W H O DRUG

INFORMATION V O L U M E 7 • N U M B E R 2 • 1 9 9 3

P R O P O S E D I N N L I S T 6 9 I N T E R N A T I O N A L N O N P R O P R I E T A R Y N A M E S F O R P H A R M A C E U T I C A L S U B S T A N C E S

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

WHO DRUG INFORMATION

WHO Drug Information provides an overview of topics relating to drug development and regulation that are of current relevance and importance, and 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 designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.

Authors alone are responsible for views expressed in signed contributions.

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

ISSN 1010-9609

Volume 7, Number 2, 1993 World Health Organization, Geneva

WHO Drug Information Contents

General Policy Topics Drug labelling

Reports on Individual Drugs Malaria: a first stride towards effective

vaccination? Zidovudine and the natural history of

HIV infection Halofantrine in multidrug-resistant malaria Poisoning with aconite alkaloids: an unwanted

legacy of traditional medicine Herbal slimming regimens and nephrotoxicity

General Information HIV infection and drug-induced cutaneous

reactions Mucosal immunity re-evaluated: a new

departure in vaccine development Peptic ulcer: a definitive cure emerges New threats from streptococci: the re-emergence

of suppurative disease and rheumatic fever... ... And the widening spectrum of group B

streptococcal disease

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47 49

51 52

54

55 56

60

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Regulatory Matters Reporting reactions to biotechnology products Ketorolac: restrictions on parenteral dosage Paroxetine: dystonia and withdrawal symptoms Quinolone antibiotics: serious adverse reactions Sotalol: approved for life-threatening

arrhythmias Stavudine: a new antiviral for HIV infection Sulfasalazine: fatal blood dyscrasias Sumatriptan: acute treatment of migraine Halofantrine: revised data sheet

Essential Drugs Guidelines for antimicrobial susceptibility

testing (intermediate laboratories)

Recent Publications Pharmacists in Europe

Proposed International Nonproprietary Names: List 69

64 64 64 65

65 65 66 66 66

68

79

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WHO Drug Information Vol. 7, No. 2, 1993

General Policy Topics

Drug labelling Perhaps the most significant outcome of modern national drug legislation is the requirement that product labelling, directed both to doctors and to patients, should provide instructions on how to use medicines as safely and as effectively as possible. Until the relevant sections of these acts were implemented, the situation in many otherwise highly-developed countries was a vestige of a now-rejected professional ethos: patients were to be advised but not informed. Working on the premise that a little knowledge can always prove harmful, pharmacists were commonly required to dispense anonymous-prescribed and unidentified medicines in pill boxes and bottles that bore no more than the name of the patient and some terse dosage instructions. Doctors, in turn, were reliant upon commercially-sponsored and largely unregulated, pocket "prescribing guides".

There is still much scope, virtually everywhere, for improving the way in which information about drug use is conveyed both to health professionals and to patients. The current procedure in highly-developed countries is to require manufacturers of newly-registered branded products to issue data sheets approved by the national drug regulatory authority to doctors, either by direct mailings, publication in journal advertisements and drug compendia, or in package inserts. The expectation is that the information should be objective, but since it is product specific it provides no guidance on choice of treatment.

To be credibly neutral, comparative guidance for doctors on the selection of drugs and general approaches to the therapeutic management of specific conditions needs to derive from sources independent of pharmaceutical manufacturers. Increasingly, refereed journals are devoting space to signed reviews of the therapeutic management of common conditions. Similarly, health professionals are seeking spontaneously to fulfil the same need both by forming ad hoc or institutional therapeutics committees and by issuing independent drug bulletins, sometimes with the active backing of consumer associations. In increasing numbers, governments themselves — motivated primarily by the need to curb prescribing costs — have either

set up or commissioned advisory bodies to compile national formularies, essential drugs lists and restrictive reimbursement lists in an attempt to encourage effective and cost-conscious prescribing. WHO has attempted to assist developing countries in this regard by producing source material consonant with its Model List of Essential Drugs. Regardless of its provenance, however, printed information is costly to produce and distribute. Financial constraints determine that, in many countries, doctors remain predominantly dependent upon pharmaceutical companies for prescribing information.

The expectation is that multinational companies will set an exemplary standard in correctly labelling their products in every country in which they possess a marketing authorization. Whereas, in most countries, the national regulatory authority has statutory control over labelling, the end-product is inevitably determined in large measure by the copy proposed by the manufacturer. To help promote uniformity of standards, the World Health Assembly decided in 1992 that the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce should be extended, inter alia, to embrace a copy of all labelling authorized in the country of export as an element of the product certificate (1).

Against this background, the results of a recent evaluation by the Office of Technology Assessment of the US Congress (2) of labelling of products exported to four developing countries by companies based in the United States is perplexing. In the opinion of the independent expert review group undertaking the assessment, two-thirds of the labels "failed to provide the kind of complete information a physician needs to use the drugs safely and effectively" and more than half had "severe labelling deficiencies" that could result in serious or even life-threatening situations.

The study, which was launched in 1987, stemmed from Congressional concerns aroused during the passage of the US Drug Export Act of 1986 about the labelling of domestically-manufactured drug products exported to developing countries. A random sample of 241 products sold by 18 major US companies in four countries — Brazil, Kenya,

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General Policy Topics WHO Drug Information Vol. 7, No. 2, 1993

Panama and Thailand — was selected for review. The categories of information most often judged to be inadequate were "warnings and precautions" and, to a lesser extent, "indications and adverse reactions".

