative group of drug regulatory Other concerns are more recent. One sign of officials and the WHO Secretariat. changing times is a general acceptance of the need to validate all data that contribute to the drug At the first meeting, both the acronym ICDRA and development process. Hence the need to develop the objectives of the conference were established. globally-recognized standards of good clinical and The principle aims are to: good laboratory practice. This need is uncontested, but the requirements will have to be interpreted with • promote collaboration between national drug sensitivity and with concern for practicability. There regulatory authorities; is always a danger that overzealous commitment to standards may serve only to frustrate the process • forge a consensus on matters of mutual interest; that they are intended to protect.

• facilitate timely and adequate exchange of Extensive discussion within the ICDRA has resulted technical information; and in better understanding of underlying problems. At the same time, in the course of debate, the frailty of of WHO's Ethical Criteria for Medicinal Drug the drug registration process in many countries has Promotion and the responsibilities of the various become evident. This has stimulated WHO to parties involved, including pharmaceutical develop Guiding Principles for Small Drug companies, consumers and governments, in Regulatory Authorities and to complement this text assuring standards of promotional practice. with a computer software package for drug registration. One of the most encouraging These are but examples of the work and influence experiences of ICDRA, thus far, has been the of the ICDRA. In fact, the agenda of each meeting frequency with which discussion of one topic has is overloaded to the extent that much time is brought into focus other important subjects. devoted to small parallel workshop discussions, each of which has a global focus. Topics that have Regulatory authorities, like pharmaceutical captured attention range from the assessment and companies, have many interests that merit frank control of traditional and herbal medicines to the and confidential discussion. The informality and prevention and treatment of HIV infection and the spontaneity of debate that characterizes the ICDRA prospects of improving the management of the is one of its greatest strengths. It accepts the need disease in developing countries. for dialogue between drug regulatory officials and One particularly encouraging feature of the their counterparts in the pharmaceutical industry. conferences is that the single afternoon reserved to Opportunity has thus been offered in the past to discuss current topics is appreciated to the extent international pharmaceutical industry associations that both selection of subjects and time for debate to provide luncheon speakers. During the last have to be rigorously controlled. Regulators Conference in Ottawa in 1991 a panel of speakers working in strikingly different environments and was invited from the industry to a special session to grappling with totally different situations meet to discuss various topics with drug regulatory discuss common responsibilities from their various authorities. The issues that attracted attention perspectives. They are given a unique opportunity included detection of counterfeiting; harmonization to understand at first hand the challenges faced by of registration requirements; transfer of summary- their counterparts around the world, and the need basis-of-approval documents; criteria for for collective approaches to issues, both technical designation of prescription and non-prescription and administrative, that cannot be solved effectively medicines; and control of pharmaceutical products from an isolated position. moving in international commerce. The ICDRA has already celebrated its first decade The next conference, which is co-sponsored by the of existence and its future is assured for many Government of the Netherlands, will take place in years ahead. Its success is a reflection of its April 1994 immediately prior to the World Health symbiotic value in promoting the complementary Assembly. This will offer a timely occasion to interests of national authorities and the international discuss the outcome of a meeting held by WHO community. Its recent formal recognition by the and the Council of International Organizations of World Health Assembly provides proof of its Medical Sciences (CIOMS) on the implementation relevance and vitality. Personal Perspectives

including any risks and any alternatives, before they Patient's rights and the decide whether they will agree to treatment". A therapeutic dialogue more substantive statement appears in a circular directed to doctors (A Guide to Consent for Dr J. Collier Examination and Treatment). In this, the govern­ ment states that "a patient has the right under Head, Clinical Pharmacology Unit common law to give or withhold consent prior to St George's Hospital Medical School examination or treatment". Patients are entitled to London receive information in a way they can understand about the proposed treatments, the possible Relationships between patients and doctors are alternatives and any substantial risks, so that they changing. Gradually, patients are moving from a can make a balanced judgement. Patients must be position of subservience — in which they are allowed to decide whether they will agree to excluded from decision-making — to one in which treatment. they are becoming more closely involved in discussions about therapy, and are treated as In theory, it should be no great burden for doctors partners. The arguments for such a partnership — to provide the patient with information since if they in which the patient and doctor decide together on are choosing a course of treatment rationally, they each particular health strategy — are compelling. It will know enough about the drug to satisfy the is, after all, the patient's body that will receive the patient's enquiries. Moreover, most patients ask few treatment and inevitably patients, as individuals, questions and leave decision-making to the doctor have the right to determine what happens to their as a matter of trust. On other occasions, the doctor body. At a more pragmatic level, there is wide­ might find the process of explanation time- spread recognition that by being involved in the consuming and challenging, and perhaps even feel decision-making, by being included in the thera­ that the process is a threat to professional status. peutic dialogue, and by being more in control, This possibility merits serious consideration since it patients are more likely to take their medicines, to should not be allowed to undermine what is clearly comply with instructions, to feel more satisfied and an advance in patient/doctor relationships. actually to respond better to treatment. Finally, if there is full partnership in decision-making, and if To satisfy the requirements of patient's rights, the treatment leads to mishap, as it sometimes will, (assuming the patient is conscious and of sound or if "absolute" knowledge is incomplete, the burden mind during each consultation), the prescriber of responsibility for the outcome can more easily be should raise the issues of information, provide an shared. In effect, by accepting to take the treatment explanation about the proposed course of action after explanation and discussion, the patient will and describe, for example, any material risks that have given his or her informed consent. In order to may be associated with the drug to be taken and establish the therapeutic dialogue and the what action to take if they occur. All this should be principles of informed consent as standard practice, done in such a way as to invite a dialogue and to there are three basic requirements: the patient has meet two basic requirements: a right to health care, the doctor has a duty to explain, and the patient has a right to information. 1. The prescriber should provide information that is accurate, impartial, relevant, complete and clear.

In many countries, the patient's rights to information 2. The recipient should accept treatment from a are already established - in some as a matter of position of knowledge, understanding and choice. custom, in others as part of national codes or law. In the United Kingdom, the Patient's Charter which In reality, these are demanding requirements and was adopted by the Government in 1992 states that they are rarely likely to be fully met. There will be all citizens treated within the National Health very few occasions when even the most conscien­ Service have the established right "to be given a tious doctor will know the details about both the clear explanation of any treatment proposed, treatment and the various alternatives (other drugs, surgery, talk, no drugs), and whether the just about the medicine, but about their rights to information available is accurate, impartial and information. With this change of attitude must come relevant to the patient. For example, how useful is the recognition that even the most well-informed information gained from studies in young men in the doctor will be faced by some questions for which United Kingdom to the treatment of an elderly the answers are not yet available. A change in woman in Tanzania? From the patients too, the understanding will come with the provision of demands are great. Even in an ideal setting, there information directed specifically to patients, and to is rarely time for full discussion, the stress of the this end regulations are now in place in the situation causes much of what is said to be European Community requiring there to be clear forgotten and without background training, and informative leaflets and labels with all understanding is likely to be compromised. dispensed drugs. But much more too will be needed, with consumer groups, the media, schools Despite these constraints, which must be recog­ and colleges, local administration and teachers, nized, every attempt should be made to honour the patient interest groups, even street theatres, all demands set by patient's rights and for this both the contributing to a general understanding about the doctor and the patient will need support — certainly proper use of medicines. such constraints should not lead to thoughts of abandoning this goal. For the doctor there must be There are many difficulties encountered in the more impartial, reliable and clear information about provision of medicines. Many drugs are prescribed treatment alternatives. This will require resources to irrationally and rationally-prescribed drugs are used allow national formularies to be introduced, wastefully. The introduction of patient's rights independent drug bulletins to be established, drug should spur the greater involvement of the public as information centres set up and local treatment patient, consumer and taxpayer and through shared guidelines written. For the patient, there needs to responsibility and understanding lend itself to a be greater awareness and full understanding, not more rational and efficient use of resources. Reports on Individual Drugs

P. carinii or T. gondii infection. Half were randomly Dapsone-pyrimethamine: dual allocated to a combination of dapsone 50 mg/day therapy in HIV infection? and pyrimethamine 50 mg/week, and half to aerosolized pentamidine 300 mg/month. By the end Where the incidence of Pneumocystis carinii of a median follow-up period of 18 months there pneumonia is declining among HIV-positive patients was no significant difference either in overall as a result of primary prophylaxis (1), the incidence mortality or the incidence of P. carinii pneumonia in of other opportunistic infections, notably toxo­ the two groups. In contrast, toxoplasmosis occurred plasmic encephalitis, is increasing (2-4). This trend in 32 patients who were taking pentamidine and in is particularly evident in Europe where, in some only 19 patients taking dapsone/pyrimethamine. areas, the seroprevalence of Toxoplasma gondii in Among over 250 patients with serological evidence adults exceeds 70% (5). In France, for instance, of past exposure to T. gondii, the relative risk of toxoplasmic encephalitis now provides the first symptomatic toxoplasmosis was almost 2.5 times clinical indication of AIDS in almost one-quarter of higher among patients assigned to pentamidine. cases reported (3). Significant adverse effects occurred in only 3 There is consequently a strong incentive to develop patients who received pentamidine. In contrast, a single prophylactic regimen providing protection dapsone/pyrimethamine had to be withdrawn against both of these potentially fatal manifestations definitively in 4 patients and dosage was attenuated of AIDS. There is optimism that atovaquone or or interrupted in a further 39 because of unwanted another hydroxynaphthoquinone compound with effects, notably anaemia, neutropenia, fever or skin broad-spectrum antiprotozoal activity may even­ rash. This difference is clearly of clinical import­ tually qualify (see p. 125) but no obvious candidate ance, but it may not operate decisively against the drug is at hand. The drug combinations that are use of dapsone/pyrimethamine: in other settings currently used to treat toxoplasmosis — pyrimeth­ substantial failure rates have been reported with the amine/sulfadiazine and pyrimethamine/clinda-mycin pentamidine regimen used in this trial (11-16) and — are too toxic to be considered for prophylaxis (6, it is no longer officially recommended by the US 7). Nor do the two regimens used to protect against Food and Drug Administration as first-line prophy­ P. carinii pneumonia (8-16) hold promise: laxis against P. carinii pneumonia (23). It has been aerosolized pentamidine has no activity against superseded in this role by trimethoprim/sulfameth­ T. gondii and there is no reason to expect that oxazole which has been demonstated to be more trimethoprim/sulfamethoxazole would be effective, effective in at least two recent trials (16, 24), but although this remains unproven. which may be no better tolerated than dapsone/ pyrimethamine. The need now is for a direct clinical Regimens based on the sulfone compound, comparison of the performance of these two dapsone, could well provide a solution. Dapsone is combination treatments. effective in protecting against P. carinii pneumonia References in an animal model (17) and, combined with trimethoprim, it has provided effective protection in 1. Guidelines for prophylaxis against Pneumocystis carinii HIV-positive patients (18). Sulfones also inhibit pneumonia for persons infected with human immunodefi­ dihydropteroate synthetase, a component of a vital ciency virus. Morbidity and Mortality Weekly Report, 38 T. gondii enzyme system (19) and this action is (suppl 5): 1-9(1989). potentiated by pyrimethamine (20, 21). 2. Schwartlander, B., Horsburgh, C, Hamouda, O. et al. Changes in the spectrum of AIDS-defining conditions and The potential of this combination for protecting decrease in CD4+ lymphocyte counts at AIDS manifesta­ against both P. carinii pneumonia and symptomatic tion in Germany from 1986 to 1991. AIDS, 6: 413-420 toxoplasmosis has recently been explored in a (1992). clinical context (22). The 349 patients admitted to 3. Surveillance du SIDA en France: situation au 31 mars the study had symptomatic HIV infection and CD4+ 1992. Bulletin Epidémiologique Hebdomodaire, 19: 81-87 cell counts below 200/cm3, but no clinical history of (1992). 4. Clumeck, N. Some aspects of the epidemiology of 15. Murphy, R., Lavelle, J., Allan, J. et al. Aerosol toxoplasmosis and pneumocystosis in AIDS in Europe. pentamidine prophylaxis following Pneumocystis carinii European Journal of Clinical Microbiology and Infectious pneumonia in AIDS patients: results of a blinded, dose- Disease, 10: 177-178 (1991). comparison study using an ultrasonic nebuliser. American Journal of Medicine, 90: 418-426 (1991). 5. Derouin, F., Beauvais, B., Larivière, M. Serological study of the prevalence of toxoplasmosis in 167 patients 16. Schneider, M., Hoepelman, A., Eeftinck Schattenkirk, with acquired immunodeficiency syndrome (AIDS) or J. et al. A controlled trial of aerosolized pentamidine or chronic lymphadenopathy syndrome (LAS). Biomedical trimethoprim/sulfamethoxazole as primary prophylaxis Pharmacotherapy, 40: 231-232 (1986). against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. New England 6. Dannemann, B., McCutchan, J., Israelski, D. et al. Journal of Medicine, 327: 1836-1841 (1992). Treatment of toxoplasmic encephalitis in patients with AIDS: a randomized trial comparing pyrimethamine plus 17. Hughes, W., Smith, B. Efficacy of diaminodiphenyl- clindamycin to pyrimethamine plus sulfadiazine. Annals of sulphone and other drugs in murine Pneumocystis carinii Internal Medicine, 116: 33-43 (1992). pneumonitis. Antimicrobial Agents and Chemotherapy, 26: 436-440(1984). 7. Jacobson, M., Besch, C, Child, C. et al. Toxicity of clindamycin as prophylaxis for AIDS-associated toxoplas­ 18. Medina, I., Mills, J., Leoung, G. et al. Oral therapy for mic encephalitis. Lancet, 339: 333-334 (1992). Pneumocystis carinii pneumonia in the acquired immuno­ deficiency syndrome: a controlled trial of trimethoprim- 8. Hughes, W., Kuhn, S., Chaudhary, S. et al. Successful sulfamethoxazole versus trimethoprim-dapsone. New chemoprophylaxis for Pneumocystis carinii pneumonitis. England Journal of Medicine, 323: 776-782 (1990). New England Journal of Medicine, 297: 1419-1426 (1977). 19. Allegra, C, Boatman, D., Kovacs, J. et al. Interaction of sulfonamide and sulfone compounds with Toxoplasma 9. Hughes, W., Rivera, G., Schell, M. et al. Successful gondii dihydropteroate synthetase. Journal of Clinical intermittent chemoprophylaxis for Pneumocystis carinii Investigation, 85: 371-379 (1990). pneumonitis. New England Journal of Medicine, 316: 1627-1632(1987). 20. Beverley, J., Fry, B. Sulfadimidine, pyrimethamine and dapsone in the treatment of toxoplasmosis in mice. British 10. Fischl, M., Dickenson, G., La Voie, L. Safety and Journal of Pharmacology and Chemotherapy, 12: 189-193 efficacy of sulfamethoxazole and trimethoprim chemo­ (1957). prophylaxis for Pneumocystis carinii pneumonia in AIDS. Journal of the American Medical Association, 259: 1185- 21. Derouin, F., Piketty C, Chastang, C. et al. Anti- 1189(1988). Toxoplasma effects of dapsone alone and combined with pyrimethamine. Antimicrobial Agents and Chemotherapy, 11. Girard, P., Landman, R., Gaudebout, C. et al. 35:252-255(1991). Prevention of Pneumocystis carinii pneumonia relapse by pentamidine aerosol in zidovudine-treated AIDS patients. 22. Girard, P., Landman, R., Gaudebout, C. et al. Lancet, 1: 1348-1353 (1989). Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis 12. Leoung, G., Feigal, D. Montgomery, A. et al. carinii pneumonia and toxoplasmosis in HIV infection. Aerosolized pentamidine for prophylaxis against New England Journal of Medicine, 328: 1514-1520 Pneumocystis carinii pneumonia: the San Francisco (1993). Community Prophylaxis Trial. New England Journal of Medicine, 323: 769-775 (1990). 23. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults infected with 13. Montaner, J., Lawson, L, Gervais, A. et al. Aerosol human immunodeficiency virus. Morbidity and Mortality pentamidine for secondary prophylaxis of AIDS-related Weekly Report, 41 (RR-4): 1-11 (1992). Pneumocystis carinii pneumonia: a randomized, placebo controlled study. Annals of Internal Medicine, 114: 948- 24. Hardy, W., Feinberg, J., Finkelstein, D. et al. A 953(1991). controlled trial of trimethoprim/sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of 14. Hirschel, B., Lazzarin, A., Chopard, P. et al. A Pneumocystis carinii pneumonia in patients with the controlled study of inhaled pentamidine for primary acquired immunodeficiency syndrome: AIDS Clinical prevention of Pnemocystis carinii pneumonia. New Trials Group Protocol 021. New England Journal of England Journal of Medicine, 324: 1079-1083 (1991). Medicine, 327: 1842-1848 (1992). Diethylstilbestrol: has been concern that it might rise further as the period of observation is extended. No such a human carcinogen increase has been reported in a recently published assessment for periods of 30 years or more Diethylstilbestrol, a synthetic estrogenic substance, following exposure (20). It now seems reasonable was introduced into obstetric practice in the USA in to conclude that exposure to diethylstilbestrol is the late 1940s and was subsequently withdrawn comparable in carcinogenic effect with several from use by the US Food and Drug Administration other exogenous risk factors for breast cancer (21, as a proven carcinogen (1). 22).

The product was claimed to exert a protective effect References in high-risk pregnancy by correcting deficient endogenous progesterone secretion (2, 3), but no 1. Richmond, J. Physician Advisory: Health effects of the satisfactory evidence was ever adduced either that pregnancy use of diethylstilbestrol, DES task force it exerted such an effect (4, 5) or that it had thera­ summary report. United States Department of Health, Education and Welfare, 4 October 1978. peutic value (6, 7). Not until 15 years later, during which time diethylstilbestrol had been used in as 2. Smith, O., Smith, G., Hurwitz, D. Increased excretion of many as 2 million pregnancies in the United States pregnandiol in pregnancy from diethylstilbestrol with alone, was suspicion aroused that its use held special reference to the prevention of late pregnancy unacceptable long-term risks. accidents. American Journal of Obstetrics and Gyne­ cology, 51:411-415(1946). A cluster of cases of a hitherto rare tumour — clear cell adenocarcinoma of the vagina and cervix — 3. Smith, O. Diethylstilbestrol in the prevention and seen in young women presenting at Massachusetts treatment of complications of pregnancy. American Journal of Obstetrics and Gynecology, 56: 821 -834 General Hospital inspired a series of case-control (1948). studies that decisively associated the lesion with prenatal exposure to diethylstilbestrol (8-10). 4. Davis, M., Fugo, N. Does administration of diethyl­ Overall, it has been estimated that about 60% of stilbestrol to pregnant women result in increased output of these tumours are associated with such exposure urinary pregnandiol? Proceedings of the Society of and that an exposed daughter has about 1 chance Experimental Biology and Medicine, 69: 436-438 (1948). in 1000 of developing clear cell adenocarcinoma by her mid-thirties (11). 5. Sommetville, I., Marrian, G., Clayton, B. Effect of diethylstilbestrol on urinary excretion of pregnandiol and endogenous oestrogen during pregnancy. Lancet, 1: 680- Early reports of vaginal dysplasia in several of 682(1949). these daughters suggested that prenatal exposure might predispose to commonly-occurring squamous 6. Ferguson, J. Effect of stilbestrol on pregnancy cell cancers as well as to adenocarcinoma (12). As compared to the effect of placebo. American Journal of yet, a relationship between such exposure and risk Obstetrics and Gynecology, 65: 592-601 (1953). of subsequent development of squamous cell cancer is not proven (13), although, by 1984, 7. Dieckmann, W., Davis, M., Rynkiewicz, L, Pottinger, R. follow-up of some 4000 daughters had indicated Does the administration of diethylstilbestrol during that exposure is associated with an increase in the pregnancy have therapeutic value? American Journal of incidence of cervical dysplasia and carcinoma in Obstetrics and Gynecology, 66: 1062-1081 (1953). situ particularly among those with extensive 8. Herbst, A„ Ulfelder, H., Poskanzer, D. Adenocarcinoma squamous metaplasia around areas of adenosis of the vagina: association of maternal stilbestrol therapy (14). with tumor appearance in young women. New England Journal of Medicine, 284: 878-881 (1971). In contrast, a moderate but firm association between exposure and increased risk of breast 9. Noller, K., Decker, G., Lanier, A., Kurland, L Clear cell cancer has been firmly established in mothers who adenoma of the cervix after treatment with synthetic received diethyl-stilbestrol (15-20). No increase in estrogens. Mayo Clinic Proceedings, 47: 629-630 (1972). risk has been demonstrated within the first 20 years 10. Herbst, A., Poskanzer, D., Robboy, S., Scully, R. following exposure. Over the next decade, Prenatal exposure to stilbestrol: a new prospective however, the excess risk progressively increases. comparison of exposed female offspring with unexposed Between 20 and 29 years following exposure, the controls. New England Journal of Medicine, 292: 334-339 relative risk has been estimated to be 1.6 and there (1972). 11. Melnick, S., Cole, P., Anderson, D., Herbst, A. Rates and risks of diethylstilbestrol-related clear-cell Tacrine: a first step towards adenocarcinoma of the vagina and cervix. New England management of Alzheimer's disease Journal of Medicine, 316: 514-516 (1987). Alzheimer's disease, which was first characterized 12. Stafl, A., Mattingly, R. Vaginal adenosis — a 90 years ago (1), is the most common of the precancerous lesion? American Journal of Obstetrics and neurodegenerative disorders. Decline in memory, Gynecology, 126: 543-548 (1976). cognition, and neurologic function leads eventually to severe dementia and death (2, 3). It is estimated 13. Report of the 1985 DES Task Force. Office of Cancer Communications, National Cancer Institute, Bethesda, to afflict between 2 to 4 million persons aged over MD., 1985. 65 in the United States alone (4-6).