The report proposes five policy options for Congressional action to:

• require that all pharmaceuticals sold by US companies in developing countries bear the labelling approved by the US Food and Drug Administration in an appropriate language;

• support the adoption of an international code of conduct for pharmaceutical labelling developed under the aegis of WHO or the United Nations;

• strengthen and expand WHO's Ethical Criteria for Medicinal Drug Promotion;

• continue to support and expand direct assistance to developing countries for projects to improve pharmaceutical regulation, and provide additional information on pharmaceuticals to regulatory authorities; and

• support further surveys of product labelling in developing countries.

In response to an earlier draft of the report, the US Pharmaceutical Manufacturer's Association had argued that the assessment should be carried out having regard to labelling approved not only within the USA, but also within other developed countries deemed to have comparable regulatory standards. Had this comparison been made, the industry claimed, the dichotomy in perceived standards would have been greatly diminished. The report concedes that labelling standards do differ among industrialized countries, and that if a composite of labelling approved in all these countries had been used for comparison, the results of the survey would have been very different, and clearly more favourable to the companies.

The view is sometimes expressed that "warnings and precautions" in US labelling are inspired, on occasion, by a need to protect the manufacturer from speculative litigation and not only to assure the safe use of the product. However, this contention does not provide a plausible defence against the final conclusions set out in the report. Twenty-three drugs among those assessed were also the subject of prescribing information

published by WHO for products included in its Model List of Essential Drugs. Of a total of 52 criticisms directed to manufacturer's labelling of these products, the WHO information fully supported the findings of the review group in 40 instances, offered partial support in 5 others, and supported the existing manufacturer's labelling in only 7 cases.

In discussing the options for future action, the Office of Technology Assessment recognizes that any legislation creating an obligation for exported drugs to be labelled in accordance with FDA requirements should be aimed at assisting countries that do not possess the resources to evaluate and regulate pharmaceutical labelling, and not to impose US regulations unilaterally on other countries. It commends WHO's Model Prescribing Information, its Certification Scheme, and the WHO Ethical Criteria for Medicinal Drug Promotion as conceptually attuned to the needs of regulatory authorities seeking a means of assuring the adequacy of product labelling. It also emphasizes that "efforts must be made to improve the legal and technical drug regulatory infrastructure in developing countries so that the information provided can be used effectively".

This priority is also acknowledged within WHO. The Division of Drug Management and Policies is currently developing a series of guidelines to assist countries wishing to review their statutory and administrative infrastructure for drug regulation. These highlight the need for drug labelling to meet acceptable standards of quality. They also emphasize that, if this information is to have utility, it must be reliably accessible to the prescriber and the end-user. When, as often happens, finished drug products are exported in cheap bulk packaging, and where there is no requirement upon manufacturers to supply all potential prescribers with an officially-approved product data sheet as a condition of registration, the delivery of information becomes as problematic as assuring its quality.

References

1. WHO Certification Scheme on the Quality of Pharma­ceutical Products moving in International Commerce. WHO Technical Report Series, No. 823, Annex 3 (1992).

2. US Congress, Office of Technology Assessment. Drug Labelling in Developing Countries, OTA-H-464, US Government Printing Office, Washington, DC, February 1993.

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Reports on Individual Drugs

Malaria: a first stride towards effective vaccination? For many years, several independent groups have been engaged in the development of candidate vaccines against malaria. Optimism has been sustained by recognition that a degree of natural immunity is a consequence of prolonged and intense exposure to the disease and that protective immunity can be induced by repeated inoculations of irradiated, non-infective sporozoites (1, 2). This has been tempered, however, by the organism's evident capacity to resist the immune response.

Identification of suitable antigenic targets has been hampered by the size of the parasite's genome, and the antigenic transformations involved in the successive stages of its complicated life-cycle within the human host. However, advances in DNA recombinant technology and other molecular techniques have created the means of obtaining uncontaminated antigenic material and of identify­ing protective epitopes. This has resulted in the development of several subunit vaccines derived from antigens present in malaria sporozoites (3-6) or peptide sequences present in early liver stages and the merozoite blood stages responsible for the clinical manifestations of the disease (7). Several such vaccines now hold promise as candidates for field trials and one oral vaccine is already being administered in phase 1 studies (see page 56).

For the moment, these efforts have been outpaced by demonstration of a substantial protective effect of a vaccine derived empirically — in the tradition of most currently-used vaccines — from epitopes contained in three merozoite antigens linked in a stable complex to the dominant sporozoite antigen (6). Early trials of this preparation (9-13) aroused criticism concerning various aspects of their design, particularly the lack of placebo controls (14-16), but a recently-published study undertaken within a semi-immune community, largely of West African descent, living on Colombia's southern Pacific coast has been more rigorously conducted (17). Infants under one year, pregnant women and patients with allergic or potentially serious diseases were excluded from the study. Among the 2496 eligible individuals, 738 subjects received three

standard doses of the vaccine and 810 received placebo, each at 0, 30 and 180 days. During a follow-up period of one year, starting one month after administration of the third dose, 168 episodes of falciparum malaria were recorded among the vaccinated subjects compared to 297 episodes among those who had received placebo. The estimated crude protective efficacy of the vaccine was thus 39%.

Any vaccine that can reduce the attack rate of falciparum malaria by more than one-third is clearly of potential value. Since malaria is a complex disease from an immunological perspective (18, 19), it may be that partial suppression of the disease rather than complete prevention will be all that is possible to achieve in the immediate future (13). A priority is now to obtain confirmation of these encouraging results and to obtain better insight into some evident inconsistencies in relevant published studies.

Some of these inconsistencies have been attributed to difficulties in formulating the vaccine. At least two attempts to confirm a previously demonstrated protective effect against falciparum malaria in owl monkeys were unsuccessful, in part possibly because of differences in coupling procedures (16, 17). Similarly, substantial batch variation in immu¬ nogenicity may explain the relatively low protective effect obtained in the recent trial in comparison with that obtained in earlier studies by the Colombian group.

Secondly, the vaccine has not provided similar protection to all age groups. Efficacy was greatest among children aged 1-4 years (77%) and among adults over 45 years (67%). In contrast, protection was marginal among the older children and younger adults who are at greatest risk of attack. These differences cannot be attributed solely to differences in exposure since, within each age group, efficacy did not change demonstrably with seasonal changes in the intensity of transmission. Moreover, protection was greater against second attacks than first attacks, which suggests that efficacy is enhanced by natural boosting.

Thirdly, although the vaccine was prepared with a view to obtaining an antibody rather than a cellular

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Reports on Individual Drugs WHO Drug Information Vol. 7, No. 2, 1993

response, no correlation has been established — either in human or animal studies — between IgG antibody titres against the synthetic protein of the vaccine and the incidence of malaria episodes (9, 2 1 , 22). Perhaps immunoglobulin classes other than IgG are correlated with protection (21), or it may be that cell-mediated responses are involved (24, 25).

These findings underscofe the need for confirma­tory clinical studies to be undertaken in a variety of settings. Results of additional trials currently on­going in Colombia, south-east Asia and East and West Africa (14, 16) will be crucial determinants of the future of the vaccine.

References

1. Clyde, D.F. Immunity to falciparum and vivax malaria induced by irradiated sporozoites: a review of the University of Maryland studies, 1971-1975. Bulletin of the World Health Organization, 68 (suppl): 9-12 (1990).

2. Harpaz, R., Edelman, R., Wasserman, S.S. et al. Serum cytokine profiles in experimental human malaria. Relationship to protection and disease course after challenge. Journal of Clinical Investigation, 90 (2): 515-523 (1992).

3. Ballou, W., Sherwood, J., Neva, F. et al. Safety and efficacy of a recombinant DNA Plasmodium falciparum sporozoite vaccine. Lancet, 1: 1277-1281 (1987).

4. Herrington, D., Clyde, D., Losonsky, G. et al. Safety and immunogenicity in man of a synthetic peptide malaria vaccine against Plasmodium falciparum sporozoites. Nature, 74:257-259 (1987).

5. Nussenzweig, R., Nussensweig, V. Antisporozoite vaccine for malaria: experimental basis and current status. Reviews of Infectious Diseases, 2: 579-585 (1989).

6. Fries, L, Gordon, D., Schneider, I. et al. Safety, immunogenicity and efficacy of a Plasmodium falciparum vaccine comprising a circumsporozoite protein repeat region peptide conjugated to a Pseudomonas aeruginosa toxin A. Infection and Immunity, 60: 1834-1839 (1992).

7. Cox, F. Malaria vaccines — progress and problems. Trends in Biotechnology, 9: 389-394 (1991).

8. Moreno, A., Patarroyo, M. Development of an asexual blood stage malaria vaccine. Blood, 74: 389-394 (1989).

9. Patarroyo, M., Amador, R., Clavijo, P. et al. A synthetic vaccine protects humans against challenge with asexual blood stages of Plasmodium falciparum. Nature, 332:158-161 (1988).

10. Rocha, C, Murillo, L, Mora, A. et al. Determination of the immunization schedule for field trials with the synthetic malaria vaccine SPf66. Parasitology and Immunology, 14: 95-109 (1992).

11. Patarroyo, G., Franco, L, Amador, R. et al. Study of the safety and immunogenicity of the synthetic malaria SPf66 vaccine in children aged 1 to 14 years. Vaccine, 10: 175-178 (1992).

12. Amador, R., Moreno, A., Valero, V. et al. The first field trial of the chemically synthesized malaria vaccine SPf66: safety, efficacy and protectivity. Vaccine, 10: 179-184 (1992).

13. Amador, R., Moreno, A., Murillo, L. et al. Safety and immunogenicity of the synthetic malaria vaccine SPf66 in a large field trial. Journal of Infectious Diseases, 166: 139-144 (1992).

14. Marsh, K. Patarroyo's vaccine. Lancet, 341: 729-730 (1993).

15. Cox, F. Malaria: that vaccine passes a trial. Nature, 362:410 (1993).

16. Maurice, J. Controversial vaccine shows promise. Science, 259: 1689 (1993).

17. Valero, M., Amador, L, Galindo, C. et al. Vaccination with SPf66, a chemically synthesised vaccine, against Plasmodium falciparum malaria in Colombia. Lancet, 341: 705-710 (1993).

18. Cox, F. Malaria vaccines — progress and problems. Trends in Biotechnology, 9: 389-394 (1991).

19. Riley, E., Olerup, O., Troye-Blomberg, M. The immune recognition of malaria antigens. Parasitology Today, 7: 5-11 (1991).

20. Ruebush, T, Campbell, G., Moreno, A. et al. Immunization of owl monkeys with a combination of Plasmodium falciparum asexual stages synthetic peptide antigens. American Journal of Tropical Medicine and Hygiene, 43: 355-366 (1990).

21. Patarroyo, M., Romero, P., Torres, M. et al. Induction of protective immunity against experimental infection with malaria using synthetic peptides. Nature, 328: 629-632 (1987).

22. Rodriguez, R., Moreno, A., Gusman, F. et al. Studies in owl monkeys leading to the development of a synthetic vaccine against the asexual blood stages of Plasmodium falciparum. American Journal of Tropical Medicine and Hygiene, 43:355-366 (1990).