14. Robboy, S., Noller, K., O'Brien, P. et al. Increased The disease is characterized histopathologically by incidence of cervical and vaginal dysplasia in 3 980 neurofibrillary tangles in the hippocampus and diethylstilbestrol-exposed young women: experience of cortex and deposition of beta-amyloid in extra­ the National Collaborative Diethylstilbestrol Adenosis cellular senile plaques and in cerebral blood Project, Journal of the American Medical Association, vessels (7). Evidence is accumulating that these 252: 2979-2983 (1984). changes are genetically influenced, and that the most important risk factor is the gene which codes 15. Bibbo, M., Haenszel, W., Wied, G. et al. A twenty-five year follow-up study of women exposed to diethylstilbes­ for apolipoprotein E4, one of three versions of a trol during pregnancy. New England Journal of Medicine, protein important in cholesterol transport and which 298: 763-767 (1978). also binds and precipitates beta-amyloid (8, 9).

16. Beral, V., Colwell, L Randomised trial of high doses of Of more immediate importance, since it provides a stilbestrol and ethisterone in pregnancy: long-term follow- possible approach to palliative management, is up of mothers. British Medical Journal, 281: 1098-1101 evidence that the disease is associated in many (1980). patients with impairment of central cholinergic 17. Vessey, M., Fairweather, D., Norman-Smith, B., transmission (10-14). Optimism that relatively Buckley, J. A randomised double-blind controlled trial of simplistic pharmacological interventions might be the value of stilbestrol therapy in pregnancy: long-term beneficial has been tempered by clinical and follow-up of mothers and their offspring. British Journal of biochemical indications that the disease is a hetero­ Obstetrics and Gynaecology, 90: 1007-1017 (1983). genous condition sometimes involving other neurotransmitter systems (15-17). This might be 18. Greenberg, E., Barnes, A., Resseguie, L. et al. Breast explained, however, if the basic abnormality were in cancer in mothers given diethylstilbestrol in pregnancy. the neuronal synthesis, storage or secretion of the New England Journal of Medicine, 311: 1393-1398 enzyme acetylcholinesterase (16, 18) which is (1984). present and functional in many non-cholinergic, as 19. Hadjimichael, O., Meigs, J., Falcier, F. et al. Cancer well as cholinergic, neurons in the cortex and in risk among women exposed to exogenous estrogens subcortical nuclei (11, 12, 19). An added incentive during pregnancy. Journal of the National Cancer Institute, to explore this approach has been provided by 73:831-834(1984). recent demonstration of an anomalous, relatively inefficient form of acetylcholinesterase with 20. Colton, T., Greenberg, E., Noller, K. et al. Breast distinctive kinetic properties in the cerebrospinal cancer in mothers prescribed diethylstilbestrol in preg­ fluid of the majority of patients with Alzheimer's nancy: further follow-up. Journal of the American Medical disease (20). Association, 269: 2096-2100 (1993).

21. Evaluation of Carcinogenic Risks to Humans — Early clinical studies of the evanescent effect of Overall Evaluations of Carcinogenicity: An Updating of intravenous infusion of the naturally-occurring IARC Monographs Vol 1-42: International Agency for anticholinesterase substance, physostigmine, on Research on Cancer, Lyon, France, 1987. memory processes in these patients were encouraging (21-23), and more recent experience 22. Recommendations of DES Task Force. FDA Drug with tacrine hydrochloride, an orally-effective, Bulletin, Vol. 15, December 1985. centrally-active, longer-acting reversible cholin- esterase inhibitor (24, 25), has been promising enough (26-29) to justify the organization of large- 2. Reisberg, B., Ferris, S., De Leon, M., Crook, T. The Global Deterioration Scale for assessment of primary scale, multicentre, controlled trials. degenerative dementia. American Journal of Psychiatry, 139: 1136-1139(1982). In the first of these studies, which involved some 200 patients preselected for apparent responsive­ 3. McKhann, G., Drachman, D., Folstein, M. et al. Clinical ness to tacrine, a double-blind comparison of diagnosis of Alzheimer's disease: report of the NINCDS- ADRDA Work Group under the auspices of the Depart­ placebo and tacrine taken in a divided daily dose of ment of Health and Human Services Task Force on 40 or 80 mg for 6 weeks provided evidence of a Alzheimer's Disease. Neurology, 34: 939-944 (1984). marginal reduction in the rate of decline of cognitive function among the treated patients (30). The 4. Plum, F. Dementia: an approaching epidemic. Nature, second study, which involved almost 500 patients, 279:372-373(1975). compared responses to tacrine and placebo over a treatment period of 12 weeks at dosages ranging 5. Katzman, R. Alzheimer's disease. New England Journal up to 80 mg daily (31). Towards the end of the of Medicine, 314: 964-973 (1986). treatment period, about half the patients who received the highest dose showed clinically 6. Schoenberg, B., Anderson, O., Haerer, A. Severe detectable cognitive improvement. However, dementia: prevalence and clinical features in a biracial US population. Archives of Neurology, 42: 740-743 (1985). monitoring of liver function was shown to be essential to avoid clinically significant toxicity: 7. Khachaturian, Z. Diagnosis of Alzheimer's disease. tacrine induced asymptomatic and reversible Archives of Neurology, 42: 1097-1105 (1985). increases in serum transaminases in some 25% of patients ranged as high as 10-fold above the upper 8. Corder, E., Saunders, A., Strittmatter, W. et al. Gene limit of normal. dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science, 261: Since 1991, the US Food and Drug Administration 921-923(1993). has allowed doctors participating in an open 9. Travis, J. New piece in Alzheimer's puzzle. Science, assessment of tacrine to treat selected patients with 261:828-829(1993). a dose of 40 mg daily for an initial 6-week period, which — when well tolerated — has eventually 10. Davies, P., Moloney, A. Selective loss of central been titrated up to 120 mg daily. Serum trans­ cholinergic neurones in Alzheimer's disease. Lancet, 2: aminases have been monitored weekly for the first 1043(1976). 18 weeks and subsequently at less frequent intervals. Overall, it has been estimated that about 11. Mesulam, M., Geula, C. Acetylcholinesterase-rich 30% of patients both tolerate the drug and show pyramidal neurons in the human neocortex and hippo­ clinically meaningful improvement (32). campus: absence at birth, developing during the life span, and dissolution in Alzheimer's disease. Annals of Neurology, 24: 765-773 (1988). It is on this basis that the Food and Drug Administration has decided to approve tacrine for 12. Smith, A., Cuello, A. Alzheimer's disease and general palliative use. As yet, there is no means of acetylcholinesterase neurons. Lancet, 1: 513 (1984). predicting either responsiveness or sensitivity to treatment: this has to be assessed by individual 13. Bartus, R., Dean, R., Beer, B., Lippa, A. The cholin­ therapeutic trial. Nor has there been any ergic hypothesis of geriatric memory disfunction. Science, experience of extended exposure. Tacrine is 217:408-414(1982). obviously not the final solution to the management of Alzheimer's disease, but the fact that it offers 14. Perry, E. The cholinergic hypothesis — ten years on. modest help to some patients will provide impetus British Medical Bulletin, 42: 63-69 (1986). and direction to further research efforts. 15. Bondareff, W., Mountjoy, C, Roth, M. et al. Age and histopathologic heterogeneity in Alzheimer's disease: References evidence for subtypes. Archives of General Psychiatry, 44:412-417(1987). 1. Alzheimer, A. Uber ein eigenartige Erkrankung der 16. Farrer, L, Myers, R., Cupples, L. et al. Transmission Himrinder. Allgemeine Zeitung Psychiatrie, 64: 146-148 and age-at-onset patterns in familial Alzheimer's disease: (1907). evidence for heterogenicity. Neurology, 40: 395-403 (1990). 17. Reinikeinen, K., Paljarvi, L., Halonen, T. et al. Dopa­ 30. Davis, K., Thai, L, Gamzu, E. et al. and the Tacrine minergic system and monoamine oxidase-B activity in Collaborative Study Group. A double-blind, placebo- Alzheimer's disease. Neurobiology of Aging, 9: 245-252 controlled multicenter study of tacrine for Alzheimer's (1987). disease. New England Journal of Medicine, 327: 1253- 1259(1992). 18. Drachman, D., Leavitt, J. Human memory and the cholinergic system: a relationship to aging? Archives of 31. Farlow, M., Gracon, S., Hershey, L. et al. A controlled Neurology,30: 113-121 (1974). trial of tacrine in Alzheimer's disease: for the Tacrine Study Group. Journal of the American Medical Associa­ 19. Nakamura, S., Vincent, S. Acetylcholinesterase and tion, 268: 2523-2529 (1992). somatostatin-immunoreactivity coexist in human neo­ cortex. Neurosciences Letter, 61: 183-187 (1985). 32. Small, G. Tacrine for treating Alzheimer's disease. Journal of the American Medical Association, 268: 2564- 20. Navaratnum, D., Priddle, J., McDonald, B. et al. 2565(1992). Anomalous molecular form of acetylcholinesterase in cerebrospinal fluid in histologically diagnosed Alzheimer's disease. Lancet, 337: 447-450 (1991). Folic acid and spina bifida

21. Davis, K., Mohs, R. Enhancement of memory Many fetuses with neural tube defects are aborted processes in Alzheimer's disease with multiple-dose early in pregnancy. Among babies born at term, intravenous physostigmine. American Journal of Psy­ those with anencephaly die immediately. Most of chiatry, 139: 1421-1424 (1982). those with spina bifida reach adulthood, but some are severely handicapped by paralysis and varying 22. Thai, L, Flud, P., Masur, D., Sharpless, N. Oral physostigmine and lethicin improve memory in degrees of bowel and bladder incontinence. Alzheimer's disease. Annals of Neurology, 13: 491-496 (1983). In 1991, the British Medical Research Council published the results of a large multicentre, double- 23. Mohs, R., Davis, B., Johns, C. et al. Oral physo­ blind trial indicating that extended daily pericon- stigmine treatment of patients with Alzheimer's disease. ceptional supplements of 4 mg folic acid by women American Journal of Psychiatry, 142: 28-33 (1985). who had already had a conceptus with a neural tube defect reduced the incidence of a recurrence 24. Nielsen, J., Mena, E., Williams, I. et al. Correlation of by a factor of 3 to 4 (1). This study conclusively brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioural changes. European confirmed the protective effect of folic acid Journal of Pharmacology, 173: 53-64 (1989). supplements (2, 3). However, it left open at least three important questions: whether these 25. Dawson, R. Tacrine slows the rate of ageing of sarin- supplements also prevent first occurrences of inhibited acetylcholinesterase. Neurosciences Letter, 100: neural tube defects; whether dosage can be 227-230 (1989). reduced without loss of protection; and how long supplementation needs to be maintained to obtain 26. Summers, W., Viesselman, J., Marsh, G., Candelora, the greatest possible protection. K. Use of THA in treatment of Alzheimer-like dementia: pilot study in twelve patients. Biology and Psychiatry, 16: 145-153(1981). There is no apparent reason to assume that folic acid should be less effective in preventing the large 27. Kaye, W., Siraram, H., Weingartner, H. et al. Modest majority of neural tube defects that are first facilitation of memory in dementia with combined lecithin occurrences. Indeed, a prospective randomized and anticholinesterase treatment. Biology and Psychiatry, controlled trial undertaken in Hungary, involving 17: 275-280 (1982). women who had not had a prior affected preg­ nancy, was closed prematurely because of 28. Summers, W., Majovski, L, Marsh, G. et al. Oral evidence of a protective effect of folic acid in doses tetrahydroaminoacridine in long-term treatment of senile as low as 0.8 mg daily (4, 5). However, other dementia, Alzheimer-type. New England Journal of Medicine, 315: 1241-1245 (1986). relevant observational studies have provided inconsistent results (6-9). 29. Division of Neuropharmacological Drug Products, Food and Drug Administration. Tacrine as a treatment for Given that there may be a case for administering Alzheimer's dementia: an interim report from the FDA. folic acid supplements to all prospective mothers, New England Journal of Medicine, 324: 349-352 (1991). an appropriate starting point for investigation is to associated with birth defects. The use of very high establish whether any association can be demon­ dose regimens of folic acid (4 mg daily) is still strated between neural tube defects and normal accepted as a reasonable option — although it is maternal dietary intake of folic acid including no longer positively recommended — for women at regular use of multivitamin supplements. It is risk of recurrence who are planning a further estimated that about 20% of women in North pregnancy. America now regularly take multivitamin prepara­ It is striking that all the published observational and tions that typically include folic acid at a daily dose intervention studies concerned with neural tube of 0.4 mg (10). defects have thus far been conducted in affluent Using a case-control design, a retrospective study populations with a relatively high average daily has recently been conducted in the United States intake of folate. It has not yet been confirmed (11) comparing the folic acid content in the diet and whether these defects become more prevalent with multivitamin preparations containing folic acid more severe degrees of maternal folate deficiency. among mothers giving birth to a child either with a If this is shown to be the case, attention for neural tube defect (436 cases) or a range of other preventive strategies should also focus on the less major malformations (2615 cases). A dose-related affluent countries of the developing world. decline in the risk of a neural tube defect was References demonstrated for dietary folate according to the quintile of intake. Moreover, among mothers who 1. Medical Research Council Vitamin Study Research had taken folic acid supplements daily for 4 weeks Group. Prevention of neural tube defects: results of the before and after the last menstrual period, the risk Medical Research Council Vitamin Study. Lancet, 338: was decreased by 60% (relative risk 0.4; 95% 131-137(1991). confidence interval, 0.2 to 0.6). 2. Smithells, R., Nevin, N., Seller, M. et al. Further The authors of the study emphasize, having regard experience of vitamin supplementation for prevention of to the embryologic timing of neural tube closure, neural tube defect recurrences. Lancet, 1: 1027-1031 (1983). that folic acid intake must be enhanced in advance of pregnancy if a protective effect is to be assured. 3. Laurence, K., James, N., Miller, M. et al. Double-blind, However, within the total sample of women involved randomised controlled trial of folate treatment before in this study, 40% of the pregnancies were conception to prevent recurrence of neural tube defects. unplanned — a figure which accords closely with British Medical Journal, 282: 1509-1511 (1981). independent national statistics (12) — and half the women who had planned their pregnancies had not 4. Czeizel, A., Fritz, G. Letter to the Editor. Journal of the sought early professional advice. Given these American Medical Association, 262: 1634 (1989). circumstances, any public health initiative intended to reduce the incidence of spina bifida must be 5. Czeizel, A. Cited in: Morbidity and Mortality Weekly aimed, if it is to have impact, at all women who may Report, 41: RR-14 (1992). become pregnant. 6. Mulinare, J., Cordero, J., Erikson, J., Berry, J. Periconceptional use of multivitamins and the occurrence of By appropriate selection of foods, women in North neural tube defects. Journal of the American Medical America can readily increase their intake of folate to Association, 260: 3141-3145 (1988). more than 0.4 mg daily. However, it is estimated that their average consumption of dietary folate — 7. Bower, C, Stanley, F. Dietary folate as a risk factor for which, in general, is not as well absorbed as folic neural tube defects: evidence from a case-control study in acid — does not exceed 0.2 mg daily (13). Women Western Australia. Medical Journal of Australia, 150: 613- of child-bearing potential within the United States 619(1989). are consequently advised by the Centers for Disease Control and Prevention to take a daily 8. Mills, J., Rhoads, G., Simpson, J. et al. The absence of a relation between the periconceptual use of vitamins and supplement of 0.4 mg folic acid as a preventative neural tube defects. New England Journal of Medicine, measure (14). At the same time they are advised to 321:430-435(1989). avoid unnecessary over-consumption of folate by restricting total daily dietary intake to less than 1 9. Milunsky, A., Jick, H., Jick, S. et al. Multivitamin/folic mg. They are also advised to avoid excessive use acid supplementation in early pregnancy reduces the of multivitamin preparations or fortified foods prevalence of neural tube defects. Journal of the containing vitamin A, since these have also been American Medical Association, 262: 2847-28542 (1989). 10. Moss, A., Levy, A., Kim, I. et al. Use of vitamin and and complexity of administering them on a routine mineral supplements in the United States: current users, basis excludes the use of combined regimens in types of products and nutrients. National Center for Health developing countries. Statistics, Hyattsville, MD. No. 174 (1989). A more practicable approach could be to administer 11. Werler, M., Shapiro, S., Mitchell, A. Periconceptional a supplemental dose of injectable vaccine to folic acid exposure and risk of occurrent neural tube defects. Journal of the American Medical Association, children who have already received three doses of 269: 1257-1261 (1993). oral vaccine at 2, 3, and 4 months of age. A comparison has recently been completed in Cote 12. Grimes, D. Unplanned pregnancies in the U.S. d'lvoire of the immunogenicity of a supplementary Obstetrics and Gynecology, 67: 438-442 (1986). dose of randomly allocated injectable or oral vaccine administered at the same time as Schwarz 13. National Academy of Sciences. Nutrition during measles vaccine to some 800 children aged 6-9 pregnancy. Institute of Medicine, Food and Nutrition months (14). Among children with no detectable Board. National Academy Press, Washington, DC. p 365 antibody prior to the supplemental dose, sero­ (1990). conversion occurred 14-fold more frequently among 14. Centers for Disease Control and Prevention. Recom­ those receiving the injectable vaccine. The rise in mendations for use of folic acid to reduce number of spina antibody titre among children who had detectable bifida cases and other neural tube defects. Journal of the antibody was also significantly greater among American Medical Association, 269: 1233-1238 (1993). children who received this preparation.