23. Bouharoun-Tayoun, H., Druilhe, P. Plasmodium falciparum malaria: evidence for an isotype imbalance which may be responsible for delayed acquisition of protective immunity. Infection and Immunity, 60: 1473-1481 (1992).

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24. Good, M., Miller, L. Involvement of T-cell in malaria immunity: implications for vaccine development. Vaccine, 7:2-9 (1989).

25. Taveme, J., Bate, C, Sarkar, D. et al. Human and murine macrophages produce TNF in response to soluble antigens of Plasmodium falciparum. Parasite Immunology, 12: 33-43 (1990).

Zidovudine and the natural history of HIV infection The pressure exerted upon the research establish­ment to accelerate the clinical development of antiviral and other drugs that may retard the progression of HIV infection is inevitable and compelling. Trials conducted on a relatively small sample of patients or for a relatively short period of time cannot reflect the response to treatment of the full spectrum of infected patients. Important questions then remain to be answered by inference rather than fact. In such circumstances, it is not surprising that the value of zidovudine, particularly in patients with asymptomatic HIV infection, continues to excite controversy some eight years after its initial clinical development.

Consensus is now firm that antiviral treatment with zidovudine, when employed in conjunction with specific treatment for opportunistic and other in­fections, usefully retards the progression of the disease in symptomatic patients. This clinical effect is accompanied by a rapid decrease in the titre of virus in the blood (1, 2). The first placebo-controlled, double-blind study of the influence of zidovudine on the survival of such patients was discontinued ahead of schedule in 1987 after only 17 weeks as soon as a significant advantage became evident among the treated patients (3). Only four years later was information published that provided quantita­tive data on survival among treated and untreated patients over longer periods of time. Two un¬ randomized comparative studies, in which follow-up was maintained for 2 years or more, and in which treated patients were compared with patients who either refused treatment or who were intolerant of zidovudine, confirmed that the drug extends survival, often for a year or more (4, 5). Despite continued treatment with zidovudine, the end-stage of the disease is characterized by a return of a high titre of virus in the blood (6, 7) associated with reduced sensitivity to zidovudine (8).

More difficult to assess has been the effect of sustained treatment with zidovudine in asympto­

matic HIV-positive patients: because the latent period from the time of infection is highly variable and in some patients apparently indefinite, pro­longed periods of observation are required to obtain a full appreciation of the effect of zidovudine on the presymptomatic course of the disease.

The first randomized, placebo-controlled studies designed to examine the effect of zidovudine, either in a suppressive context (9, 10) or in patients with early symptomatic infection (11), each generated data to indicate that zidovudine delays clinical progression to symptomatic disease and possibly also confers some advantage in survival. However, each of these studies was terminated early as soon as a statistically discernible drug-associated effect emerged. In each case this occurred when average follow-up time was, at most, little more than one year. A fourth study (12) in which the average follow-up time was extended to 2 years also indicated that zidovudine prolonged the symptom-free interval, but no survival difference was demon­strated.

Within the past few months, a preliminary account has been published of a considerably larger and more extensive comparison of zidovudine (1g daily from the time of diagnosis) and placebo in asymp­tomatic HIV-positive patients undertaken in centres located within France, Ireland and the United Kingdom (the Concorde study) (13). Had this study been terminated within the same time-frame as the earlier studies, it would have yielded similar results. In the event, and after much contention over ethical considerations (14), it was continued on a modified basis to allow all patients to take zidovudine when two CD4 counts performed at least one month apart fell below 500 x 106/L. Initial findings based upon 3-year follow-up data from some 1750 patients are of interest in two respects. The first of these relates to the CD4 count. Although these counts initially rose, as expected, in patients treated early with zidovu­dine, they later fell in parallel with those of patients whose treatment had been deferred. In contrast, there were no demonstrable differences after 3 years of follow-up between the two groups in clinical outcome. The survival rates (92% and 93% overall among those receiving early and deferred treatment respectively) and the progression rates to AIDS or death (18% in both groups) were uninfluenced by zidovudine regardless of the magnitude of the CD4 count on entry into the trial.

These results have two crucial implications. Firstly, they cast doubt on the value of the CD4 count as

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Reports on Individual Drugs WHO Drug Information Vol. 7, No. 2, 1993

an indicator of the benefit of antiviral therapy (15). It has been suggested that less convenient markers, such as lymph-node biopsy (16, 17), may become necessary to assess the clinical potential of new candidate antiviral agents (15).

Secondly, they may well presage abandonment of prophylactic use of zidovudine — at least when administered alone — in infected but asymptomatic patients. Concern persists about the emergence of resistant strains of HIV during exposure to antiviral agents (18, 19). It was first reported 5 years ago that, notwithstanding sustained treatment with zidovudine, the concentrations of free virus and antigen in the blood of some symptomatic patients returned to pre treatment levels after one year (20). Subsequently, strains of HIV-1 virus with reduced sensitivity to zidovudine (8), didanosine (21) and zalcitabine (22) have been isolated from patients treated for several months. More recently, two case reports have been published offering evidence that mutant virus resistant to zidovudine may be transmitted (23, 24).

Given the extent to which zidovudine is used, the prevalence of resistant HIV clones must be expected to rise progressively (25). Knowledge that these resistant organisms are likely to be transmis­sible from person to person must weigh heavily in the formulation of any policy relating to the use of zidovudine, particularly in asymptomatic individuals (26).