The authors of this study suggest, without direct Poliovirus vaccines: proof, that the incorporation of a single supple­ mental dose of injectable vaccine into the existing the case for a supplemental dose vaccination regimen "could substantially reduce the numbers of paralyses in countries where immuniza­ Intensive use of live attenuated oral poliovirus tion coverage with 3 or more doses of oral vaccine vaccine has virtually eliminated paralytic polio­ is high (c. 90%), but where immunogenicity studies myelitis from industrialized countries (1) and from have revealed large gaps in immunity to poliovirus South and Central America (2, 3). These successes types 1 and 3". They calculate that the incremental reflect three vital properties of these vaccines: they are simple to administer, they induce high levels of cost of providing this dose is similar to or lower than secretory antibody in the gut as well as serum the cost of mass vaccination campaigns (15-17) neutralizing antibody, and secondary spread can and less than the cost of extending the routine result in immunization of susceptible contacts (4). immunization schedule to provide additional doses. However, outbreaks of poliomyelitis have occurred They also emphasize, however, as others have in several developing countries despite high uptake done (2, 9) that resources would be better spent, of oral vaccine (5-7). This has been attributed to where high immunization coverage has not been relatively low immunogenicity against poliovirus attained, in raising the immunity of the population types 1 and 3 among children in many developing through a combination of improved routine services countires (8) and it has raised concerns about the and the organization of mass campaigns. feasibility of eradicating poliomyelitis by the year References 2000 (2, 5, 8). 1. World Health Organization. Poliomyelitis in 1988, 1989, There is no doubt that orally administered vaccine and 1990. Weekly Epidemiological Record, 67: 113-117 will remain the cornerstone of the current global (1992). eradication programme during the years ahead. 2. de Quadros, C, Andrus, J., Olive, J. et al. Polio However, additional operational measures need to eradication from the western hemisphere. Annual Reviews be devised to prevent or contain the disease when of Public Health, 13: 239-252 (1992). the basic strategy fails (9). The obvious approach is to introduce injectable, enhanced potency, in­ 3. Pan American Health Organization. Update: eradication activated poliovirus vaccine into the immunization of poliomyelitis in the Americas. Morbidity and Mortality Weekly Report, 41: 681-683 (1992). schedule, since this induces detectable neutralizing antibody in almost all recipients after three doses 4. Wright, P., Kim-Farley, R., de Quadros, C. et al. (10-12). Immunization schedules using both oral Strategies for the global eradication of poliomyelitis by the and injectable vaccine have already been used with year 2000. New England Journal of Medicine, 335: 1174- success in a community setting (13), but the cost 1179(1992). 5. Sutter, R., Patriarca, P., Brogan, S. et al. Outbreak of 11. McBean, A., Thorns, M., Albrecht, P. et al. Serologic paralytic poliomyelitis in Oman. Evidence for widespread response to oral poliovirus vaccine and enhanced-potency transmission among fully vaccinated children. Lancet, inactivated polio vaccines. American Journal of Epidemi­ 338: 715-720(1991). ology, 128: 615-628 (1987).

6. Otten, M., Deming, M., Jaiteh, K. et al. Epidemic 12. Swartz, T., Handsher, R., Stoekel, P. et al. Immuno­ poliomyelitis in a well-vaccinated population, The Gambia, logic memory induced at birth by immunization with 1986. Part 1. descriptive findings. American Journal of inactivated polio vaccine in a reduced schedule. European Epidemiology, 135: 380-392 (1992). Journal of Epidemiology, 5: 143-145 (1989). 7. Reichler, M, Abbas, A., Alexander, J. et al. Outbreak of poliomyelitis in a highly immunized population in Jordan 13. Tulchinsky, T., Abed, Y., Shaheen, S. et al. A ten-year [Abstract 1723] In: Program and Abstracts of the 32nd experience in the control of poliomyelitis through a Interscience Conference on Antimicrobial Agents and combination of live and killed vaccine in two developing Chemotherapy. American Society for Microbiology: areas. American Journal of Public Health, 79: 1648-1652 Washington, DC, 1992, p 398. (1989).

8. Patriarca, P., Wright, P., John, T. Factors affecting the 14. Moriniere, B., van Loon, F., Rhodes, P. et al. immunogenicity of oral polio vaccine in developing Immunogenicity of a supplemental dose of oral versus countries: a review. Reviews of Infectious Diseases, 13: inactivated poliovirus vaccine. Lancet, 341: 1545-1550 926-939(1991). (1993).

9. Patriarca, P., Linkins, R., Sutter, R., Orenstein, W. 15. Creese, A. Cost-effectiveness of alternative strategies Optimal schedule for the administration of oral poliovirus for poliomyelitis immunization in Brazil. Reviews of vaccine. In: Kurstak, E. ed. Measles and poliomyelitis. Infectious Diseases, 6 (suppl): 404-407 (1984). Vaccines and immunization. Springer-Verlag, New York, 1993. 16. Creese, A., Dominguez-UIGA, M. Cost-effectiveness of immunization programmes in Colombia. Bulletin of the 10. Simoes, E., Padmini, B., Steinhoff, M. et al. Antibody Pan American Health Organization, 21: 377-394 (1987). response of infants to two doses of inactivated poliovirus vaccine of enhanced potency. American Journal of 17. Shepard, D.S. et al. Cost-effectiveness of routine and Diseases of Childhood, 139: 977-980 (1985). campaign vaccination strategies in Ecuador. Bulletin of the World Health Organization, 67: 649-662 (1989). General Information

Guillain-Barré syndrome: demonstrably beneficial. Practice had been determined largely by precept, but also by some immunoglobulins or steroids? persuasive collateral evidence. Steroid regimens had been shown to hasten improvement in a The Guillain-Barré syndrome, first described by two clinically related condition, chronic idiopathic eminent French neurologists in the early decades of demyelinating polyradiculoneuropathy (8), and two this century, is now recognized to be the most independent trials had indicated that short courses common cause in developed countries of acute of high-dose intravenous methylprednisolone can neuromuscular paralysis (1). Within hours or days attenuate relapses in patients with multiple of a short prodromal illness characterized by sclerosis (9,10). Moreover, the characteristic headache, vomiting, pyrexia and pain in the back inflammation and oedema which develops in the and limbs, flaccid paralysis develops which usually proximal segments of the spinal nerves had been progresses rapidly to involve all four limbs, the shown to be strikingly similar to an allergic steroid- trunk and respiratory muscles. Some 10% of responsive neuritis that can be induced in animals patients subsequently die and a further 20% remain (11,12). seriously disabled one year later (2, 3). Among the patients who survive, recovery is spontaneous but As yet, however, use of steroids under controlled slow. Some 10—30% initially require assisted conditions has been largely discouraging. Only in ventilation (1, 4) and the median period during one small trial, in which two groups of 8 patients which patients receiving supportive treatment are were randomized to receive either adrenocortico- unable to walk has been variously estimated to trophic hormone or placebo, has there been any range from 12 to 16 weeks (5, 6). suggestion of accelerated recovery (13). A second, larger study provided no indication of benefit from a The initial assumption that the disease results from low-dose regimen of oral prednisolone: 60 mg daily a viral infection remains unsupported. It is now for one week, 40 mg daily for 4 days, and 30 mg widely considered to represent an autoimmune daily for 3 days (14). In this trial, three of the response to an unidentified antigen present in patients treated with prednisolone relapsed within Schwann cells or peripheral nerve myelin (1). The 12 months. Negative findings have also recently cell count in the cerebrospinal fluid remains been reported from a European collaborative study unchanged, but the protein content typically rises sponsored by the British Medical Research Council as high as 100-1000 mg/dl. Two independent trials which involved almost 250 patients who were undertaken respectively in the USA (5) and France randomized within 15 days of the onset of neuro­ (6), and each involving some 250 patients, have logical symptoms to receive either intravenous indicated that recovery is accelerated by exchange methylprednisolone 500 mg or placebo in a single transfusion undertaken within two weeks of the first infusion (15). In this study, 4 patients — each of signs of paralysis. It seems probable, however, whom had received the steroid — relapsed within 4 having regard to recently-released interim results weeks. However, at the end of one year a similar from a trial in the Netherlands, that greater benefit number of relapses had occurred within both can be obtained more simply by intravenous groups of patients. This parenteral dose of administration of immunoglobulin (7). After only 75 methylprednisolone is similar to that used routinely patients had been randomly allocated to each in the management of multiple sclerosis (16) and group, a significant difference had emerged in the transplant rejection. It is also as large as might time by which they were able to walk unaided reasonably be administered to patients at (median 69 days for patients undergoing plasma substantial risk of chest infection. exchange, and 55 days for those receiving intravenous immunoglobulin). Various suggestions have been offered to explain its failure to produce a therapeutic response in this Although steroids have long been used to treat the setting (15). Guillain-Barré syndrome is commonly disease, little direct comparative information had associated with circulating complement-fixing been generated until recently on whether they are antibody to a component of peripheral nerve myelin (17), whereas lymphocytic infiltration in the affected 9. Milligan, M., Newcombe, R., Compston, D. A double- spinal nerves is rarely pronounced (18). Both these blind controlled trial of high-dose methylprednisolone in findings suggest — as does the success claimed patients with multiple sclerosis. 1. Clinical effects. Journal for immunoglobulin therapy — that antibody pro­ of Neurology, Neurosurgery and Psychiatry, 50: 511-516 (1987). duction in this disease is dependent upon a humoral mechanism and not upon the cell- 10. Bames, M., Bateman, D., Cleland, P. et al. Intra­ mediated mechanism operative in the animal venous methylprednisolone for multiple sclerosis in model. Alternatively, steroids might prevent the relapse. Journal of Neurology, Neurosurgery and development of suppressor T-cells or of anti­ Psychiatry, 48: 157-159 (1985). idiotypic antibodies; they might interfere with 11. Watts, P., Taylor, W., Hughes, R. High-dose methyl­ macrophage function and impede the clearance of prednisolone suppresses experimental allergic neuritis in myelin debris (19); or they might prevent remyelin- the Lewis rat. Experimental Neurology, 103: 101-104 ation by suppressing Schwann cell proliferation. (1989). 12. King, R., Craggs, R., Gross, M., Thomas, P. Effects of Whatever the explanation that underlies these glucocorticoids on experimental allergic neuritis. Experi­ results, treatment of the Guillain-Barré syndrome mental Neurology, 87: 9-19 (1985). seems set to move decisively away from steroid therapy towards administration of immunoglobulin. 13. Swick, H., McQuillen, M. The use of steroids in Ethical difficulties loom large, but there is urgent idiopathic polyneuritis. Neurology, 26: 205-212 (1976). need for confirmation of the findings of the Netherlands trial (7) before the debate is closed. 14. Hughes, R., Newsom-Davis, J., Perkin, G., Pierce, J. Controlled trial of prednisolone in acute polyneuropathy. References Lancet, 2:750-753(1978).

1. Hughes, R. Guillain-Barré syndrome. Springer-Verlag, 15. Hughes, R., Swan, A., Guillain-Barré Syndrome Heidelberg, 1990. Steroid Trial Group. Double-blind trial of intravenous methylprednisolone in Guillain-Barré syndrome. Lancet, 341: 586-590(1993). 2. Winer, J., Hughes, R., Osmond, C. A prospective study of acute idiopathic neuropathy. 1, Clinical features and their prognostic value. Journal of Neurology, Neuro­ 16. Hughes, R. Prospects for the treatment of multiple surgery and Psychiatry, 51: 605-612 (1988). sclerosis. Journal of the Royal Society of Medicine, 84: 63-64(1991). 3. Raphael, J., Masson, C, Morice, V. et al. Le syndrome de Guillain-Barré: etude retrospective de 233 observa­ 17. Vriesendorp, F., Mayer, R., Koski, C. Kinetics of anti- tions. Seminaires des Hôpitaux de Paris, 60: 2543-2546 peripheral nerve myelin antibody in patients with Guillain- (1984). Barré syndrome treated and not treated with plasma­ pheresis. Archives of Neurology, 48: 858-861 (1991). 4. Ropper, A., Wijdicks, E., Truax, B. Guillain-Barré syndrome. F. A. Davis Co., Philadelphia, 1991. 18. Honovar, M., Tharakan, J., Hughes, R. et al. A clinicopathological study of Guillain-Barré syndrome: nine 5. The Guillain-Barré Syndrome Study Group. Plasma­ cases and literature review. Brain, 114: 1245-1270 (1991). pheresis and acute Guillain-Barré syndrome. Neurology, 35: 1096-1104(1985). 19. Griffin, J., Stall, G, Li, C. et al. macrophage responses in inflammatory demyelinating neuropathies. Annals of Neurology, 27: S64-S68 (1990). 6. French Cooperative Group on Plasma Exchange on Guillain-Barré Syndrome. Efficacy of plasma exchange in Guillain-Barré syndrome: role of replacement fluids. Annals of Neurology, 22: 753-761 (1987). Artemisinin and its derivatives: 7. Van der Meché, F., Schmitz, P., Dutch Guillain-Barré use as antimalarials Study Group. A randomised trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré A consultative group was convened by WHO in syndrome: one-year follow-up. New England Journal of Geneva on 27-29 September 1993 (1) to consider Medicine, 326: 1123-1129 (1992). the use of artemisinin and its derivatives as anti­ malarial drugs. Its advice, as summarized below, 8. Dyck, P., O'Brien, P., Oviatt, K. et al. Prednisolone seeks to assure effective treatment and to reduce, improves chronic inflammatory demyelinating poly­ as far as is practicable, the risk of emergence of radiculoneuropathy more than no treatment. Annals of Neurology, 11: 136-141 (1982). strains of Plasmodium falciparum resistant to these vital, newly-developed agents. The following recommendations on treatment policy 2) Severe falciparum malaria were developed for presentation to the WHO Expert Parenteral artemether or artesunate should be Committee on The Use of Essential Drugs. reserved for the treatment of severe falciparum malaria where treatment with quinine is ineffective. Reserve antimalarials Research on a limited scale has suggested that artemisinin suppositories may be comparably Artemisinin and related compounds are the most effective and this needs to be confirmed. To assure rapidly acting of all antimalarial drugs. They offer radical cure following parenteral treatment, a thera­ particular advantage in the management of severe peutic dose of mefloquine should be added to the malaria and multidrug-resistant falciparum malaria. regimen. However, there is concern that the widespread irregular and uncontrolled use of these compounds, Situations in which multidrug-resistant malaria particularly of oral formulations, could lead to rapid evolution of drug resistance. In order to assure their is rare or absent effective use and to limit as far as possible the development of resistance, importation and distribu­ In Africa and other areas of the world not affected tion must be controlled, policy for their utilization by multidrug-resistant malaria, it was agreed that must be settled and prescribing guide-lines must be there is no indication to use artemisinin or its readily available. The use of these drugs should be derivatives. In fact their use should be discouraged limited to the treatment of Plasmodium falciparum for the following reasons: infectons and they should not be used for prophy­ laxis. 1) Available, and more conveniently administered drugs such as chloroquine, sulfadoxine/pyrimeth- amine and mefloquine are still effective for the Most of the information on the use of these com­ treatment of uncomplicated malaria. pounds has been obtained in studies on adults, but children also tolerate the drugs well. Because 2) Trials in progress in Africa indicate that quinine is embryotoxicity has been demonstrated in animal studies even in low dosages, these drugs are not at least as effective as artemether in reducing case recommended for use during the first trimester of fatality rates in patients with severe and compli­ pregnancy, except when their use is necessary to cated disease. protect the mother. 3) Premature use of the artemisinin group of drugs, especially oral dosage forms, creates an For use in situations where multidrug-resistant unwarranted risk of facilitating the emergence of malaria is prevalent resistance. This would compromise their efficacy when their use ultimately becomes necessary. 1) Uncomplicated multidrug-resistant malaria Where resistance to chloroquine and sulfadoxine/ The group emphasized that the latter warning pyrimethamine is prevalent, it may be appropriate should be heeded, in particular, by those countries to use mefloquine or quinine (usually in combina­ where there is no current indication for their use, tion with tetracycline). Only when there is evidence but in which they have already been registered. of resistance to these latter drugs, should use of artemisinin and its derivatives be considered. They Every competent national authority should regularly should be administered by mouth in combination review national policy on the use of these drugs, with mefloquine — even where mefloquine having regard to the results of ongoing trials and of resistance is emerging — for a minimum of three monitoring the efficacy of currently available drugs. successive days. If, for any reason, the artemisinin compounds have to be used alone, they should be Recommendations used for a minimum of five successive days. Oral Taking into consideration the clinical and epidemio­ artesunate in a total dose of 10 mg/kg has given logical situation and clinical experience with the cure rates greater than 90% assessed at 28 days. available formulations, the following were selected Equivalent results have been obtained with as the most appropriate for routine use: artemisinin using a total dose of 50 mg/kg. Studies are now in progress with oral artemether and other Parenterally administered preparations related compounds, but appropriate dosage Artemether for intramuscular injection (oil-based regimens have not yet been established. solution) 80 mg in 1-ml ampoule Artesunate for intravenous or intramuscular tional feasibility. It must be emphasized that the injection (anhydrous artesunic acid powder) 60 mg primary objective of a tuberculosis programme is in 1-ml ampoule for reconstitution in 5 % sodium the interruption of tuberculosis transmission by the bicarbonate in 0.6 ml ampoule. curative treatment of infectious tuberculosis cases. Thus, programme implementation of preventive Orally administered preparations therapy would only be considered in areas where Artesunate tablets 50 mg tuberculosis programmes are achieving the global targets established by WHO (i.e., a cure rate of Members emphasized the need for pharmacopoeial 85% and a case detection rate of 70% for new monographs to be established for these prepara­ smear-positive cases) and where voluntary testing tions and for responsible national regulatory and counselling for HIV infection is available. This authorities to collaborate with WHO in ensuring that will require close collaboration between national internationally recognized standards of good AIDS and tuberculosis control programmes. manufacturing practice are implemented. WHO was asked to assure the effective monitoring of their use It is now well established that HIV infection is one of and the adequacy of regulatory measures and to the most potent predisposing factors for the develop means of monitoring parasitic resistance to development of tuberculosis in individuals infected these drugs and possible adverse effects. with Mycobacterium tuberculosis. The estimated annual risk of tuberculosis in persons with HIV and Note tuberculosis co-infection is 5-8 percent, with a lifetime risk as high as 50 percent or greater (1, 2). 1. Participants at the meeting were: In areas where both HIV infection and tuberculosis Professor Marcos Boulos, Instituto de Medicina Tropical, are common — notably countries in sub-Saharan Sao Paulo, Brazil; Brigadier General Kyaw Win, Ministry Africa — HIV infection has had an impact on the of Defence, Yangon, Myanmar; Dr Lê Dinh-Công, Institute tuberculosis situation (3). of Malariology, Parasitology and Entomology, Hanoi, Viet Nam; Professor L. Salako, Federal Ministry of Health and Social Services, Lagos, Nigeria; Dr Shen Jiaxiang, State A large number of placebo-controlled clinical trials Pharmaceutical Administration, Beijing, People's Republic in tuberculin-positive persons at increased risk of of China; Dr Suwit Wibulpholprasert, Food and Drug tuberculosis have shown that the administration of Administration, Bangkok, Thailand; Dr T. Taylor, Michigan daily isoniazid for periods of 6 to 12 months sub­ State University, East Lansing, United States of America; stantially reduces the risk of tuberculosis (4). In Dr N. White, Wellcome Trust Research Unit, Mahidol areas with low annual rates of tuberculosis infection University, Bangkok, Thailand; Professor D. Clyde, this protection is probably life long. Current University of Maryland, Baltimore, United States of IUATLD guidelines on tuberculosis in children America. recommend isoniazid preventive therapy for child­ hood contacts of infectious cases (5). The same recommendation has been made by the WHO Tuberculosis preventive therapy Tuberculosis Programme (6). in HIV-infected individuals Available information suggests that isoniazid The following is a joint statement of the Inter­ therapy is also effective in preventing tuberculosis national Union Against Tuberculosis and Lung in individuals with HIV infection (1, 7, 8). Thus, Disease (IUATLD) and the World Health preventive therapy is the single intervention which Organization (Global Programme on AIDS and the is both readily available and affordable and which Tuberculosis Programme) might reduce the occurrence of HIV-associated tuberculosis in co-infected persons (9). Moreover, This statement is intended to assist health care there are preliminary observations that tuberculosis providers in considering the use of isoniazid may increase progression of HIV infection (10), and preventive therapy in persons with HIV infection. At that tuberculosis preventive chemotherapy may present there is insufficient information to indicate offer the possibility of prolonging the survival of that tuberculosis preventive therapy for co-infected persons with HIV infection (8). persons be implemented in programme settings worldwide; more detailed information is needed on Thus, tuberculosis preventive therapy with isoniazid efficacy of preventive therapy and, in particular, may be indicated for an HIV-seropositive person confirmation of its cost-effectiveness and opera­ with a positive tuberculin test (co-infection) as an individual health measure, if the subject is shown to Administration of isoniazid preventive therapy be free of active tuberculosis. To administer Isoniazid preventive therapy is indicated for preventive therapy safely, it is mandatory that tuberculin-positive, HIV-infected persons who do appropriate facilities to screen individuals for active not have active tuberculosis. For preventive tuberculosis are available and that patients are therapy in both children and adults, isoniazid, at a monitored during therapy. The minimum require­ daily dose of 5 mg/kg up to a maximum of 300 mg, ments for screening are chest X-ray and acid-fast should be given for 6-12 months. Drug supplies microscopy. Facilities for culturing specimens for should be given at monthly intervals and patients mycobacteria are desirable. assessed for compliance, drug toxicity and signs of active tuberculosis. Isoniazid may be given twice Screening for tuberculosis and weekly at the dose of 15 mg/kg for those requiring tuberculosis infection supervision, although there are no clinical studies Education about tuberculosis and the link with HIV demonstrating the efficacy of intermittent preventive infection should be a part of HIV/AIDS pre-test and therapy. Patients who interrupt treatment may be post-test counselling. Individuals who are found to restarted with the aim of providing at least 6 months be HIV-seropositive should be screened for tuber­ of preventive therapy within a twelve-month period. culosis by clinical examination. Those being In this regard, such persons should not have considered for tuberculosis preventive therapy treatment restarted if they have developed signs should receive an intradermal tuberculin skin test and symptoms of tuberculosis and active (Mantoux test) with a product equivalent to 5 TU of tuberculosis has not been excluded. PPD-S or 2 TU of PPD-RT23. A positive test indicating tuberculosis infection is defined as a Isoniazid-associated hepatotoxicity is the most reaction of at least 5 mm of induration at 48-72 important adverse consequence of isoniazid, hours. Although BCG vaccination induces reactivity occurring in up to 2 percent of persons over 50 to PPD, information suggests that the 5-mm cutoff years of age receiving the drug (13). Isoniazid for a positive skin-test is appropriate for adults with preventive therapy is contraindicated in persons HIV infection regardless of vaccination (11). with chronic active hepatitis and should be given with caution to persons who consume alcohol daily. It is critically important to exclude the presence of Although routine biochemical monitoring for active tuberculosis before beginning preventive hepatitis is not recommended, patients should be therapy. Those persons with a positive tuberculin carefully educated about signs and symptoms of skin test should have a chest radiograph. Persons hepatitis and instructed to discontinue the drug with symptoms compatible with pulmonary tuber­ promptly should these occur. culosis and those with abnormal chest radiographs should also have sputum specimens collected for Alternative preventive therapy regimens bacteriological examination. Those with signs and Some authorities have recommended alternative symptoms consistent with extrapulmonary tuber­ preventive therapy regimens for persons intolerant culosis (such as peripheral lymphadenopathy) of isoniazid and for those who are infected with should have appropriate investigations performed. isoniazid-resistant organisms (14). Limited clinical and experimental data support their use (15, 16). HIV-positive persons with negative tuberculin skin- Efficacy in preventing tuberculosis in persons with tests living in areas endemic for tuberculosis may HIV infection has not yet been demonstrated, and be retested periodically (i.e., every six months) for at present no alternative regimen to isoniazid is tuberculosis and new tuberculosis infection, and recommended for preventive therapy. managed accordingly. Anergy to tuberculin is commonly found in persons with HIV infection, Research Issues especially in advanced stages of immuno­ There are a number of questions about tuberculosis suppression. Although there are only limited data preventive therapy in HIV infection which can only supporting isoniazid preventive therapy for anergic be answered by research studies. Among the more persons at risk of tuberculosis, some authorities important questions requiring further studies are: have recommended this practice (12). However, the administration of isoniazid preventive therapy to •the efficacy of "short-course" multidrug therapy; HIV-infected persons without tuberculin testing has not been evaluated and cannot presently be • the role of life long or extended preventive therapy recommended. in areas of high tuberculosis transmission; and • the role of preventive therapy for persons who are 11. Johnson, M.P., Coberly, J.S., Clermont, H.C. et al. anergic. Tuberculin skin test reactivity among adults infected with human immunodeficiency virus. Journal of Infectious Also of paramount importance are operational Diseases, 166: 194-198 (1992). studies to define the role of preventive therapy in 12. Centers for Disease Control. PPD-tuberculin anergy in programme conditions. Included in these studies is persons with HIV infection. Guidelines for anergy testing an analysis of the feasibility of preventive therapy and management of anergic persons at risk of tuberculous as measured by demand, sustainability, and cost- infection. Morbidity and Mortality Weekly Report, 40(Suppl effectiveness. RR-5): 27-33 (1991).

References 13. Kopanoff, D.E., Snider, D.E., Caras, G.J. Isoniazid- related hepatitis. A U.S. Public Health Service cooperative 1. Selwyn, P.A., Hartel, D., Lewis, V.A. et al. A prospec­ surveillance study. American Review of Respiratory tive study of the risk of tuberculosis among intravenous Diseases, 117: 991-1001 (1978). drug users with human immunodeficiency virus infection. New England Journal of Medicine, 320: 545-50 (1989). 14. American Thoracic Society/Centers for Disease Control. Treatment of tuberculosis and tuberculosis 2. Allen, S., Batungwanayo, J., Kerlikowske, K. et al. infection in adults and children. American Review of Two-year incidence of tuberculosis in cohorts of HIV- Respiratory Diseases, 1993 (in press). infected and uninfected urban Rwandan women. American Reviews of Respiratory Diseases, 146:1439- 15. Hong Kong Chest Service/Tuberculosis Research 1444(1993). Centre, Madras/British Medical Research Council. A double-blind placebo-controlled clinical trial of three 3. De Cock, K.M., Soro, B., Coulibaly, I.M., Lucas, S.B. antituberculosis chemoprophylaxis regimens in patients Tuberculosis and HIV infection in sub-Saharan Africa. with silicosis in Hong Kong. American Review of Respira­ Journal of the American Medical Association, 268: 1581- tory Diseases, 145: 36-41 (1992). 1587. 16. Lecoeur, H.F., Truffot-Pemot, C, Grosset, J.H. 4. Ferebee, S.H. Controlled chemoprophylaxis trials in Experimental short-course preventive therapy of tuber­ tuberculosis. A general review. Advanced Tuberculosis culosis with rifampin and pyrazinamide. American Review Research, 17: 29-106 (1969). of Respiratory Diseases, 140: 1189-1193 (1989).

5. International Union Against Tuberculosis and Lung Diseases. Tuberculosis in children — guidelines for diagnosis, prevention and treatment. Bulletin of the Advertising in medical journals International Union of Tuberculosis and Lung Diseases, 66:61-67(1991). The International Committee of Medical Journal Editors issued the following statement during its 6. Managing Tuberculosis at the District Level. WHO meeting in Chicago in August 1993. Tuberculosis Programme, Geneva, 1992. "Most medical journals carry advertising, and 7. Wadhawan, D., Hira, S., Mwansa, N., Perine, P. advertising generates income for owners of Preventive tuberculosis chemotherapy with isoniazid journals, but advertising must not be allowed to among persons infected with HIV. Presented at the Eighth influence editorial decisions. Editors must have full International Conference on AIDS. Amsterdam, July 1992. responsibility for advertising policy, and readers should be able to distinguish readily between 8. Pape, J.W., Jean, S.S., Ho, J.L., Hafner, A., Johnson, advertising and editorial matter. Juxtaposition of W.D. Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet, editorial and advertising material on the same 342:268-272(1993). product or subject should be avoided wherever possible. Finally, editors should consider for 9. Narain, J.P., Raviglione, M.C., Kochi, A. HIV-associated publication all criticisms of advertisements". tuberculosis in developing countries: epidemiology and strategies for prevention. Tuberculosis and Lung Representatives of the following journals are Diseases, 73: 311 -321 (1992). current members of the Committee: Annals of 10. Wallis, R.S., Vjecha, M., Amir-Tahmasseb, M. et al. Internal Medicine, Medical Journal of Australia, Influence of tuberculosis on human immunodeficiency British Medical Journal, Journal of the American virus (HIV-1): enhanced cytokine expression and elevated Medical association. Lancet, Tidsskrift for den β2-microglobulin in HIV-1-associated tuberculosis. Norske Laegeforening, Index Medicus, New Journal of Infectious Diseases, 167: 43-48 (1993). England Journal of Medicine, New Zealand Medical Journal, Canadian Medical Association Journal, drug (6). The hypothesis is that suppression of Western Medical Journal. inducibility predicts a long-term beneficial response to a drug (7). Source: International Committee of Medical Journal Editors. Advertising in Medical Journals. British Medical Many of the factors that need to be considered in Journal, 307: 795 (1993). formulating this assumption have been extensively discussed (8, 9). None the less, the predictive value of both techniques has recently been described Antiarrhythmic agents: the (10) as based "almost entirely upon forceful opinion (11), observational evidence (12) and one small problems of clinical assessment randomized trial (13)". Moreover, in controlled Attitudes towards the use of antiarrhythmic agents settings, both randomly-allocated amiodarone (14) were changed fundamentally in 1989. A multicentre and beta-blockade with metoprolol (15) have been trial designed to assess the effect of the powerful found respectively to be as effective in survivors of Na+ channel blocking agents, flecainide and cardiac arrest and patients with symptomatic, encainide, in suppressing ventricular ectopic beats sustained ventricular tachyarrhythmias as electro- in patients with a recent myocardial infarction was physiologically-guided antiarrhythmic drug therapy. stopped prematurely because patients receiving Pending resolution of this controversy, both either of these drugs appeared to be at greater risk techniques remain under assessment as predictors of dying than those receiving placebo (1). Similar of antiarrhythmic drug efficacy for ventricular results were subsequently obtained with moraci- arrhythmias (16). It is attractive to consider that zine, a drug with similar pharmacological properties they are complementary rather than duplicative in (2). In the light of these findings many national drug the information that they provide. Electrocardio­ regulatory authorities restricted the indications for graphic monitoring might be expected to have these drugs to the treatment of life-threatening greater value in patients with frequent, complex ventricular arrhythmias. They also required ventricular ectopic beats, while electrophysiological warnings to be issued to doctors that antiarrhythmic tests manifestly provide little information about agents can exacerbate potentially fatal ventricular triggers but, instead, reveal potential substrates that arrhythmias, including sustained ventricular may have clinical relevance (10). However, the tachycardia and ventricular fibrillation, in vulnerable definitive results of the recent Cardiac Arrhythmia individuals. Suppression Trial (17) has cast doubt on the extent These results posed two complementary to which theory translates into practice. In this challenges. By which criteria can the safest and study, drug-induced suppression of ventricular most effective antiarrhythmic agent be selected ectopic beats in patients with recent myocardial from among the various types available (3) in any infarction was unexpectedly and unaccountably given therapeutic situation? How can patients who associated with an increased risk of death, rather are vulnerable to treatment with any or all of these than the reduced risk consonant with the study drugs be identified prospectively? hypothesis. Since the 1960s two techniques — prolonged In the light of this experience, a comparison of electrocardiographic monitoring (4) and electro­ seven classical antiarrhythmic drugs using these physiological testing (5) — have been used in two models (18) sets some intangible problems. On attempts both to determine the prognosis for the basis of electrophysiological studies sotalol was survival and to select appropriate therapy for predicted to be effective in the highest proportion patients with sustained ventricular tachycardia. (35%) of a narrowly-selective subpopulation of Electrocardiographic monitoring holds the patients with ventricular tachyarrhythmias. Sotalol advantage that it is a non-invasive technique. was also significantly more effective in preventing Electrophysiological testing, which is an invasive death and recurrences of arrhythmia in these procedure, and which is a fundamental diagnostic patients. For each drug, electrocardiographic tool in a patient with broad complex tachycardia, is monitoring and electrophysiological study provided used to reproduce and record clinical arrhythmias predictions of drug efficacy of similar accuracy. induced by programmed electrical stimulation of the ventricle. It is also employed to assist in the On the basis of these findings, the authors propose selection of appropriate antiarrhythmic therapy by use of sotalol evaluated by ambulatory monitoring determining whether the arrhythmia remains as an appropriate approach to clinical management inducible following administration of a candidate (18). But, at the same time, they concede that the lower mortality associated with use of sotalol in this 6. Shenasa, M., Borggrefe, M., Haverkamp, W. et al. study does not necessarily indicate that its use Ventricular tachycardia. Lancet, 341: 1512-1519(1993). reduces the risk of death. Because no comparison was made with placebo, the possibility cannot be 7. Fisher, J., Cohen, H., Mehra, R. et al. Cardiac pacing and pacemakers II. Serial electrophysiologic-pharma­ excluded that sotalol might even have increased cologic testing for control of recurrent tachyarrhythmias. mortality, but to a lesser degree than the other American Heart Journal, 93: 658-668 (1977). drugs. 8. Wellens, H., Brugarda, P., Stevenson, W. Programmed Some indirect and inconclusive support for assum­ electrical stimulation: its role in the management of ing that sotalol has a true protective effect is ventricular arrhythmias in coronary artery disease. Progress in Cardiovascular Disease, 24: 165-180 (1986). provided by an earlier retrospective analysis of data relating to patients with ventricular tachyarrhyth­ 9. Fromer, M., Shenasa, M. A critical reappraisal of serial mias who had undergone electrophysiological electrophysiologic drug testing for sustained ventricular assessment: one of the strongest predictors of tachycardia. American Heart Journal, 114: 1537-1543 sudden death in this series was failure of any (1987). candidate drug to protect against electrically- induced arrhythmias (19). 10. Ward, D., Camm, A. Dangerous ventricular arrhyth­ mias — can we predict drug efficacy? New England Journal of Medicine, 329: 498-499 (1993). The basic obstacle in resolving the uncertainty and controversy surrounding the use of antiarrhythmic 11. Bigger, J., Reiffel, J. Holter versus electrophysiologic agents is the current impossibility of undertaking studies in the management of malignant ventricular placebo controlled studies within an ethically- arrhythmias. American Journal of Cardiology, 51: 1464- acceptable setting. One possible solution that has 1466(1983). been proposed is to enrol volunteers from among 12. Swerdlow, C, Peterson, J. Prospective comparison of the growing numbers of patients that carry Holter monitoring and electrophysiologic study in patients implanted cardioverter-defibrillators (20). The with coronary artery disease and sustained ventricular protection from arrhythmias that is afforded by such tachyarrhythmias. American Journal of Cardiology, 56: devices may be sufficient to permit ethically- 577-580(1985). acceptable use of placebo, and it has been suggested that onging trials designed to evaluate 13. Mitchell, L, Duff, H., Manyari, D., Wyse, D. A the efficacy and potential of these devices may be randomized clinical trial of the noninvasive and invasive sufficient to establish the feasibility and approaches to drug therapy of ventricular tachycardia. New Engalnd Journal of Medicine, 317: 1681-1687 practicability of this approach (10). (1987). References 14. Maynard, C, Powell, J., Graham-Renfroe, E. et al. 1. The Cardiac Arrhythmia Suppression Trial (CAST) CASCADE Investigators. Rehospitalization in survivors of Investigators. Preliminary report: effect of encainide and out-of-hospital ventricular fibrillation: results from the flecainide on mortality in a randomized trial of arrhythmia CASCADE study. Journal of the American College of suppression after myocardial infarction. New England Cardiologists, 21 (suppl A): 104 (1993). Journal of Medicine, 321: 406-412 (1989). 15. Steinbeck, G., Andresen, D., Bach, P. et al. A 2. The Cardiac Arrhythmia Suppression Trial II. Investiga­ comparison of electrophysiologically guided antiarrhythmic tors. Effect of the antiarrhythmic agent moricizine on drug therapy with beta-blocker therapy in patients with survival after myocardial infarction. New England Journal symptomatic, sustained ventricular tachyarrhythmias. New of Medicine, 327: 227-233 (1992). England Journal of Medicine, 327: 987-992 (1992).