Immediate reactions to the published results of the Concorde study have been mixed and vociferous. The findings have been contested on the grounds that the period of follow-up was still too short to demonstrate potential benefits with reasonable certainty. It has also been suggested — notwith­standing the notably low rate of zidovudine-induced toxicity reported by the investigators — that the relatively high dose of zidovudine selected might have been associated with adverse effects likely to be confused with the early phases of AIDS (27). More definitive conclusions, it is suggested, may follow from an overview of all existing randomized trials of early versus deferred treatment (28). Others point out that, because of the prevalence of resistance, use of zidovudine alone has been largely superseded by combination or sequential therapy with other antiviral agents (29).

Trials to assess combination therapy are, in fact, already in progress. One particularly ambitious study sets out to compare zidovudine/didanosine and zidovudine/zalcitabine combinations with zido­

vudine monotherapy in asymptomatic and symp­tomatic patients (30). The challenge is to obtain a convincing measure of not only clinical progression of the disease, but also the emergence of strains of virus throughout the period of treatment.

References

1. Clark, S., Saag, M., Decker, W. et al. High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. New England Journal of Medi­cine, 324: 954-960 (1991).

2. Daar, E., Moudgil, T., Meyer, R., Ho, D. Transient high levels of viremia in patients with primary immunodefi­ciency virus type 1 infection. New England Journal of Medicine, 324: 961-964 (1991).

3. Fischl, M., Richman, D., Grieco, M. et al. The efficacy of 3-azido-3-deoxythymidine (azidothymidine) in the treatment of AIDS and AIDS-related complex: a double-blind placebo-controlled trial. New England Journal of Medicine, 317: 185-191 (1987).

4. Moore, R., Hidalgo, J., Sugland, B., Chaisson, R. Zidovudine and the natural history of the acquired immunodeficiency syndrome. New England Journal of Medicine, 324: 1412-1416 (1991).

5. Vella, S., Guiliano, M., Pezzolotti, P. et al. Survival of zidovudine-treated patients with AIDS compared with that of contemporary untreated patients. Journal of the American Medical Association, 267: 1232-1236 (1992).

6. Ho, D., Moudgil, T., Alam, M. Quantitation of human immunodeficiency type-1 virus in the blood of infected persons. New England Journal of Medicine, 321: 1621-1625 (1989).

7. Coombs, R., Collier, A., Allain, J. et al. Plasma viremia in human immunodeficiency virus infection. New England Journal of Medicine, 321: 1626-1631 (1989).

8. Larder, B., Darby, G., Richman, D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science, 243: 1731-1734 (1989).

9. Volberding, P., Lagakos, S., Koch, M. et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. New England Journal of Medicine, 332: 941-949 (1990).

10. Merigan, T., Amato, D., Balsley, J. Placebo-controlled trial to evaluate zidovudine treatment of human immuno­deficiency virus infection in asymptomatic patients with hemophilia. Blood, 78: 900-906 (1991).

11. Fischl, M., Richman, D., Hansen, N. et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodefi­ciency virus type-1 (HIV) infection. Annals of Internal Medicine, 112: 727-737 (1990).

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12. Hamilton J., Hartigan, P., Simberkoff, M, et al. A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. New England Journal of Medicine, 326: 437-443 (1992).

13. Aboulker, J., Swart, A. Preliminary analysis of the Concorde trial. Lancet, 341: 889-890 (1993).

14. Editorial. Concorde remains aloft. Lancet, 334: 1017-1018 (1989).

15. Maddox, J. The next step in AIDS treatment. Nature, 362:493 (1993).

16. Fauci, A. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature, 362: 355-358 (1993).

17. Haase, T. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature, 362: 359-362 (1993).

18. Richman, D., Grimes, J., Lagakos, S. Effect of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus. Journal of the Acquired Immunodeficiency Syndrome, 3: 743-746 (1990).

19. Larder, B., Kemp, S. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science, 246: 1155-1158 (1989).

20. Jackson, G., Paul, D., Falk, L et al. Human immuno­deficiency virus (HIV) antigenemia (p24) in the acquired immunodeficiency syndrome (AIDS) and the effect of treatment with zidovudine (AZT). Annals of Internal Medicine, 108: 175-180 (1988).

21. St. Clair, M., Martin, J., Tudor-Williams, G. et al. Resistance to ddl and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science, 253: 1557-1559 (1991).

22. Fitzgibbon, J., Howell, R., Haberzetti, C. et al. Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2', 3'-dideoxycytidine. Antimicrobial Agents and Chemotherapy, 36: 153-157 (1992).

23. Erice, A., Mayers, D., Strike, D. et al. Brief report: primary infection with zidovudine-resistant human immunodeficiency virus type-1. New England Journal of Medicine, 328: 1163-1165 (1993).

24. Anonymous. HIV seroconversion after occupational exposure despite early prophylactic zidovudine therapy. Lancet, 341: 1077-1078 (1993).

25. Heagy, W., Crumpacker, C , Lopez, P., Fineberg, R. Inhibition of immune functions by antiviral drugs. Journal of Clinical Investigation, 87: 1916-1924 (1991).

26. Tindall, B., Gaines, H., Imrie, A. et al. Zidovudine in the management of primary HIV-1 infection. AIDS, 5: 477-484 (1991).

27. Saah, A. Immediate versus deferred zidovudine. Lancet, 341:1023 (1993).

28. Peto, R., Collins, R. Immediate versus deferred zidovudine. Lancet, 341:1022-1023 (1993).

29. Gazzard, B. After Concorde. British Medical Journal, 306: 1016-1017 (1993).

30. Editorial. Disappointing results in zidovudine study in asympomatic patients. Pharmaceutical Journal, 251: 493 (1993).

Halofantrine in multidrug-resistant malaria Where multidrug-resistant strains of falciparum malaria are prevalent, mefloquine remains the only widely-available alternative to quinine. Clinical and laboratory data now available from Thailand suggest that the sensitivity of Plasmodium falciparum to mefloquine has fallen substantially since 1989 and that the rate of decline is accelerat­ing (1-4).