3. Singh, B., Vaughan Williams, E. Classification of 16. Mason, J. for the Electrophysiologic Study versus antiarrhythmic drugs. In: Sandoe, E., Flensted-Jensen, E., Electrocardiographic Monitoring Investigators. A compari­ Olesen, K. eds. Symposium on cardiac arrhythmias. son of electrophysiologic testing with Holter monitoring to Sodertalje: AB Astra, 1970. predict antiarmythmic-drug efficacy for ventricular tachy­ arrhythmias. New England Journal of Medicine, 329: 445- 4. Holter, N. New method for heart studies. Science, 134: 451 (1993). 1214-1220(1961). 17. Echt, D., Liebson, P., Mitchell, L et al. Mortality and 5. Wellens, H., Schuilenburg, R., Durrer, D. Electrical morbidity in patients receiving encainide, flecainide, or stimulation of the heart in patients with ventricular tachy­ placebo — the Cardiac Arrhythmia Suppression Trial. cardia. Circulation, 46: 216-226 (1972). New England Journal of Medicine, 324: 781-788 (1991). 18. Mason, J. for the Electrophysiologic Study versus with highly-purified active components derived from Electrocardiographic Monitoring Investigators. A compari­ biologically-assisted methods of synthesis. son of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. New England Journal of This need has been most tragically illustrated by Medicine, 329: 452-458 (1993). deaths of many haemophiliacs worldwide from HIV 19. Swerdlow, C, Winkle, R., Mason, J. Determinants of infection transmitted in plasma concentrates survival in patients with ventricular tachyarrhythmias. New prepared from pooled sera derived from many England Journal of Medicine, 308: 1436-1442 (1983). individual donations. Heat processing has greatly reduced the hazard, but contamination is difficult to 20. O'Nunain, S., Ruskin, J. Cardiac arrest. Lancet, 341: eliminate with complete confidence (1). Recent 1641-1647(1993). reports cite transmission of HIV in chemically- treated factor IX complex (2); transmission of hepatitis C virus by monoclonal-antibody-purified or Biological products and vapour-treated concentrates of factors VIII and IX (3-5); and transmission of parvovirus by factor VIII transmissible pathogens concentrates either pasteurized or treated with solvent detergent (6, 7). The manufacture of many biological preparations, including vaccines, hormones and plasma fractions, The known risks, however, are not circumscribed to involves the extraction of active components from plasma-derived clotting-factor concentrates. Con­ animal or human tissues. The processes by which cerns also remain extant about the consequences these products are manufactured are intended to of using growth hormone and gonadotrophins preserve the biological activity of the active com­ prepared from the human pituitary gland to treat ponent, to assure the potency of the final prepara­ dwarfism and anovulatory infertility. Human growth tion, and to exclude extraneous matter including, in hormone extracted from glands removed at particular, viable pathogens and sensitizing necropsy was first employed in clinical practice in material. 1959 (8). This form of replacement therapy first aroused concern in 1985 when Creutzfeldt-Jacob The efficacy and safety of many such preparations disease was diagnosed in two young adult patients remains exemplary but, in recent years, new who, from early childhood, had received growth hazards have been identified that have challenged hormone regularly for more than a decade (9, 10). both manufacturers and regulators responsible for The disease, which is a rare subacute spongiform the safety of these products. In part, this is a degeneration of the central nervous system that consequence of better means of detection of results in a rapidly progressive and uniformly fatal remote hazards. Computerized storage of dementia, is attributed to transmission of a sub-viral information and refinement of case-control tech­ protease-resistant protein structure (or prion) (11- niques have greatly facilitated the identification of 14). Two further cases reported within a matter of rare adverse drug-related events. However, it is months in previously treated young adults (15, 16) also a consequence of discovery of newly identified were sufficient to establish a causal relationship — and in some cases, newly-emerging — patho­ beyond reasonable doubt (17). gens including retroviruses, prions and other subviral particles, and the use of new starting Later in the same year, use of human growth materials, including brain and hypophyseal tissues, hormone was abruptly terminated in many countries derived from human sources. as further cases were notified (18, 19). In all, some 30 cases of the disease have now been notified These hazards are compounded by the scale of worldwide among patients who had received these modern commercial manufacturing processes. preparations (20). It remains possible, however, Whenever large pools of donor or cadaver material given the extremely long latency of the infection, are used for batch manufacture, reliance cannot be that the preparations in use at the time of with­ vested exclusively in meticulous screening of drawal may not have been associated with sources to exclude viable pathogens. In these discernible risk. Extraction and purification circumstances, sterilization of the final preparation procedures had been refined in 1977 (21) in a way by some form of physical or chemical processing that may have largely eliminated contamination with becomes mandatory. In the longer term, the ideal the causative agent (22). must be to avert all risk of transmission of patho­ More recently, the same hazard has been gens by replacing naturally-derived animal extracts associated with the use of necropsy-derived human pituitary gonadotropins which were used briefly in 6. Lyon, D., Chapman, C, Martin, C. et al. Symptomatic the United Kingdom during the mid-1970s — and parvovirus B19 infection and heat-treated factor IX con­ for a longer period in some centres in Australia — centrate. Lancet, 1: 1085 (1989). for the treatment of anovulatory infertility (23,24). 7. Azzi, A., Ciappi, S., Zakvrzewska, K. et al. Human Elsewhere, hormones derived from urine of parvovirus B19 infection in hemophiliacs first infused with postmenopausal women were generally preferred. two high-purity, virally attenuated factor VIII concentrates. In all, four Australian women who received human American Journal of Hematology, 39: 228-230 (1992). pituitary extracts are reported to have died from 8. Raben, M. Treatment of a pituitary dwarf with human Creutzfeldt-Jacob disease over the past 3 years growth hormone. Journal of Clinical Endocrinology, 18: (25). Two of these patients had been treated with a 901-903(1958). batch administered to some 30 other women, and concern regarding the possibility of vertical trans­ 9. Koch, T., Berg, B., De Armond, S., Gravina, R. mission has recently been heightened as a result of Creutzfeldt-Jacob disease in a young adult with idiopathic a report from Japan that infectious material has hypopituitarism. New England Journal of Medicine, 313: been detected in placental and umbilical cord blood 731-733(1985). taken from a pregnant woman in whom the disease had been confirmed (26). 10. Gibbs, C, Joy, A., Heffner, R. et al. Clinical and patho­ logical features and laboratory confirmation of Creutzfeldt- Jacob disease in a recipient of pituitary-derived human These experiences drive home the reality that any growth hormone. New England Journal of Medicine, 313: therapeutic transfer of human tissue — whether by 734-738(1985). parenteral injection, or by implantation of tissues or organs (27) — carries an innate risk of infection 11. Merz, P., Rohwer, R., Kascsak, R. et al. Infection (17). They provide perhaps the most persuasive specific particle from the unconventional slow virus diseases. Science, 225: 437-440 (1984). demonstration, as yet, of the need to develop biologically-assisted techniques for synthesizing 12. Beckman, J., Kingsbury, D., McKinley, M. et al. pharmacologically-active peptides and other Creutzfeldt-Jacob disease prion proteins in human brains. naturally-occurring substances. Recombinant DNA- New England Journal of Medicine, 312: 73-78 (1985). derived versions of factor VIII, growth hormone and gonadotrophins are already available. Their use not 13. Weissmann, C. A unified theory of prion propagation. only excludes the risk of transmissible disease Nature, 352: 679-683 (1991). associated with the naturally-derived products; it 14. Prusiner, S. The molecular biology of prion diseases. averts the protracted anguish generated in all Science, 252: 1515-1522(1991). patients who recognize that they have been exposed to such risk. 15. Fatal degenerative neurologic disease in patients who References received pituitary-derived human growth hormone. Leads from the Morbidity and Mortality Weekly Report. Journal of 1. Rouzioux, C. Absence of antibodies to AIDS virus in the American Medical Association, 254: 475-476 (1985). haemophiliacs treated with heat-treated factor VIII concentrate. Lancet, 1: 271 (1985). 16. Powell-Jackson, J., Weller, R., Kennedy, P. et al. Creutzfeldt-Jacob disease after administration of human 2. Kleim, J., Bailley, E., Schneweis, K. et al. Acute HIV-1 growth hormone. Lancet, 2: 244-246 (1985). infection in patients with hemophilia B treated with beta- propriolactone-UV-inactivated clotting factor. Thrombosis 17. Brown, P., Gajdusek, D., Gibbs, C, Asher, D. and Hemostasis, 64: 336-337 (1990). Potential epidemic of Creutzfeldt-Jacob disease from human growth hormone therapy. New England Journal of 3. Bemtorp, E., Nilsson, I., Ljung, R., Widell, A. Hepatitis Medicine, 313: 728-731 (1985). C virus transmission by monoclonal antibody purified factor VIII concentrate. Lancet, 335: 1531-1532 (1990). 18. US Food and Drug Administration, Human growth hormone distribution discontinued. FDA Drug Bulletin, 15: 4. Mannucci, P., Zanetti, A., Colombo, M. et al. Antibody 17-18(1985). to hepatitis C virus afer a vapour-treated factor VIII concentrate. Thrombosis and Hemostasis, 64: 232-234 19. Lazarus, L. Suspension of the Australian human (1990). pituitary hormone programme. Medical Journal of Australia, 143: 57-59 (1985). 5. Lusher, J. and Transfusion Safety Study Group. Hepatitis C virus (HCV) transmission with clotting factor 20. Hintz, R. Untoward events in patients treated with concentrates in current use. Blood, 78 (suppl. 1): 1409 growth hormone in the USA. Hormone Research, 38: (1991). 44-49(1992). 21. Chapman, G., Renwick, A., Livsey, J. The isolation of frequently block capillaries. Chronic haemolysis human pituitary hormones from frozen glands. Journal of results in anaemia which may be aggravated by Clinical Endocrinology and Metabolism, 53: 1008-1013 episodes of bone marrow aplasia (often triggered (1981). by parvovirus or other viral infection), or visceral — and particularly splenic — sequestration of sickled 22. Tayler, D., Dickinson, A., Frazer, H. et al. Preparation cells. Acute splenic sequestration can induce a of growth hormone free from contamination with uncon­ precipitous fall in circulating haemoglobin which is ventional slow viruses. Lancet, 2: 260-262 (1985). life-threatening in infants and, in patients of any 23. Pfeffer, N. Early infertility treatments derived from age, it can trigger a potentially fatal syndrome human pituitary. British Medical Journal, 306: 112-119 characterized by chest pain, fever, leukocytosis and (1993). thrombocytopenia. Because of splenic dysfunction, which inhibits phagocytosis of opsonized bacteria, 24. Lazarus, L. Creutzfeldt-Jacob disease and human encapsulated organisms, including pneumococci pituitary-derived hormone therapy. Royal Australian and meningococci, present a major risk in young College of Physicians: Fellowship Affairs. November children (4-8). Pneumococcal infection, which is 1991:21-28. frequently fulminant and associated with disseminated intravascular coagulation and 25. Healy, D., Evans, J. Creutzfeldt-Jacob disease after cerebrovascular accidents, has been estimated to pituitary gonadotropins. British Medical Journal, 307: 517-518(1993). be 600 times more frequent than in the general population among children under 3 years of age (5). 26. Tamai, Y., Kojima, H., Kitajima, R. et al. Demonstra­ tion of the transmissible agent in tissue from a pregnant Acute sickle cell crisis, sometimes accompanied by woman with Creutzfeldt-Jacob disease. New England painful localized bone-marrow infarction, is typically Journal of Medicine, 327: 649 (1992). precipitated by infection, cold or dehydration. Localized foci of stasis, hypoxia and infarction 27. Rappaport, E. Iatrogenic Creutzfeldt-Jacob disease. Neurology, 37: 1520-1522 (1987). provide a nidus for infection and result in clinical expressions as diverse as recurrent stroke, proliferative retinopathy, renal impairment, aseptic Sickle cell disease: a trend towards necrosis of the hip, priapism and leg ulcers. less invasive management Treatment of the condition is directed to sympto­ matic relief, simple transfusion or exchange Sickle cell disease is an autosomal recessive transfusion of blood, and to the prevention and disorder that occurs in persons of African, Mediter­ treatment of consequential infection. ranean and Indian descent. It is most prevalent among persons of Afro-Carribean origin, in whom In developing countries use of blood transfusion the prevalence has been estimated to be about one has been largely restricted to severely anaemic in 30 (1). The affected gene codes for the beta- patients with sickle cell disease. It is now used in an chain of adult haemoglobin. The phenotype is increasingly conservative way in developed virtually normal in carriers possessing the gene in countries having regard to the dangers of infection, only one chromosome. Sickle cell disease — iron overload and alloimmunization (9, 10). Acute characterized by an abnormal haemoglobin which splenic sequestration and aplastic episodes are polymerizes and aggregates in rod-like structures settings in which patients clearly benefit from as oxygen tension falls — results when both genes transfusion (11). It is still sometimes routinely used are abnormal, or when one affected gene is with the aim of preventing potential vaso-occlusive inherited concurrently with alpha or beta thalas- complications, particularly recurrent cerebro­ saemia trait (a double Reterozygote condition). vascular episodes, but evidence of benefit from Even with the highest level of care, some 10-20% controlled trials is lacking (9, 10). Formerly, it was of children with the disease die within 10 years (2, also widely advocated during pregnancy in the 3). Those that survive have to contend throughout belief that reduction in sickling would reduce life with persistent haemolytic anaemia and maternal morbidity, fetal distress and perinatal recurrent painful vaso-occlusive crises. Ultimately, mortality, but the results of a controlled, prospective renal failure and bone necroses cause chronic study have provided no evidence to support such disability. intervention (11, 12).

Sickled red blood cells, which are more fragile than Before the introduction of penicillin prophylaxis, normal red blood cells, increase blood viscosity and pneumococcal infection was the most frequent cause of death among young children with sickle and lethargy during epidemics of aplastic crises — cell disease. Even in the USA, case fatality was has contributed to a 90% reduction in mortality from estimated to approach 35% (13). It has been acute splenic sequestration (25). Much more could claimed that this was not initially reduced by the still be achieved, it is suggested, by creating day introduction of pneumococcal vaccines or prompt care centers with facilities for administering prophy­ use of antibiotics for febrile illnesses in children at lactic and therapeutic antibiotics, observing febrile risk (14). In contrast, the value of penicillin children, assessing their response to analgesics in prophylaxis was convincingly demonstrated in the painful crises, and giving transfusions to relieve mid-1980s. Randomized studies involving children acute anaemia associated with aplastic crises and under 3 years showed that either twice-daily oral acute splenic sequestration (10). penicillin (13) or a 4-weekly injection of a depot References preparation (15) provided very substantial protection. These results created a basis for public 1. Brosovic, M., Anionwu, E. Sickle cell disease in Britain. health action. They demonstrated that, wherever Journal of Clinical Pathology, 37: 1321-1326 (1984). resources permit, children at risk should be screened for sickle haemoglobinopathy and 2. Mann, J. Sickle haemoglobinopathies in England. penicillin prophylaxis be provided to those with the Archives of Diseases of Children, 138: 44-48 (1981). disease within a few months of birth (14). 3. Brozovic, M. Davies, S. Management of sickle cell disease. Postgraduate Medical Journal, 63: 605-609 Presumably because of lapses in compliance with (1987). penicillin prophylaxis (16), and despite routine administration of pneumococcal and Haemophilus 4. Robinson, M., Watson, R. Pneumococcal meningitis in influenzae type b vaccine, septicaemia — usually sickle cell anaemia. New England Journal of Medicine, 274: 1006-1008(1966). attributable to S. pneumoniae — remains a major cause of morbidity and mortality among young 5. Barrett-Connor, E. Bacterial infection and sickle cell children with sickle cell disease (17, 18). These anemia: an analysis of 250 infections in 166 patients and infections were considered to be best treated in a review of the literature. Medicine, 50: 97-112 (1971). hospital with parenterally-administered, high doses of antibiotics. However, there is now a growing 6. Seeler, R., Metzger, W., Mufson, M. Diplococcus body of evidence that — in the absence of clinical pneumoniae infections in children with sickle cell and indicators of serious complications (19) — no serious infections due to encapsulated bacteria. Journal of advantage is gained by routine admission (16, 20, Infectious Diseases, 136 (suppl): 325-330 (1977). 21). Regimens based upon one or more parenteral 7. Powars, D., Overturf, G., Lee, S. et al. Pneumococcal doses of the third-generation cefalosporin ceftriax­ septicemia in children with sickle cell anaemia. Journal of one, supplemented by oral antibiotics have been the American Medical Association, 245: 1839-1842 shown to be as effective when administered on an (1981). outpatient basis as in a hospital setting. Avoidance of hospital admission has also been found to offer 8. Topley, T, Cupidore, L, Vaidya, S. et al. Pneumo­ other benefits. Not only does it greatly decrease the coccal and other infections in children with sickle cell- cost of management (10, 21), it reduces social and haemoglobin C (SC) disease. Journal of Pediatrics, 101: 176-179(1982). psychological disturbance for patients and families (22), and it lessens the risk of parvovirus infections 9. Transfusion in management and therapy of sickle cell and other complications of the disease (23). disease. Eds. Charache, S., Lubin, B., Reid, C, (NIH publication 85-2117). National Institutes of Health, The evidence underlying the current trend to treat Bethesda, MD., 1985. children with sickle cell disease on a less invasive and more cost-effective basis is particularly 10. Serjeant, G. Clinical judgement and sickle cell encouraging to clinicians in developing countries disease. New England Journal of Medicine, 329: 501-502 where scant facilities exist for hospital admission (1993). (10). Just as important to the management of the 11. Platt, O. Is there treatment for sickle cell anemia? New disease, regardless of the setting, is effective England Journal of Medicine, 319: 1479-1480 (1988). coordination of clinical, social, educational services (24) and well-informed, highly motivated family 12. Koshy, M., Burd, L, Wallace, D. et al. Prophylactic support (10). It is estimated that parental education red-cell transfusions in pregnant patients with sickle cell — by drawing attention to prodromal signs of pallor disease: a randomized cooperative study. New England Journal of Medicine, 319: 1447-1452 (1988). 13. Gaston, H., Verter, J., Woods, G. et al. Prophylaxis 20. Chadwick, E., Connor, E., Shulman, S., Yogev, R. with oral penicillin in children with sickle cell anemia. New Efficacy of ceftriaxone in treatment of serious childhood England Journal of Medicine, 314: 1593-1599 (1986). infections. Journal of Pediatrics, 103: 141-145 (1983).

14. Editorial. Penicillin prophylaxis for babies with sickle- 21. Wilimas, J., Flynn, P., Harris, S. et al. A randomized cell disease. Lancet, 2: 1432-1433 (1986). study of outpatient treatment with ceftriaxone for selected febrile children with sickle cell disease. New England 15. John, A., Ramlal, A., Jackson, H. Prevention of Journal of Medicine, 329: 472-476 (1993). pneumococcal infection in children with homozygous sickle cell disease. British Medical Journal, 288: 1567- 22. Vichinsky, E. Comprehensive care in sickle cell 1570(1984). disease: its impact on morbidity and mortality. Seminars in Hematology, 28: 220-226 (1991). 16. Rogers, Z., Morrison, R., Vedro, D., Buchanan, G. Outpatient management of febrile illness in infants and 23. Evans, J., Rossiter, M., Kumaran, T. et al. Human young children with sickle cell anemia. Journal of parvovirus aplasia: case due to cross-infection in a ward. Pediatrics, 117: 736-739 (1990). British Medical Journal, 288: 681 (1984). 17. Zarkowski, H., Gallagher, D., D., Gill, F. et al. Bacteremia in sickle hemoglobinopathies. Journal of 24. Franklin, I. Services for sickle cell disease: unified Pediatrics, 109: 579-585 (1986). approach needed. British Medical Journal, 296: 592-593 (1988). 18. Leikin, S., Gallagher, D., Kinney, T., et al. Mortality in children and adolescents with sickle cell disease. 25. Emond, A., Collis, R., Darvill, D. et al. Acute splenic Pediatrics, 84: 500-508 (1989). sequestration in homologous sickle cell disease: natural history and management. Journal of Pediatrics, 107: 201- 19. McCarthy, P., Sharpe, M., Spiesel, S. et al. Observa­ 206 (1985). tion scales to identify serious illness in febrile children. Pediatrics, 70: 802-809 (1982). Regulatory Matters

Source: Adverse Drug Reactions Advisory Committee. Antihyperlipidaemic agents: Australian Adverse Drug Reactions Bulletin, Vol 12, May paraesthesia and neuropathy 1993. Australia — Doctors in Australia have been alerted to a possible association between use of antihyper­ Atovaquone as an alternative lipidaemic agents and neuropathic reactions. Thus treatment for Pneumocystis far, it seems that an apparent association has been identified only with simvastatin and gemfibrozil. pneumonia United States of America — In November 1992, Since the introduction of simvastatin, 22 notifi­ the Food and Drug Administration approved the use cations of paraesthesia associated with its use of atovaquone in the treatment of mild to moderate have been received. The symptoms, which were Pneumocystis carinii pneumonia in patients varied and ranged from hypoaesthetic to hyper- intolerant of trimethoprim/sulfamethoxazole (1). aesthetic sensations, most frequently involved the Atovaquone is one of several highly potent face, scalp, tongue and limbs. These sensations hydroxynaphtho-quinone compounds with potent were often accompanied by less specific com­ antiprotozoal activity (2). It has been shown to block plaints, including, fatigue, weakness, ataxia, synthesis of pryimidines in Plasmodium falciparum insomnia, headache, dyspnoea and myalgia/ by indirectly inhibiting the activity of the enzyme, arthralgia. dihydroorotate dehydrogenase (3) and it is presumed to act in the same way against The temporal relationship to treatment was in­ Toxoplasma gondii (4) and P. carinii (5). constant. In a few cases, symptoms occurred immediately on starting treatment. In others, they were not noticed until the drug had been taken for Clinical findings obtained from small open studies up to one year. None the less, in the majority of have suggested that atovaquone is an effective and cases, simvastatin was the sole suspected drug, well-tolerated alternative treatment for patients with Pneumocystis pneumonia (6, 7) — and, at higher the majority of patients recovered shortly after dosage (750 mg four times daily for 6 weeks) for withdrawal of treatment, and in 5 instances patients with cerebral toxoplasmosis — who are symptoms recurred on rechallenge. intolerant of standard therapies (8). In addition, 4 cases documenting more serious Evidence of efficacy of atovaquone in Pneumocystis neurological damage have been reported. One was pneumonia has been confirmed in two double-blind, described as motor neurone disease, and two as multicentre clinical studies involving a total of 582 sensory neuropathy, which in one instance was patients in which oral atovaquone (750 mg daily for associated with impaired peripheral nerve con­ 21 days) was compared respectively with oral duction. The outcome of these cases remains trimethoprim/sulfamethoxazole and injectable unknown. However, recovery has been reported pentamidine. The results of the larger of these two following withdrawal of simvastatin in a patient who studies, which involved clinics in the United States developed sensory and motor neuropathy in whom and Belgium, have recently been published (9). Of the results of nerve conduction and electromyo­ 322 patients with histologically-confirmed P. carinii graphic tests were abnormal. pneumonia, half were randomly allocated to trimethoprim/sulfamethoxazole and half to The only other compound mentioned in this review atovaquone. When given as initial treatment, both is gemfibrozil, which, in a total of 6 patients, was drugs cured about 60% of infections without any the only drug suspected of inducing paraesthesia. recorded adverse effects. A change of treat-ment One of these patients developed a median nerve was necessary following adverse effects in 7% of deficit which was relieved by discontinuing gem­ patients who received atovaquone and in 20% of fibrozil, but not by an attempt at surgical decom­ those who received trimethoprim/sulfa­ pression. methoxazole. Most importantly, within 4 weeks of the completion 8. Kovacs, J. and the NIAID-Clinical Center Intramural of treatment, 11 patients who had received atova- AIDS Program. Efficacy of atovaquone in treatment of quone had died compared with 1 patient who had toxoplasmosis in patients with AIDS. Lancet, 340: 637- received trimethoprim/sulfamethoxazole. Death 638(1992). correlated both with the severity of P. carinii pneu­ 9. Hughes, W., Leoung, G., Kramer, F. et al. Comparison monia and with diarrhoea on entry into the trial. of atovaquone (566C80) with trimethoprim/sulfamethox­ Four patients who received atovaquone and who azole to treat Pneumocystis carinii pneumonia in patients were judged to have moderate P. carinii pneumonia with AIDS. New England Journal of Medicine, 328: 1521- on entry to the trial subsequently died of the 1527(1993). condition after completion of the treatment. Other causes of death among patients who received atovaquone included three cases of Streptococcus Bovine brain gangliosides: pneumoniae infection, and one case each of cryptococcal meningitis, Pseudomonas aeruginosa marketing suspension and Staphylococcus aureus pneumonia, renal and recommended pulmonary failure with bacterial pneumonia, and Klebsiella and pseudomonas infection with adult European Community —The Committee for respiratory distress syndrome. The patient who died Proprietary Medicinal Products of the European following treatment with trimethoprim/sulfamethox­ Communities recommended to its Member States azole developed the AIDS wasting syndrome. in March 1993 that marketing authorizations for products containing bovine brain gangliosides References (Cronassial®, Fidia) be suspended because of an apparent association with cases of Guillain-Barré 1. Food and Drug Administration. Talk Paper, T92-61. 27 syndrome (1). November 1992. The association was first suspected in 1989 when 6 2. Hudson, A., Randall, A., Fry, M. et al. Potent and cases of the syndrome — a form of polyneuritis selective hydroxynaphthoquinones with broad-spectrum which can lead to irreversible paralysis involving the anti-protozoal activity. Parasitology, 90: 45-55 (1985). respiratory muscles — were reported among patients in Germany who had taken the preparation 3. Hammond, D., Burchell, J., Pudney, M. Inhibition of pyrimidine biosynthesis de novo in Plasmodium falci­ (2). Subsequently, 17 such cases were reported parum by 2-(4-t-butylcyclohexyl)-3-hydroxy-1, 4-naphtho­ from Spain and, early in 1993, a significant quinone in vitro. Molecular Biochemistry and Parasitology, association was established in an unpublished case 14: 97-109 (1985). control study.

4. Araujo, F., Huskinson, J., Remington, J. Remarkable in An ad hoc group has been set up within the vitro and in vivo activities of the hydroxynaphthoquinone Committee which will issue a final recommendation 566C80 against tachyzoites and tissue cysts of Toxo­ in the light of any representation that the manufac­ plasma gondii. Antimicrobial Agents and Chemotherapy, 35:293-299(1991). turer may wish to submit.

5. Hughes, W., Gray, V., Gutteridge, W. et al. Efficacy of a Sources: hydroxynaphthoquinone, 566C80, in experimental 1. Committee for Proprietary Medicinal Products. Position Pneumocystis carinii pneumonitis. Antimicrobial Agents statement on gangliosides (cronassial). Unit lll/C-3, and Chemotherapy, 34: 225-228 (1990). Internal Market and Industrial Affairs, Commission of the European Communities, 17 March 1993. 6. Falloon, J., Kovacs, J., Hughes, W. et al. A preliminary evaluation of 566C80 for the treatment of Pneumocystis 2. WHO Drug Information, 5(4): 175 (1991). pneumonia in patients with the acquired immunodefi­ ciency syndrome. New England Journal of Medicine, 325: 1534-1538(1991). Antiretroviral therapy: 7. Hughes, W., Kennedy, W., Shenep, J. et al. Safety and recommendations for use pharmacokinetics of 566C80, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity: a phase 1 study in United States of America — Preliminary human immunodeficiency virus (HlV)-infected men. recommendations for the use of antiretroviral drugs Journal of Infectious Diseases, 163: 843-848 (1991). in patients with HIV infection have been issued by the National Institute of Allergy and Infectious months. The median duration of treatment with Diseases. They constitute the advice of an zidovudine before a change is indicated is 13 independent panel of experts formulated following a months. two-day conference at which more than 30 investigators, patients and leaders of public opinion Patients intolerant of zidovudine; CD4+ count >50 presented their views. mm3: Switch to didanosine monotherapy.

The ultimate choice to accept or decline anti- Patients intolerant of zidovudine; CD4+ count <50 retroviral treatment, it is emphasized, rests with the mm3: Switch to monotherapy with either didanosine patient. Early intervention is regarded as creating a or zalcitabine, or discontinue antiretroviral therapy. commitment to provide not only antiviral therapy, but also emotional and psychological support, and Patients deteriorating clinically while on zidovudine; primary medical care. CD4+ count >50mm3: Either continue zidovudine and add didanosine or zalcitabine, or replace In summarized form, the options recommended are zidovudine with either of these antiretroviral agents. as follows: Patients deteriorating clinically while on zidovudine; 1. Initial antiretroviral therapy CD4+ count <50mm3: Switch to alternative Zidovudine 600 mg/day in divided doses is monotherapy, either didanosine or zalcitabine. recommended as first-line antiretroviral therapy. Zidovudine in combination with either didanosine or Source: News from the National Institute of Allergy and zalcitabine "may also be considered, although Infectious Diseases, 25 June 1993. clinical trials have not conclusively demonstrated advantage (in multidrug therapy) to date". Short-acting hypnotics: a It is suggested that treatment should be introduced as follows: comparative assessment

3 European Community — Having regard to its Patients with no symptoms; CD4+ count >500/mm : earlier position statement on triazolam (1), the Treatment deferred; clinical and immunological Committee on Proprietary Medicinal Products has status (CD4+ T-cell counts) to be monitored every 6 recently endorsed a report of an ad hoc group months. convened to review available information on short- acting hypnotics (2) Patients with no symptoms; stable over time; 3 CD4+ count 200-500/mm : Antiretroviral therapy Seven benzodiazepine or benzodiazepine-like may either be started immediately, or it may be hypnotics — brotizolam, flunitrazepam, midazolam, deferred pending evidence of clinical or laboratory temazepam, triazolam, Zolpidem, zopiclone — were deterioration. included in the review which focused on the following objectives: Symptomatic patients; CD4+ count 200-500 mm3 3 All patients with a CD4+ count below 200 mm — to re-evaluate, in the light of current scientific Severe AIDS-related complex or AIDS, regardless knowledge and clinical experience, the benefit/ of CD4+ count. Start antiviral therapy. risk ratio of each of these hypnotics, in absolute and comparative terms; 2. Indications for changing antiretroviral therapy — to identify the measures and information Patients should remain on zidovudine for as long as required to minimize the risks associated with they remain tolerant of the required dosage, the their use; clinical condition is stable and the CD4+ T-cell 3 — to review the existing guidelines on the summary count remains >300 mm . of product characteristics for benzodiazepines When the CD4+ count falls below 300 mm3 the used as hypnotics and anxiolytics. option of changing to didanosine should be considered. The strongest data supporting a In summary, the Committee concludes that change to didanosine have been derived from preparations containing these compounds have patients who had received zidovudine for at least 4 value in the relief of insomnia, but that — because of the risk of dependence — their use is justified both the product and the holder of the marketing only for short periods when the disorder is severe, authorization. disabling or the cause of extreme distress. In its final rule the FDA has moved away from the It recommends that, in the case of flunitrazepam, concept of a rigid alphanumeric system of temazepam, Zolpidem and zopiclone treatment imprinting that would uniquely identify each active should be limited to a maximum of 4 weeks, ingredient in a given dosage form. This has been including a period of tapering off that is adjusted to rejected on the grounds that updating and individual needs. For brotizolam, midazolam, and maintaining such a listing would have imposed triazolam, the corresponding maximum recom­ "a significant and unnecessary burden on FDA mended period for treatment is 2 weeks, having resources". Instead, it has accepted that other regard, in particular, to concerns of dependence, factors, including shape, size and colour are tolerance and central nervous effects. This infor­ important elements of identification. The intention of mation, the Committee recommended, should be the rule is that "an individual product, including conveyed to both health professionals and patients each strength of a particular line of drug products, in the package insert. should be identifiable through a composite of its colour, shape, size, and imprint"..."even if either the The Committee accepted the ad hoc group's pro­ imprint or the appearance is duplicated in another posals that the profiles of the products reviewed product". The imprint is required to consist of "at should be revised with regard to adverse effects least one number, letter, mark, monogram, symbol including neuropsychiatric and behavioural or logo". Investigational drugs and placebos reactions, tolerance and rebound phenomena, intended for use in clinical investigations are to be impairment of memory, and risks of dependence exempted from these requirements. and abuse. A large majority of solid oral dosage forms marketed in the USA already bear imprints and The ad hoc group noted, in undertaking the review, many manufacturers had expressed concern that that direct comparisons between products were introduction of an inflexible code would restrict use hindered by lack of standardization in methodology of familiar imprints, including recognizable logos and definition of end-points, and that many of the and trademarks. However, the FDA "does not clinical trials were not conducted in accordance with foreclose the possibility of reconsidering a uniform modem standards. There is a need for such code in the future". standards to be followed, it emphasizes, if informa­ tion is to be obtained on which to base more Source: Food and Drug Administration. Imprinting of solid precise comparative judgements. oral dosage form drug products for human use. Federal Register, 58(175): 47948 (1993). Sources 1. Committee on Proprietary Medicinal Products. Triazolam: pharmacovigilance opinion no 11. CommissionMisoprostol : unsafe in pregnancy of the European Communities. Directorate-General for Internal Market and Industrial Affairs, III/E3, Brussels, 11 United Kingdom — The Committee on Safety of December 1991. Medicines has warned doctors that the prosta­ glandin analogue, misoprostol, is contraindicated in 2. Summary Report of the ad hoc Group on Short-actingpregnanc y and should not be prescribed for women Hypnotics to the Committee for Proprietary Medicinal Products. Commission of the European Communities, of child-bearing age unless a reliable method of Directorate-General for Internal Market and Industrial contraception is used. Misoprostol, which is Affairs, III/E3,111/5519/93, Brussels, 15 September 1993. indicated exclusively for the treatment of peptic ulcer and prevention of ulcers induced by non­ steroidal antiinflammatory drugs (NSAIDs), is Identification codes for available in the United Kingdom both as a single component formulation and in combination with the tablets and capsules NSAIDs naproxen or diclofenac. United States of America — The Food and Drug Concern has been generated by evidence that Administration has issued regulations, which will misoprostol may cause abortion by stimulating the become effective in September 1995, that require pregnant uterus, and by anecdotal reports from manufacturers to imprint solid oral dosage forms of Brazil of unusual congenital abnormalities pharmaceutical products in a way that identifies associated with its use in early pregnancy. Source: Committee on Safety of Medicines. Current Reye's syndrome, the Food and Drug Adminis­ Problems in Pharmacovigilance. Volume 19, February tration considers that a causal relationship must be 1993. assumed with this salicylate compound. Retail packages are consequently required to carry a prominent warning that children or teenagers who Propofol: adverse have, or are recovering from chickenpox or neurological events influenza should not use the product. Australia — Over a period of almost two years' Source: Food and Drug Administration. Federal Register, intensified monitoring terminating in February 1993, 58(85): 26886-26888 (1993). doctors in Australia notified a total of 105 serious neurological events associated with use of the short-acting intravenous anaesthetic agent, Tacrine approved for the sympto­ propofol. matic relief of Alzheimer's disease Over 40% of these notifications described seizures, United States of America — The Food and Drug most of which were convulsive states — including 8 Administration has announced that it has approved cases of grand mal — together with some cases of tacrine hydrochloride, a potent acetylcholinester­ twitching and opisthotonos which occurred either ase, for symptomatic treatment of impaired memory immediately or shortly after induction or with a and reasoning ability in patients with mild to latent interval of up to 6 hours. In most cases the moderate Alzheimer's disease (see also p. 104). disorder lasted no more than a few minutes, but in a few cases it persisted for 1-2 hours, and one Adverse effects include nausea, vomiting, diarrhoea patient previously well controlled with anticonvul­ and rash. Because tacrine has caused minor and sants developed status epilepticus. Only in one reversible impairment of hepatic function, it is instance, in which hypoxia probably occurred, was recommended that dosage be incremented any permanent damage recorded. progressively up to a maximum of 160 mg daily while monitoring is undertaken to identify vulnerable Most of the patients had received doses of 100- patients. 200 mg propofol. No predisposing factors were Source: Food and Drug Administration. HHS News, P93- identified, save that 5 patients had a previous 37(1993) history of epilepsy, and three others had experienced convulsions following drug therapy or general anaesthesia. Quality control of propylene glycol

The Committee re-emphasizes the pre-existing Australia — The Therapeutic Goods Administration concern that there may be increased risk of has issued a general warning to manufacturers of convulsions when propofol is administered to therapeutic goods which contain propylene glycol to epileptic patients. prevent any repetition of the fatal incidents which have occurred in other parts of the world when Source: Adverse Drug Reactions Advisory Committee. diethylene or ethylene glycol has been substituted Australian Adverse Drug Reactions Bulletin, Vol. 12, Mafoy r propylene glycol in medicinai products. 1993. All manufacturers of goods which contain propylene glycol have been advised that auditors will be Bismuth subsalicylate: association monitoring the quality control procedures used to check the identity and purity of propylene glycol and with Reye's syndrome will be particularly concerned that the procedures United States of America — A case of Reye's used should distinguish this substance from syndrome, a rare condition which has been diethylene glycol and ethylene glycol. Procedures associated with use of acetylsalicylic acid by febrile should include as a minimum the sampling of every children and adolescents, was reported in 1989 in a container of a delivery for identification, unless 6-year-old child who had taken the recommended assurance of non-contamination or substitution is dose of a preparation containing bismuth subsali­ otherwise available. cylate to treat diarrhoea and nausea during an Reference: GMP Newsletter. Number 13, September influenza-like illness. Because of the rarity of 1993. Essential Drugs

The resulting liver damage is probably immuno­ Viral hepatitis logically mediated. The initial phase of intense viral Viral hepatitis, which is probably the most common replication is unaccompanied by evidence of liver of all serious viral diseases, comprises several dysfunction. Biochemical and clinical evidence of clinically similar infections that are etiologically and such injury develops in parallel with the formation of epidemiologically distinct. Hepatitis A virus causes a specific antibody (IgM anti-HAV) and at a time of an acute, usually self-limiting infection that can decreasing viral replication. This antibody is usually cause a variable degree of liver damage but does no longer detectable after 2-6 months, but IgG anti- not cause chronic disease. Hepatitis B virus HAV usually persists for life, providing protection infection can also present as an acute infection, but against reinfection. many patients, and particularly young children, become chronic carriers of the virus. They are The disease varies considerably in severity. Mild important in the transmission of the disease and infections with few or no symptoms are common in many ultimately die from chronic liver disease and children, but death occasionally results from primary liver cancer. Hepatitis C, formerly referred fulminant hepatitis. Children under 6 years to as parenterally-transmitted non-A, non-B generally experience no more than transient hepatitis, is responsible for most cases of blood malaise, nausea, vomiting and diarrhoea; only transmitted hepatitis. Hepatitis E virus causes large about 10% become icteric. Older children and epidemics of waterborne hepatitis in developing adults develop the classical symptoms of malaise, countries as well as sporadic disease and has a nausea, vomiting and loss of appetite, and more high mortality rate in pregnant women. Delta than 3 in 4 become jaundiced. Chronic carriers hepatitis is caused by an "incomplete" RNA virus — have not been identified. or delta agent —that replicates only in the presence of hepatitis B virus and augments the Control severity of the primary infection. Prevention is primarily dependent upon maintaining satisfactory standards of sanitation and personal Hepatitis A hygiene. The hepatitis A virus (HAV) is usually transmitted A specific hepatitis A vaccine which provides a high from person to person or through faecal con­ tamination of water or food and, particularly, level of long-term protection in travellers and other contaminated shellfish. It is also transmitted by groups at risk is now available in many countries. sexual contact and, very rarely, by transfusion of However, human immunoglobulin (IgG) remains infected blood. widely used, both as a cheaper means of providing pre-exposure prophylaxis in travellers to endemic regions, and also to provide post-exposure prophy­ Sporadic cases occur everywhere but, where sani­ laxis. Used for the latter purpose, it confers tation is inadequate, entire communities become immediate but transient (2-4 months) protection infected during childhood. The age of infection when it is administered within a week or two of tends to shift progressively to older children and exposure. It is of particular value in protecting close young adults as sanitary conditions improve. household and sexual contacts of confirmed cases and in containing outbreaks of the disease in The incubation period ranges from 14 to 45 days. institutions such as day-care centres for children The virus replicates only in the liver and is excreted and homes for the mentally disabled. via the biliary tract into the faeces. The viral load in the faeces is greatest during the last 1-2 weeks of the incubation period, before symptoms appear. Hepatitis B Thereafter, it decreases substantially. Viraemia is also detectable late in the incubation period and Hepatitis B occurs throughout the world and it is sometimes during the first few days of the clinical hyperendemic in sub-Saharan Africa and south­ illness. east Asia. In hyperendemic areas most children become infected during the first few years of life. In communities exposed to lesser risk of infection, Infants born to mothers who are chronic carriers of vaccination should also be given to individuals at the disease are at high risk of developing infection relatively high risk. These include intravenous drug during the perinatal period. Transmission in utero is abusers, homosexuals, persons in household rare because the virus does not readily cross the contact with a chronic carrier, patients requiring intact placental barrier. In early childhood, trans­ chronic haemodialysis and health workers mission readily occurs between siblings and close frequently in contact with blood. contacts. Among adults not previously infected, sexual contact and, in some countries, blood Passive vaccination with hepatitis B immuno­ transfusion are important modes of transmission. globulin may be usefully combined with hepatitis B Drug abusers and health workers are at specific vaccination to provide immediate as well as longer- risk of inoculation of infected blood. term protection to individuals accidentally exposed to infected blood, to neonates born to an infected The clinical course of the acute phase of the mother, or following sexual contact with an infected infection is similar to that of hepatitis A. Mild, non- person. icteric illness is common among infants and young children. Clinical evidence of liver damage, Vital measures to prevent parenteral transmission including jaundice, is more common among older of the virus include effective sterilization of needles children and adults. Rarely, the disease runs a and syringes, and screening of donated blood to fulminant and fatal course. The majority of infected exclude units containing hepatitis B surface anti­ infants and young children become chronic carriers gen. of the virus. The carrier state is considerably less common among individuals first infected later in The use of alfa and beta interferons is being childhood or as adults. Of an estimated global explored in the treatment of selected patients with population of some 300 million chronic carriers it is chronic hepatitis B. However, their modest efficacy estimated that 25-30% will ultimately die from and high cost preclude their routine use in many chronic hepatitis, cirrhosis or primary hepatocellular countries at present. carcinoma. Hepatitis C Infection is accompanied by the appearance of several immunological markers. A specific surface Hepatitis C is now recognized as the major cause antigen (HBsAg) first becomes detectable in the of non-epidemic, non-A, non-B hepatitis in most serum approximately 30—60 days after exposure. countries. Within the USA this organism is believed Surface antigen that remains detectable for more to be responsible for more than 90% of post­ than 6 months is presumptive evidence of chronic transfusion hepatitis infections. Drug abusers and infection. Antibodies to the surface antigen, which dialysis patients are also at risk. Most of the acute develop as the acute infection resolves, are infections are anicteric and are characterized only responsible for long-term immunity. Specific anti­ by fatigue or anorexia. Up to 80% of infections, bodies to core antigen (anti-HBc) are also detect­ however, result in chronic hepatitis, and it is able for prolonged periods. Hepatitis Be antigen estimated that at least 20% of these chronic (HBeAg) correlates with high rates of viral carriers ultimately develop cirrhosis and, among replication and with infectivity. Antibody to the e these, many subsequently develop hepatocellular antigen (anti-HBe) becomes detectable following carcinoma. acute infections and frequently persists in the sera of carriers once HBeAg has disappeared. Blood screening test-kits containing cloned recombinant viral proteins have been developed to Prevention detect antibody to the virus in serum or plasma. All infants should be vaccinated with hepatitis B These are more sensitive than the indirect markers vaccine shortly after birth. When administered of infection - including alanine amino-transferase during the first years of life by various regimens levels and antibody to hepatitis B core antigen - involving 3 or 4 doses given over a period of already used for this purpose. However, their high several months, this vaccine is highly effective in cost precludes their use in many developing protecting children from persistent infection over countries. periods as long as 10 years. In the absence of these screening tests the disease Control can only be diagnosed by exclusion of hepatitis A Effective prevention of hepatitis B, using both non­ and B, and other infectious agents that cause specific measures and vaccines, provides the only diffuse inflammatory changes throughout the liver. available strategy for stemming co-infection with the delta virus. Alfa interferon has been claimed to There is as yet no specific treatment or vaccine for attenuate the severity of these infections, but only this disease. Preliminary studies with alfa and beta in a minority of patients. interferons have provided results of some promise, with approximately 25% of patients showing sustained remission. Hepatitis B vaccine Injection Hepatitis E Plasma-derived hepatitis B vaccines are prepared A recently identified organism, hepatitis E virus, is from the plasma of human hepatitis B carriers. responsible for highly prevalent epidemic and Such vaccines have been available for more than sporadic waterborne infections that occur in parts of 10 years and have an outstanding record of safety Asia, North and West Africa, and Central America. and efficacy. These cases are characterized by an acute hepatitis which sometimes becomes fulminant, and Recombinant hepatitis B vaccines are produced by which is associated with a high fatality rate. Saccharomyces cerevisiae or mammalian cells into Pregnant women are at particular risk of developing which a plasmid containing the gene for hepatitis B fulminant hepatitis and death typically occurs during surface antigen (HBsAG) has been inserted. the third trimester. Control — as with other types of Purified HBsAG is obtained by lysing the yeast cells waterborne hepatitis viruses — is largely dependent and separating HBsAg from the yeast components upon effective sanitation and a clean water supply. by biochemical and biophysical techniques or from the supernatant of mammalian cell cultures.