The therapeutic alternatives are few. Quinine remains highly effective in Africa (5, 6), but in south-east Asia it can no longer be relied upon to cure an infection that has failed to respond to other treatment. Quinine and tetracycline in combination are more likely to be effective, but compliance with the 7-day treatment regimen is poor (7). A 7-day regimen of mefloquine and oral artesunate has recently been demonstrated to be highly effective both in primary treatment and retreatment of multidrug-resistant malaria (8). However, artesunate is not yet widely available; the regimen needs to be supervised; and, because mefloquine has a plasma half-life of 2 -3 weeks, retreatment in the short term creates a potential for toxicity.

Halofantrine, a phenanthrene-methanol compound, is a widely-available alternative. A standard 1-day course of 24 mg/kg — three doses of 8 mg/kg at 6-hourly intervals — is highly effective against falciparum malaria wherever the parasite remains sensitive (9-12). However, it has been claimed that a high degree of resistance can emerge rapidly where drug-pressure is intense (13). Largely because of in vitro evidence of cross-resistance with mefloquine to which it is structurally related (2, 14-16), it has not been used extensively where multidrug-resistant parasites are prevalent.

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As expected, it has recently been shown that at standard dosage, rates of recrudescence following treatment with halofantrine were relatively high in areas of Thailand where multidrug resistance is now endemic (17). When a higher dosage regimen — 72 mg/kg over 3 days — was used in a research setting, halofantrine appeared to be both more effective, especially in the re-treatment of recrudescent infections, and, in general, better tolerated than mefloquine (17). It gave rise to less vomiting, nausea, anorexia, fatigue and dizziness and is claimed to generate plasma concentrations no higher but more sustained than those resulting from the 1 - day regimen.

However, a finding of serious concern has since emerged. Following the death of a patient treated with the extended three-day regimen of halo­fantrine, a prospective electrocardiographic study has shown that this dose consistantly induces prolongation of the QT interval. QT prolongation is associated with increased susceptibility to ventri­cular tachyarrhythmias (18). The change was most marked among those patients likely to obtain most benefit from halofantrine: 10 patients treated for recrudescence of an attack for which they originally received mefloquine (19). This effect has not been associated with mefloquine (17, 20) but it does occur with quinidine (21) and to a lesser extent with quinine.

In addition to the one death resulting from cardiac arrest, 4 cases of first-degree heart block have thus far been described among Thai patients receiving the three-day regimen of halofantrine. No firm causal relationship with treatment has been established (19) and it is possible that other risk factors, including vitamin B1 deficiency and the co­administration of fats to enhance absorption (22), may have been operative. Nonetheless, additional case reports that underscore the need for electro­cardiographic control have since been published (23, 24) and the manufacturer of halofantrine has issued a notice setting out these findings to emphasize that halofantrine should not be used in routine situations at dosages that exceed the labelled recommendation of 24 mg/kg (see page 66).

Hazards of therapy that may be unavoidable in the management of patients dangerously ill with cerebral malaria need to be evaluated by other criteria when there is less immediate threat to life. Routine ECG monitoring is out of the question in the rural situations in which most cases of acute malaria are treated. This experience is a setback to

the use of halofantrine in the treatment of uncom­plicated malaria, but there is still hope that the high-dosage regimen might be attenuated to non¬ cardiotoxic levels without diminishing the thera­peutic effect (17).

References

1. Nosten, F., ter Kuile, F., Chongsuphajaisiddhi, T. et al. Mefloquine-resistant falciparum malaria on the Thai-Burmese border. Lancet, 337: 1140-1143 (1991).

2. Ketrangsee, S., Vijaykadga, S., Yamokgul, P. et al. Comparative trial on the response of Plasmodium falciparum to halfantrine and mefloquine in Trat province, Eastern Thailand. Southeast Asian Journal of Tropical Medicine and Public Health, 23: 55-58 (1992).

3. ter Kuile, F., Nosten, F., Thieren, M. et al. High-dose mefloquine in the treatment of multidrug-resistant falciparum malaria. Journal of Infectious Diseases, 166: 1393-1400 (1992).

4. White, N. Antimalarial drug resistance; the pace quickens. Journal of Antimicrobial Chemotherapy, 30: 571-585 (1992).

5. Brasseur, P., Kouamouo, J., Moyou, J. et al. Multidrug resistant falciparum malaria in Cameroon in 1987-1988: stable figures of prevalence of chloroquine and quinine resistant isolates in the original foci. American Journal of Tropical Medicine and Hygiene, 46: 1 -7 (1991).

6. Carme, B., Moudzeo, H., Ndounga, M. et al. La résistence médicamenteuse de Plasmodium falciparum au Congo. Bilan des enquêtes réalisées de 1985 á 1989. Bulletin de la Société de Pathologie Exotique, 83: 228-241 (1990).

7. Looareesuwan, S., Wilairatana, P., Vanijanonta, S. et al. Efficacy of quinine-tetracycline for acute uncomplicated falciparum malaria in Thailand. Lancet, 339: 369 (1992).

8. Looareesuwan, S., Viravan, C, Vanijanonta, S. et al. Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet, 339: 821-824 (1992).

9. Boudreau. E.. Pang, L, Dixon, K. et al. Malaria: treatment efficacy of halofantrine (WR 171 699) in initial field trials in Thailand. Bulletin of the World Health Organization, 66: 227-235 (1988).

10. Watkins, W., Oloo, J., Lury, J. et al. Efficacy of multi-dose halofantrine in the treatment of chloroquine-resistant falciparum malaria in children in Kenya. Lancet, 2: 247-250 (1988).

11. Wirima, J., Khoromana, C, Molyneux, M., Gilles, H. Clinical trials with halofantrine hydrochloride in Malawi. Lancet, 2: 250-252 (1988).

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12. Editorial. Halofantrine in the treatment of malaria. Lancet, 2: 537-538 (1989).

13. Brasseur, P., Bitsindou, P., Moyou, R. et al. Fast emergence of Plasmodium falciparum resistance to halofantrine. Lancet, 341: 901-902 (1993).

14. Wongsrichanalai, C , Webster, H., Wimonwattrawatee, T. et al. Emergence of multidrug-resistant Plasmodium falciparum in Thailand: in vitro tracking. American Journal of Tropical Medicine and Hygiene, 47: 112-116 (1992).

15. Shanks, G., Watt, G., Edstein, M. Halofantrine for the treatment of mefloquine chemoprophylaxis failures in Plasmodium falciparum infections. American Journal of Tropical Medicine and Hygiene, 45: 488-491 (1991).

16. Ringwald, P., Bras, J., Voyer, C , Coulaud, J. Reduced in vitro susceptibility to halofantrine of Plasmodium falciparum in West Africa. Lancet, 335: 421-422 (1990).

17. ter Kuile, F., Dolan, G., Nosten, F. et al. Halofantrine versus mefloquine in treatment of multidrug-resistant falciparum malaria. Lancet, 341: 1044-1049 (1993).

18. Hashiba, K., Moss, A., Schwartz, P. QT prolongation and ventricular arrhythmias. Annals of the New York Academy of Sciences, 664 (suppl): 1-247 (1991).

19. Nosten, S., ter Kuile, F., Luxemburger, C. et al. Cardiac effects of antimalarial treatment with halofantrine, Lancet, 341: 1054-1056 (1993).

20. Laothavom, P., Karbwang, J., Na Bangchang, K. et al. Effect of mefloquine on electrocardiographic changes in uncomplicated falciparum malaria patients. Southeast Asian Journal of Tropical Medicine and Public Health, 23: 51-54 (1992).

21. Miller, K., Greenberg, A., Campbell, C. Treatment of severe malaria in the United States with a continuous infusion of quinidine gluconate and exchange transfusion. New England Journal of Medicine, 329: 65-70 (1989).

22. Munger, R., Prineas, R., Crow, R. et al. Prolonged QT interval and risk of sudden death in South-East Asian men. Lancet, 338: 280-281 (1991).

23. Castot, A., Rapoport, P., Le Coz, P. Prolonged QT interval with halofantrine. Lancet, 341: 1541 (1993).

24. Monlun, E., Pillet, O., Cochard, J.F. et al. Prolonged QT interval with halofantrine. Lancet, 341: 1541-2 (1993).

Poisoning with aconite alkaloids: an unwanted legacy of traditional medicine Overall, serious adverse effects from Chinese traditional medicines are uncommon events (1). None the less, it has been reported that over 600

cases of aconite poisoning within China alone have been attributed to the use of these substances in herbal medicines over the past 30 years (2). This experience prompted the authorities in China to introduce restrictions on the use of herbs containing aconite alkaloids or other specified potent ingredi­ents which became effective in 1984 (3).

Aconite alkaloids are contained in the dried root-stocks of plants of the Aconitum family (4-6). They are claimed to activate the sodium channel and, in doing so, to modify the excitability of nerve, heart and muscle tissue (7). Their membrane destabiliz­ing activity is acknowledged to induce multifocal ventricular extrasystoles and hypotension (7) and they have no therapeutic application in Western medicine. However, they are accredited with anal­gesic and anti-inflammatory effects within several systems of traditional medicine in which they are still widely proposed for the treatment of rheuma­tism, neuralgia and cardiac complaints (4, 6).

Rules can never exert precise quantitative control over medicines derived from complex plant materials. When these materials are prepared as a decoction, as recommended by herbal practitioners, much pharmacologically-active material is presum­ably destroyed since aconite alkaloids are readily hydrolysed into aconines and other less toxic derivatives (4). The recommended dose of cured Aconitum rootstock officially recognized in China was formerly as high as 8-12 g and has been lowered progressively to its present level of 1.5-3 g (6). However, it is likely that the concentration of aconitine and related alkaloids in the rootstock varies considerably, depending on when and where it was harvested and the nature of the curing process (8).

Aconite alkaloids have long been recognized as cardiotoxic (9, 10), but in many countries — where preparations containing them can be purchased from herbal medicine stores — they escape the control of pharmaceutical legislation. Two small series of case reports of presumptive aconite poisoning have recently been published from Hong Kong (8, 11). Some of these patients presented with multifocal ventricular extrasystoles and hypo­tension, whereas others had only nausea and vomiting or paraesthesiae which have been described as starting typically in the mouth and tongue and in some cases extending to involve the whole body (12).

One series of 17 patients included 2 who were in ventricular fibrillation on admission. Both died within

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6 hours. Of the remainder, 13 had ventricular tachy­cardia that in most cases was sustained and multifocal (11). Eleven patients required high-dose inotropic support, 8 were ventilated mechanically, and 7 required cardiopulmonary resuscitation. In none of these 11 patients was the arrhythmia responsive to lidocaine and, in 10, repeated direct-current conversion was unsuccessful. Amiodarone suppressed ventricular tachycardia in 5 of 10 patients and others responded variously to flecainide, procainamide and mexiletine.