Delta hepatitis Both plasma-derived and DNA-recombinant Delta hepatitis is caused by an RNA virus which is vaccines which meet the WHO requirements are dependent upon the hepatitis B virus for its safe and effective and may be used in immuniza­ replication. It is transmitted by inoculation or tion programmes. transfusion of infected blood and, less frequently, by sexual contact. The surface antigen of the Uses hepatitis B virus envelops the infectious RNA of the To confer active immunity against hepatitis B delta virus. Infection with both viruses sometimes infection. occurs coincidentally, causing a relatively severe infection which, in non-fatal cases, is self-limiting. WHO recommends that "hepatitis B vaccine should Superinfection in a chronic hepatitis B carrier be integrated into national immunization usually results in a chronic mixed infection and programmes in all countries with a hepatitis B accelerated development of chronic hepatitis. carrier prevalence (HBsAg) of 8% or greater by 1995 and in all countries by 1997. Target groups Clinically, the delta virus frequently intensifies the and stategies may vary with the local epidemiology. severity of the hepatic injury. Fulminant hepatitis When carrier prevalence is 2% or greater, the most commonly occurs. This is characterized by sudden effective strategy is incorporation into the routine onset of high fever, marked abdominal pain, infant immunization schedules. Countries with lower vomiting and jaundice followed by the development prevalence may consider immunization of all of hepatic encephalopathy resulting in deep coma adolescents as an addition or alternative to infant and seizures. Mortality increases with age, and immunization.* patients over 45 years often succumb either from the acute phase of infection or — in the case of In addition, it is recommended that individuals at chronic carriers of hepatitis B —from rapidly- high risk of infection should be vaccinated. These progressive cirrhosis within the span of a few years.

* Recommendations by the WHO Expanded Programme on Immunization in: EPI for the 1990s: WHO/EPI/GEN/ 92.2 include frequent travellers to endemic areas, all Hepatitis B immune globulin health workers, intravenous drug abusers, homosexuals, household contacts of HBV carriers Injection and haemodialysis patients. Hepatitis B immune globulin is prepared from the plasma of individuals with high titres of antibody to Dosage and administration hepatftis B surface antigen (anti-HBs). It contains The vaccine should be administered intramus­ thiomersal as a preservative and glycine as a cularly into the deltoid region of the arm. The stabilizing agent. anterolateral thigh may be a preferable site in infants and neonates. Most countries recommend Uses that three intramuscular doses of vaccine be It is used, as a prophylactic measure, to generate administered, with the second and third doses passive immunity to hepatitis B infection in given one and six months, respectively, after the individuals likely to have been exposed to hepatitis first. B virus or HBsAg-positive materials. Dosage must be made with reference to the It is administered in combination with hepatitis B manufacturer's data sheet since this varies vaccine to provide post-exposure prophylaxis in between products. neonates born to HBsAg-positive mothers and in individuals exposed to presumptive percutaneous In neonates born to HBsAg positive mothers, inoculation of the virus. hepatitis immunoglobulin may be given simultaneously with the vaccine within a few hours of birth. Dosage and administration Adults: 0.06 ml/kg (about 3-5 ml) administered by Contraindications intramuscular injection into the deltoid muscle or into the anterolateral aspect of the thigh. Hypersensitivity to any component of the vaccine. Contraindications Precautions Known hypersensitivity to hepatitis B immune In haemodialysis patients or patients who are globulin or any component of the finished immunocompromised, a booster dose of the preparation. vaccine may be necessary.

As with all vaccinations, epinephrine should be Precautions immediately available if an anaphylactic reaction Because of the risk of anaphylaxis, it should be occurs. administered with care to individuals with a specific IgA deficiency. Use in pregnancy Inactivated viral vaccines, in general, pose no Use in pregnancy specific risk to the fetus. The risk of infection with Because of the serious potential long-term hepatitis B greatly outweighs any untoward effect of consequences of hepatitis B infection in the the vaccine. It should be administered during neonates, hepatitis B immunoglobulin should be pregnancy whenever it is indicated. administered to any pregnant woman exposed to risk of transmission. Adverse effects Hepatitis B vaccine is usually well-tolerated. Mild Adverse effects transient local soreness, erythema and induration at Pain and tenderness may occur at the site of the injection site are the most commonly recorded injection. reactions. Storage Storage Hepatitis B immunoglobulin should be stored Hepatitis B vaccine should be stored between 2 between 2 and 8 °C, protected from light, and and 8 °C, protected from light. It should not be should not be allowed to freeze. allowed to freeze. Human immunoglobulin Hepatitis A vaccine Injection injection Human immunoglobulin is prepared from pools of at Hepatitis A (HA) vaccine is prepared by lysing least 1000 donations of human plasma; it contains human diploid cells in which the virus has been antibody to hepatitis A, measles, mumps, varicella grown, purifying by ultrafiltration and inactivating by and other viruses that are prevalent in the general treatment with formaldehyde. Each 1 -ml dose population. Injection of human immunoglobulin contains not less than 720 ELISA units of hepatitis produces immediate passive immunity to hepatitis A viral protein adsorbed onto aluminium hydroxide A lasting up to 4 months. adjuvant together with 5 mg of 2-phenoxyethanol as preservative. A specific hepatitis A immunoglobulin is available in a few countries. However, it is considered too Uses expensive for routine use. The vaccine is used to confer active immunization against infections caused by hepatitis A virus Uses (HAV): It is used for post-exposure prophylaxis against hepatitis A in household and sexual contacts of • in travellers to areas where hepatitis A is endemic; acute cases and in children and staff in day-care and centres and institutions for the mentally disabled. • in individuals wishing to obtain protection against HAV infection. Pre-exposure prophylaxis of hepatitis A for travellers to endemic areas. The efficacy of HA vaccine in post-exposure and outbreak situations has not yet been established. Dosage and administration Research in this area is in progress. Post-exposure prophylaxis Adults: 500 mg Dosage and administration Children: 250 mg in a single intramuscular injection. Two separate intramuscular injections of 1 ml of vaccine are administered 2-4 weeks apart. Pre-exposure prophylaxis Immunity is conferred for up to one year. A 1 ml Adults: 250 mg booster dose 6-12 months after the initial dose is Children: 125 mg in a single intramuscular injection. anticipated to provide immunity for up to 10 years. For travellers who seek medical advice less than 2 Contraindications weeks before travelling, one dose of vaccine given Patients with known specific antibody to immuno­ immediately prior to travel is likely to be protective, globulin A (IgA). but further data are required to confirm this. A double dose of the vaccine will induce antibodies in more than 90% of individuals within 2 weeks and Precautions will almost certainly protect against infection. Human immunoglobulin may interfere with the Otherwise a dose of immunoglobulin may be response to live virus vaccines which should administered with the first dose of the vaccine. therefore be given at least 3 weeks before or 3 months after an injection of human immunoglobulin. For travellers, when insufficient notice is given, this Contraindications recommended interval may have to be ignored. Known hypersensitivity to any component of the vaccine. Adverse effects Severe febrile infections. Malaise, chills, fever and rarely anaphylaxis may occur following injection with human immuno­ Precautions globulin. Appropriate medication for anaphylaxis should always be readily available. Storage Human immunoglobulin should be stored between Patients with impaired immunity or those under­ 2 and 8° C and should not be frozen. going haemodialysis, may not develop adequate antibody titres after primary immuniza-tion, and Adverse effects may require additional doses of the vaccine. Mild reactions, including transient soreness, erythema and induration at the site of injection, Use in pregnancy have been recorded within the first few days after Inactivated viral vaccines, in general, pose no vaccination. specific risk to the fetus. However, it is prudent, as a general principle, that the vaccine should be administered during pregnancy only to women who Storage are at definite risk of hepatitis A. Hepatitis A vaccine should be stored, protected from light, between 2 and 8° C and must not be frozen.

The information in this section is subject to consultation prior to definitive publication in the WHO Model Prescribing Information series. Comments, which are invited at this stage, should be referred to: Division of Drug Management and Policies World Health Organization 1211 Geneva 27, Switzerland Recent Publications

Quality control of essential drugs in reliable reference materials. In other respects, however, the requirements are not demanding. A developing countries: standardized short introductory section describes the required methods laboratory layout and the necessary equipment and glassware. It also indicates how basic documenta­ This manual, currently available only in the original tion should be organized, and even provides a French language version produced with the support rudimentary description of the chemical and of the French Ministry of Cooperation and Develop­ physical principles on which the proposed tests are ment (1), presents an approach to analytical based. aspects of drug control that is geared to the needs of developing countries. It emanates from a centre One important point, unfortunately, is not concerned with epidemiological studies and emphasized in this introductory material. The preventive medicine situated in a regional hospital monographs that account for the greater part of the in Nantes, France. However, the connection manual must not be regarded as replacing between drug control and preventive medicine is pharmacopoeial specifications. They do not provide established all too clearly in the first paragraph of a sufficient analytical basis on which to clear the preface. National procurement agencies in substances for use in pharmaceutical products, nor developing countries, the author claims, need to be do they provide a basis for determining whether a particularly vigilant about the quality of drugs finished dosage form complies with the labelled offered on open tender. Products sometimes specification. contain less than the declared dose; they may contain unacceptable impurities; or they may be The value of the book is uncontested as a labora­ degraded. Sometimes legitimate products tory manual, but it would have been enhanced by deteriorate in transit, but substandard drugs and the inclusion of a short explanation of the bulk materials are also sometimes the end-product administrative safeguards, including the use of the of the fraudulent activities of clandestine WHO Certification Scheme on the Quality of manufacturers. Pharmaceutical Products moving in International Commerce, which should be applied whenever bulk materials or dosage forms are imported from a new The greater part of the manual is devoted to simple supplier. Assurance of quality cannot be based on tests for verifying the identity of pharmaceutical analytical procedures alone. It is a concept that substances and dosage forms included in WHO's requires definition in the light of fast-changing Model List of Essential Drugs and, additionally, for circumstances, and this is one of the major issues checking the content and stability of these dosage that will be placed before the WHO Expert forms. The scope of these tests is thus wider and Committee on Specifications for Pharmaceutical more ambitious than that of earlier publications emanating from WHO's basic test programme Preparations when it is next convened towards the which focused primarily on verification of identity (1, end of 1994. 2). Moreover, the methods described in this new publication, although simple and robust, require 1. Côntrole de qualité des médicaments essentiels dans les pays en developpement: méthodes standardisées. modest laboratory facilities. Those issued earlier Vincent-Ballereau, F., Le Quay, L, Lafleuriel, M-T., were designed to be undertaken, when necessary, Gomes-Mavoungou, L. Groupe d'Etudes Epidemiolo- outside a formal laboratory setting. giques et Prophylactiques et Centre Collaborateur de I'Oitjanisation mondiale de la Santé pour I'etude de la Thus, the identity and degradation tests described stabilité des médicaments. Centre Hospitalier de in this manual are based exclusively on thin-layer Villeneuve-Saint-Georges, France, 1992. chromatography, while the content of active 2. Basic Tests for Pharmaceutical Substances. World ingredient is estimated either by chemical titration Health Organization, Geneva, 1986. ISBN 92 4 154204 7. or by spectrophotometry methods. These methods are essentially comparative and, as such, their 3. Basic Tests for Pharmaceutical Dosage Forms. World performance depends upon the availability of Health Organization, Geneva, 1991. ISBN 924 154418 X. International Nonproprietary Names for Pharmaceutical Substances

Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances*, the following names are selected as Recommended International Nonproprietary Names. The inclusion of a name in the lists of Recommended International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy. Recommended International Nonproprietary Names (Rec. INN): List 33

Lists of proposed (1-65) and recommended (1-31) international nonproprietary names can be found in Cumulative List No. 8, 1992.

Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English) alestramustinum estradiol 3-[bis(2-chloroethyl)carbamate], 17-ester with L-alanine alestramustine C26H36CI2N2O4 alglucerasum glucosylceramidase (human placenta isoenzyme protein moiety reduced) alglucerase C2532H3854N672O711S16 (for non-glycosylated protein) alovudinum 3'-deoxy-3'-fluorothymidine alovudine C10H13FN2O4 altumomabum immunoglobulin G 1 (mouse monoclonal ZCE025 anti-human antigen CEA), altumomab disulfide with mouse monoclonal ZCE025 light chain, dimer amesergidum N-cyclohexyl-1-isopropyl-6-methylergoline-8p-carboxamide amesergide C25H35N3O amitivirum 1,3,4-thiadiazole-2-carbamonitrile amitivir C3H2N4S andolastum 4,4'-di-1 H-tetrazol-5-ylbenzanilide andolast C15H11N9O ardeparinum natricum Sodium salt of depolymerized heparin obtained by peroxide degradation (at ardeparin sodium elevated temperature) of heparin from pork intestinal mucosa; the end chain structure appears to be the same as the starting material with no unusual sugar residues present; the low molecular weight heparin produced differs from the starting material in molecular weight only; the average relative molecular mass range is 5,500 to 6,500 daltons, 98 per cent of which ranging between 2,000 and 15,000; the degree of sulfation is approximately 2,7 per disaccharidic unit.

* Official Records of the World Health Organization, 1955, 60, 3 (Resolution EB15.R7); 1969,173, 10 (Resolution EB43.R9). Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

artilidum (+)-4'-[(R)-4-(dibutylamino)-1-hydroxybutyl]methanesulfonanilide

artilide C19H34N2O3S

atrinositolum D-myo-inositol 1,2,6-tris(dihydrogen phosphate) atrinositol C6H15O15P3

avicatoninum 1-butyric acid-2-L-alanine-3-L-serine-7-(L-2-aminobutyric acid)-26-L-aspartic acid- avicatonin 27-L-valine-29-L-alaninecalcitonin (salmon)

C147H243N41O46

azasetronum (±)-6-chloro-3,4-dihydro-4-methyl-3-oxo-N-3-quinuclidinyl-2H-1,4-benzoxazine-8- azasetron carboxamide C17H20CIN3O3

berefrinum m-[(2R,5R)-2-fert-butyl-3-methyl-5-oxazolidinyl]phenol mixture with m-[(2S,5R)-2- berefrine tert-butyl-3-methyl-5-oxazolidinyl]phenol C14H21NO2

besigomsinum (+)-(6S,7S, biar-R)-5,6,7,8-tetrahydro-1,2,3,13-tetramethoxy-6,7- besigomsin dimethylbenzo[3,4]cycloocta[1,2-/][1,3]benzodioxol-6-ol

C23H28O7

bizelesinum 1,3-bis[2-[[(S)-1-(chloromethyl)-1,6-dihydro-5-hydroxy-8-methylbenzo[1,2-b:4,3- bizelesin b']dipyrrol-3(2H)-yl]carbonyl]indol-5-yl]urea C43H36CI2N8O5

camiglibosum methyl 6-deoxy-6-[(2R,3R,4R,5S)-3,4,5-trihydroxy- camiglibose 2-(hydroxymethyl)piperidino]-α-D-glucopyranoside C13H25NO9

carsatrinum 4-[bis(p-fluorophenyl)methyl]-α-[(9H-purin-6-ylthio)methyl]- carsatrin 1-piperazineethanol C25H26F2N6OS

carzelesinum N-[2-[[(S)-1-(chloromethyl)-1,6-dihydro-5-hydroxy-8-methyl= carzelesin benzo[1,2-b:4,3-b']dipyrrol-3(2/-/)-yl]carbonyl]indol-5-yl]-6-(diethylamino)' 2-benzofurancarboxamide carbanilate (ester) C41H37CIN6O5

celefloxacinum (-)-7-[(2S,3R)-3-amino-2-methyl-1 -azetidinyl]-1 -(2,4-difluorophenyl)-6-fluoro-1,4- cetefloxacin dihydro-4-oxo-3-quinolinecarboxylicacid C20H16F3N3O3

cilansetronum (-)-(R)-5,6,9,10-tetrahydro-10-[(2-methylimidazol-1-yl)methyl]-4H-pyrido[3,2,1- cilansetron jk:]carbazol-11 (8H)-one

cladribinum 2-chloro-2'-deoxyadenosine cladribine C10H12CIN5O3 clinafloxacinum (+)-7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro- clinafloxacin 4-oxo-3-quinolinecarboxylic acid C17H17CIFN3O3 Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English) clinprostum (+)-methyl(3aS,5R,6R,6aS)-1,3a,4,5,6,6a-hexahydro-5-hydroxy-6-[(E)-(3S)-3- clinprost hydroxy-1 -octenyl]-2-pentalenevalerate

C22H36O4 deferipronum 3-hydroxy-1,2-dimethyl-4(1 H)-pyridone deferiprone C7H9NO2 dexniguldipinum (+)-(R)-3-(4,4-diphenylpiperidino)propyl methyl 1,4-dihydro-2,6-dimethyl- dexniguldipine 4-(m-nitrophenyl)-3,5-pyridinedicarboxylate

C36H39N3O6 dezinamidum 3-[(α,α,α-trifluoro-m-tolyl)oxy]-1-azetidinecarboxamide dezinamide C11H11F3N2O2 dimiracetamum (±)-dihydro-1 H-pyrrolo[1,2-a]imidazole-2,5(3H,6/-/)-dione dimiracetam C6H8N2O2 dorzolamidum (4S,6S)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran- dorzolamide 2-sulfonamide 7,7-dioxide C10H16N2O4S3 drospirenonum (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3\4\6,6a,7,8,9,10,11,12,13,14,15,15a,16- drospirenone hexadecahydro-10,13-dimethylspiro- [17H-dicyclopropa[6,7:15,16]cyclopenta[a]phenanthrene-17,2'(5'/-0-furan]- 3,5'(2H)-dione

C24H30O3 duloxetinum (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine duloxetine C18H19NOS ecabapidum m-[[[(3,4-dimethoxyphenethyl)carbamoyl]methyl]amino]-N-methylbenzamide ecabapide C20H25N3O4 ecadotrilum N-[(S)-a-(mercaptomethyl)hydrocinnamoyl]glycine, benzyl ester, acetate (ester) ecadotril C21H23NO4S enadolinum N-methyl-N-[(5R,7S,8S)-7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-4- enadoline benzofuranacetamide

C24H32N2O3 enazadremum 4,6-dimethyl-2-[(6-phenylhexyl)amino]-5-pyrimidinol enazadrem C18H25N3O enofelastum (E)-4'-fluoro-3,5-dimethyl-4-stilbenol enofelast C16H15FO epoetinum alfa 1-165-erythropoietin (human clone λHEPOFL 13 protein moiety), glycoform a epoetin alfa C809H1301N229O240S5 (for non-glycosylated protein) epoetinum beta 1-165-erythropoietin (human clone λHEPOFL 13 protein moiety), glycoform β epoetin beta C809H1301N229O240S5 (for non-glycosylated protein) Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English) epoetinum gamma 1-165-erythropoietin (human clone λHEPOFL 13 protein moiety), glycoform y epoetin gamma C809H1301N229O240S5 (for non-glycosylated protein) fialuridinum 1-(2-deoxy-2-fluoro-p-D-arabinofuranosyl)-5-iodouracil fialuridine C9H10FIN2O5 flezelastinum (±)-4-(p-fluorobenzyl)-2-(hexahydro-1-phenethyl-1H-azepin-4-yl)-1(2H)- flezelastine phthalazinone C29H30FN3O furnidipinum (±)-methyl tetrahydrofurfuryl,1,4-dihydro-2,6-dimethyl-4-(o-nitrophenyl)- furnidipine 3,5-pyridinedicarboxylate C21H24N2O7 ganefromycinum An antibiotic produced by Streptomyces lydicus. ganefromycin Ganefromycin is a complex antibiotic with two major components: a and (3.

component a (2E,4E,6E)-7-[(2R*,3R*,5R*)-5-[7-[(3H,5E)-3-[[0-2,6-dideoxy-3-0-methyl-a-/yxo nexopyranosyl-(1-+4)-0-2,6-dideoxy-3-0-metnyl-p-r/t)o-hexopyranosyl-(1->4)-2,6- dideoxy-3-0-methyl-a-/yxo-hexopyranosyl]oxy]-2-[(2S*,3S*,4S*,6F?*)-tetrahydro- 2,3,4-trihydroxy-5,5-dimethyl-6-[(1E,32)-1,3-pentadienyl]-2M-pyran-2- yl]propionamido]-2-methoxy-1,3-dimethyl-3,5-heptadienyl]tetrahydro-3-hydroxy-2- furyl]-2,4,6-heptatrienoic acid, 23-phenylacetate

component (3 (2E,4E, 6E)-7-[(2R*,3R*,5R*)-5-[7-[(3E,5E)-3-[[0-2,6-dideoxy-3-0-methyl-a-/yxo hexopyranosyl-(1->4)-O-2,6-dideoxy-3-O-methyl-p-nfeohexopyranosyl-(1"->4)-2,6- dideoxy-3-Omethyl-α-/yxo-hexopyranosyl]oxy]-2-[(2S*,3S*,4S*,6R*)-tetrahydro- 2,3,4-trihydroxy-5,5-dimethyl-6-[(1E,3Z)-1,3-pentadienyl]-2H-pyran-2- yl]propionamido]-2-methoxy-1,3-dimethyl-3,5-heptadienyl]tetrahydro-3-hydroxy-2- furyl]-2,4,6-heptatrienoic acid, 24-phenylacetate

C65H95NO21 (empirical molecular formula) glemanserinum (+)-1-phenethyl-α-phenyl-4-piperidinemethanol glemanserin C20H25NO grepafloxacinum (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-(3-methyl-1-piperazinyl)-4-oxo-3- grepafloxacin quinolinecarboxylic acid C19H22FN3O3 guspenmus (+)-N-[[[4-[(3-aminopropyl)amino]butyl]carbamoyl]hydroxymethyl]-7- gusperimus guanidinoheptanamide C17H37N7O3 icatibantum (R)-arginyl-(S)-arginyl-(S)-prolyl-(2S,4H)-(4-hydroxyprolyl)glycyl-(S)- icatibant [3-(2-thienyl)alanyl]-(S)-seryl-(R)-[(1,2,3,4-tetrahydro-3-isoquinolyl)carbonyl]- (2S,3aS,7aS)-[(hexahydro-2-indolinyl)carbonyl]-(S)-arginine C59H89N19O13S icodextrinum dextrin, having more than 85% of its molecules with molecular masses between icodextrin 1640 and 45000 with a claimed-average molecular mass of approximatively 20000 [C6H12O6]n Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English) icodulinum 6-(2-thiazolylamino)-m-cresol icoduline C10H10N2OS tdoxtfenum 1-[2-[p-[(E-p-ethyl-α-(p-iodophenyl)slyryl]phenoxy]ethyl]pyrrolidine idoxifene C28H30INO igmesmum (+)-a-[(E)-cinnamyl]-N-(cyclopropylmethyl)-a-ethyl-A/-methylbenzylamine igmesine C23H29N intoplicinum 11-[[3-(dimethylamino)propyl]amino]-8-methyl-7H-benzo[e]pyrido[4,3-£>]= intoplicine indol-3-ol

C21H24N4O iobitridolum N,N'-bis(2,3-dihydroxypropyl)-5-[2-(hydroxymethyl)hydracrylamido]-2,4,6-triiodo- iobitridol N,N'-dimethylisophthalamide C20H28I3N3O9 iofratolum N,N"-(2-hydroxytrimethylene)bis[W-[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6- iofratol triiodo-5-[(S)-lactamido]isophthalamide] C31H36l6N6O13 itasetronum 2-oxo-N-1αH,5αH-tropan-3a-yl-1-benzimidazoline-1-carboxamide itasetron C16H20N4O2 latanoprostum isopropyl (2)-7-[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy- lalanoprost 5-phenylpentyl]cyclopentyl]-5-heptenoate

C26H40O5 leminoprazolum (±)-2-[[o-(isobutylmethylamino)benzyl]sulfinyl]benzimidazole leminoprazole C19H23N3OS levosimendanum mesoxalonitrile (-)-[p[(R)-1,4,5,6-tetrahydro-4-methyl-6-oxo-3- levosimendan pyridazinyl]phenyl]hydrazone C14H12N6O lifibrolum (±)-p-[4-(p-tert-butylphenyl)-2-hydroxybutoxy]benzoicacid lifibrol C21H26O4 linopirdinum 1-phenyl-3,3-bis(4-pyridylmethyl)-2-indolinone linopirdine C26H21N3O lomerizinum 1-[bis(p-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine lomerizine C27H30F2N2O3 losoxantronum 7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-[(2- losoxantrone hydroxyethyl)amino]ethyl]amino]anthra[1,9-cd]pyrazol-6(2H)-one C22H27N5O4 mideplaninum a mixture of six substances of which 70% is: mideplanin 34-[{2-acetamido-2-deoxy-β-D-gIucopyranosyI)oxy]-15-amino-22,31-dichIoro- 56-[[2-deoxy-2-(8-methylnonanamido)-p-D-glucopyranosyl]oxy]-/V- [3-(dimethylamino)propyl]-2,3,16,17,18,19,35,36,37,38,48,49,50,50a-tetradeca= hydro-6,11,40,44-tetrahydroxy-42-(a-D-mannopyranosyloxy)-2,16,36,50,51,59- hexaoxo-1H, 15H,34H-20,23:30,33-dietheno-3,18:35,48-bis(iminomethano)- 4,8:10,14:25,28:43,47-tetrametheno-28H-[1,14,6,22]dioxadiazacycloocta= cosino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-38-carboxamide C93H109CI2N11O32 Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

moexiprilatum (3S)-2-[(2S)-N-[(1 S)-1 -carboxy-3-phenylpropyl]alanyl]-1,2,3,4-tetrahydro- moexiprilat 6,7-dimethoxy-3-isoquinolinecarboxylic acid

C25H30N2O7

monatepilum (±)-A/-(6,11-dihydrodibenzo[i),e]thiepin-11-yl)-4-(p-fluorophenyl)-1- monatepil piperazinebutyramide

namirotenum p-[(E)-2-(5-isopropyl-2-thienyl)propenyl]benzoic acid namirotene

nasaruplasum prourokinase (enzyme-activating) (human clone pA3/pD2/pF1 protein moiety)

nasaruplase C2031H3121N585O601S31

nensopamum 1-(p-aminophenyl)-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine

nerisopam C18H19N3O2

nexopamilum (2S)-5-(hexylmethylamino)-2-isopropyl-2-(3,4,5-trimethoxyphenyl)valeronitrile nexopamil C24H40N2O3

niravolinum N-methyl-2-(m-nitrophenyl)-/V-[(1S,2S)-2-(1-pyrrolidinyl)-1-indanyl]acetamide

niravoline C22H25N3O3 olanzapinum 2-methyl-4-(4-methyl-1 -piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine olanzapine C17H20N4S orbifloxacinum 1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-5,6,8-trifluoro-1,4-dihydro-4-oxo-3- orbifloxacin quinolinecarboxylic acid

C19H20F3N3O3 osateronum (+)-6-chloro-17-hydroxy-2-oxapregna-4,6-diene-3,20-dione osaterone pegaldesleukinum 125-L-serine-2-133-interleukin 2 (human reduced), reaction product with pegaldesleukin glutaric anhydride, esters with polyethylene glycol monomethyl ester pendetidum N6-[N-[2-[[2-[bis(carboxymethyl)amino]ethyl](carboxymethyl)amino]ethyl]- pendetide N-(carboxymethyl)glycyl]-N2-(N-glycyl-L-tyrosyl)-L-lysine C31H47N7O14 pidobenzonum 5-oxo-L-proline, p-hydroxyphenyl ester pidobenzone C11H11NO4 polidroninii chloridum α-[(E)-4-[tris(2-hydroxyethyl)ammonio]-2-butenyl-o>[tris(2-hydroxyethyl)= polidronium chloride ammonio]poly[(dimethyliminio)[(E)-2-butenylene] chloride] dichloride (C6H12CIN)n • C16H36CI3N2O6 pranlukastum N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-p-(4-phenylbutoxy)= pranlukast benzamide C27H23N5O4 Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English) prezatidi cuprici acetas hydrogen [N2-(/V-glycyl-L-histidyl)-L-lysinato][N2-(N-glycyl-L-histidyl)- prezatide copper acetate i_-lysinato(2-)]cuprate(1-), diacetate C28H46CuN12O8 • 2 C2H4O2 ramorelixum 1-[N-acetyl-3-(2-naphthyl)-D-alanyl-p-chloro-D-phenylalanyl-D-tryptophyl-L-seryl-L- ramorelix tyrosyl-0-(6-deoxy-α-L-mannopyranosyl)-D-seryl-L-leucyl-L-arginyl-L- prolyl]semicarbazide C74H95CIN16O13 raxofelastum (+)-2,3-dihydro-5-hydroxy-4,6,7-trimethyl-2-benzofuranaceticacid, acetate raxofelast C15H18O5 remifentanilum 4-carboxy-4-(N-phenylpropionamido)1 -piperidinepropionic acid, dimethyl remifentanil ester C20H28N2O5 revizinonum (E)-N-cyclohexyl-N-methyl-2-[[[a.-(1,2,3,5-tetrahydro-2-oxoimidazo[2,1-£)]= revizinone quinazolin-7-yl)benzylidene]amino]oxy]acetamide C26H29N5O3 rifamexilum (9S,12E,14S,15R,16S,17R,18R,19R,20S,21S,22£,242)-2-(diethylamino)- rifamexil 5,6,16,18,20-pentahydroxy-14-methoxy-7,9,15,17,19,21,25-heptamethyl- 9,4-(epoxypentadeca[1,11,13]trienimino)furo[2',3':7,8]naphtho[1,2-d]thiazole- 10,26(9H)-dione, 16-acetate C42H55N3O11S ritipenemum (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxymethyl)-7-oxo-4-thia-1-aza= ritipenem bicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 3-carbamate C10H12N2O6S safironilum N,N'-bis(3-methoxypropyl)-2,4-pyridinedicarboxamide safironil C15H23N3O4 sanguinarii chloridum sanguinarine chloride or 13-methyl[1,3]benzodioxolo[5,6-c]-1,3-dioxolo[4,5-/]= sanguinarium chloride phenanthridinium chloride C20H14CINO4 saripidemum N-[[2-(p-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]-/V-methylbutyramide saripidem C19H20CIN3O satigrelum 4-cyano-5,5-bis(p-methoxyphenyl)-4-pentenoic acid satigrel C20H19NO4 satumomabum immunoglobulin G 1 (mouse monoclonal B72.3 anti-human glycoprotein satumomab TAG-72), disulfide with mouse monoclonal B72.3 light chain, dimer sebriplatinum (+)-cis-(1,1-cyclobutanedicarboxylato)[(2R)-2-methyl-1,4-butanediamine- sebriplatin N,N']platinum C11H20N2O4Pt semorphonum (-)-4,5α-epoxy-3,14-dihydroxy-17-(2-methoxyethyl)morphinan-6-one semorphone C19H23NO5 Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English)

sepimostatum 6-amidino-2-naphthylp-(2-imidazolin-2-ylamino)benzoate sepimostat C21Hl9N5O2

siratiazemum (+)-(2S,3S)-2,3-dihydro-3-hydroxy-5-[2-(isopropylmethylamino)ethyl]-2-(p- siratiazem methoxyphenyl)-1,5-benzothiazepin-4(5H)-one acetate (ester) C24H30N2O4S

sonerminum 3-157-tumor necrosis factor (human) sonermin C767H1204N210O229S2

sulopenemum (5R,6S)-6-[(1R)-1 -hydroxyethyl]-7-oxo-3-[[(3S)-tetrahydro-3-thienyl]thio]-4-thia-1 - sulopenem azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, (R)-S-oxide C12H15NO5S3

tallimustinum N"-(2-amidinoethyl)-4-[p-[bis(2-chloroethyl)amino]benzamido]-1,1',1"-trimethyl- tallimustine N,4':N',4"-ter[pyrrole-2-carboxamide] C32H38Cl2N10O4

tarazepidum (-)-N-[(S)-2,3-dihydro-1 -methyl-2-oxo-5-phenyl-1 H-1,4-benzodiazepin-3-yl]-5,6- tarazepide dihydro-4H-pyrrolo[3,2,1-//]quinoline-2-carboxamide

teloxantronum 7,10-dihydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2- teloxantrone (methylamino)ethyl]amino]anthra[1.9-cd]pyrazol-6(2H)-one C21H25N5O4

tetrazolastum 4-(1 H-tetrazol-5-yl)tetrazolo[1,5-a]quinoline tetrazolast C10H6N8

thymoctonanum N-[N-[N2-[1-[N-[N-(N-L-leucyl-L-α-glutamyl)-L-a-aspartyl]glycyl]-L-prolyl]-L-lysyl]-L- thymoctonan phenylalanyl]-L-leucine

C43H67N9O13 tiotroph bromidum 6p,7β-epoxy-3β-hydroxy-8-methyl-1αH,5αH-tropanium bromide, tiotropium bromide di-2-thienylglycolate C19H22BrNO4S2 tiquesidum (25R)-5α-spirostan-3p-yl 4-O-β-D-glucopyranosyl-p-D-glucopyranoside tiqueside C39H64O13 tirapazaminum 3-amino-1,2,4-benzotriazine 1,4-dioxide tirapazamine C7H6N4O2 trefentanilum N-[1-[2-(4-ethyl-5-oxo-A2-tetrazolin-1-yl)ethyl]-4-phenyl-4-piperidyl]- trefentanil 2'-fluoropropionanilide C25H31FN6O2 tripalmitinum tripalmitin or 1,2,3-propanetriyl trihexadecanoate tripalmitin C51H96O6 troglitazonum (±)-a//-rac-5-[p-[(6-hydroxy-2,5,7,8-tetramethyl-2-chromanyl)methoxy]benzyl]-2,4- troglitazone thiazolidinedione Recommended International Chemical Name or Description and Molecular Formula Nonproprietary Name (Latin, English) turosteridum 1,3-diisopropyl-1 -[(4-methyl-3-oxo-4-aza-5α-androstan-17(3-yl)carbonyl]urea turosteride C27H45N3O3 valsartanum N-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-A/-valeryl-L-valine valsartan C24H29N5O3 venritidinum (±)-(Z)-N-methyl-2-nitro-N'-[2-[[5-[(tricyclo[2.2.1.O2.6]hept-3-ylamino)= venritidine methyl]furfuryl]thio]ethyl]-1,1-ethenediamine

C18H26N4O3S zamifenacinum (R)-3-(diphenylmethoxy)-1-[3,4-(methylenedioxy)phenetyl]piperidene zamifenacin C27H29NO3 zanoteronum 1'-(methylsulfonyl)-1'H-5α,17a-pregn-20-yno[3,2-c]pyrazol-17-ol zanoterone C23H32N2O3S AMENDMENTS TO PREVIOUS LISTS

Chronicle of the World Health Organization, Vol. 9, 1955

Recommended International Nonproprietary Names (Rec. INN): List 1

p. 187 delete insert corticotrophinum corticotropinum corticotrophin corticotropin

Supplement to WHO Chronicle Vol. 33, No. 10, 1979

Recommended International Nonproprietary Names (Rec. INN): List 19

p. 6 pipecuronii bromidum replace the chemical name by the Mowing: pipecuronium bromide 4,4'-(3α-17β-dihydroxy-5a-androstan-2p,16p-ylene)bis[1,1-dimethylpiperazinium] dibromide, diacetate (ester) C35H62Br2N4O4

Supplement to WHO Chronicle Vol. 38, No. 6, 1984

Recommended International Nonproprietary Names (Rec. INN): List 24

p. 5 icospiramidum replace the chemical name by the following: 8-[c/s-4-cyano-4-(p-fluorophenyl)cyclohexyl]-1 -(p-fluorophenyl)-4-oxo-1,3,8- triazaspiro[4.5]decane-3-acetamide

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

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

p. 2 bropiriminum replace the chemical name by the following: bropinmine 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone

WHO Drug Information, Vol. 1, No. 4, 1987

Recommended International Nonproprietary Names (Rec. INN): List 27

p. 5 fosinoprilum replace the chemical name by the following: (4S)-4-cyclohexyl-l -[[(R)-[(S)-1 -hydroxy-2-methylpropoxy](4-phenylbutyl)= phosphinyl]acetyl]-L-proline propionate (ester)

WHO Drug Information, Vol. 5, No. 3, 1991

Recommended International Nonproprietary Names (Rec. INN): List 31

p. 7 leuciglumerum replace the molecular formula by the following:

leuciglumer (C6H13NO2 C6H11NO4)n

WHO Drug Information, Vol. 6, No. 3, 1992

Recommended International Nonproprietary Names (Rec. INN): List 32 p. 3 dexfosfoserinum replace the chemical name by the following: dexfosfoserine (+)-L-senne dihydrogen phosphate (ester)

SELECTED WHO PUBLICATIONS OF RELATED INTEREST

Price' (Sw. fr.)

The use of essential drugs Fifth report of the WHO Expert Committee WHO Technical Report Series, No. 825 1992 (75 pages) 10-

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

WHO model prescribing information: drugs used in parasitic diseases 1990 (128 pages) 21.

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

Guidelines for developing national drug policies 1988 (iv + 52 pages) 11

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-

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.