Aconite poisoning is both life-threatening and problematic to treat. In the opinion of one group of commentators such effects, "whatever their frequency compared with overall use, would surely be sufficient to cause withdrawal of a newly-marketed pharmaceutical drug" (8). Where relevant provisions are not already in place, the case for registering herbal medicines and controlling their manufacture and prescription, particularly when they are associated with an acknowledged pattern of toxicity, merits serious and immediate consider­ation.

References

1. Tomlinson, B., Leung, S., Chan , T., Critchley, J. Adverse effects and usage of traditional Chinese medicines in Hong Kong. British Journal of Clinical Pharmacology, 31 : 611P (1991).

2. Wu, Y. Aconite poisoning: a review of experience in China over the past 30 years. Jiangsu Journal of Chinese Medicine, 12: 39-42 (1988).

3. Tai, Y., But, P., Young, K., Lau, C. Adverse effects from traditional Chinese medicine. Lancet, 341: 892 (1993).

4. Chang, H., But, P. Pharmacology and applications of Chinese materia medica, Vols 1 and 2. World Scientific Press, Singapore, 1987.

5. Bisset, N. Arrow poisons in China, part II. Aconitum — botany, chemistry and pharmacology. Journal of Ethnopharmacology, 4: 247-336 (1981).

6. Pharmacopoeia Committee. Pharmacopoeia of the People's Republic of China, Vol 1, pp 26-28, 211-213. People's Health Publishing House and Chemical Technology Press. Beijing, 1990.

7. Pepper, K., Trautwein, W. The effect of aconitine on the membrane current in cardiac muscle. Pfuggers Archiv, 296:328-336 (1967).

8. Tomlinson, B., Chan, T., Chan, J., Critchley, J. Herb-induced aconitine poisoning. Lancet, 341: 370-371 (1993).

9. Ffrench, G. Case reports: aconit- induced cardiac arrhythmia. British Heart Journal, 20: 140-142 (1958).

10. Tai, Y., But, P., Young, K., Lau, C. Cardiotoxicity after accidental herb-induced aconitie poisoning. Lancet, 340: 1254-1256 (1992).

11. Fiddes, F. Poisoning by aconitine: report of two cases. British Medical Journal, 2: 779-780 (1958).

12. Chan, T., Tomlinson, B., Chan, W. et al. A case of acute aconitine poisoning caused by chuanwu and caowu. Journal of Tropical Medicine and Hygeine (in press).

Herbal slimming regimens and nephrotoxicity Chronic interstitial nephritis accounts for almost one-quarter of all patients on maintenance dialysis in Belgium (1). This relatively high proportion — particularly in comparison with the USA where it is 4-fold lower (2) — is widely attributed to analgesic neuropathy (3-5). Most of these cases occur in the north of the country (6, 7) and, typically, 10-20 years elapse between diagnosis and terminal renal failure (8).

Each year, some 250 patients are started on maintenance dialysis in the seven principal dialysis centres within Brussels. Only rarely have women under 50 been referred for treatment with a diagnosis of rapidly-progressing chronic interstitial nephritis. Only one such patient was accommo­dated in each of the years 1989 and 1990. In 1991 3 were accommodated, and 9 presented during the first 6 months of 1992 (9). Common causes of chronic interstitial nephritis could not be excluded with complete confidence but, remarkably, all 9 patients treated during the first half of 1992 had followed the same slimming regimen in the same clinic just before renal disease was detected, and 5 of these were known to have had normal renal function when they started the regimen. Moreover, 3 of 25 otherwise healthy women following the same slimming course were also found to have impaired renal function.

The precise cause of this striking cluster of cases remains speculative, but suspicion has focused on preparations of two herbal substances — stephania and magnolia — newly introduced into the slimming regimen some 12 to 24 months before the first cases were detected. Neither of these substances, it seems, has previously been associated with nephrotoxicity, but it remains possible that aceta¬

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zolamide — also included in the regimen — could have delayed excretion of any nephrotoxic alkaloid contaminants by making the urine alkaline. Adul­teration by diuretics or anti-inflammatory drugs (10) was excluded and no evidence supported the possibility that aristolochia — a known nephrotoxic herbal substance (11, 12) — had been accidently substituted in one or more batches for stephania, given that their respective Chinese names are very similar.

Other possibilities of contamination, which might occur at any stage between grower and dispenser, have since been raised (12). Herbal products can be contaminated during production and processing, especially by insecticides, fungicides and heavy metals. Inappropriate storage or shipping conditions may lead to fungal growth and generation of myco¬ toxins. Other plant material or minerals may be deliberately added to increase bulk. Salts of heavy metals may be used to enhance colour, and synthetic drugs have been included to enhance efficacy.

This experience offers yet another example of problems apparently associated with the uncon­trolled use of "natural" products and exotic medi­cines (14). It drives home the need for introducing procedures to identify and assure the safety of herbal medicines that are no less stringent than those applied to other medicines (13). It also underscores the general principle that medicines of any type should never be combined without careful consideration of the risks of interactions that may lead to toxicity (13).

References

1. Tufveson, G., Geerlings, W., Brunner, F. et al. Com­bined report on regular dialysis and transplantation in Europe XIX, 1988. Nephrology, Dialysis and Transplanta­tion, 4 (suppl 4): 5-29 (1989).

2. Held, P., Port, F., Blagg, C, Agodoa, L. United States Renal Data System: 1990 Annual Report. Vol III, Causes of ESRD. American Journal of Kidney Disease, 26: (suppl 2): 22-27 (1990).

3. Murray, T., Goldberg, M. Chronic interstitial nephritis: etiologic factors. Annals of Internal Medicine, 82: 453-459 (1975).

4. Bennet, W., Plamp, C, Porter, G. Drug-related syndromes in clinical nephrology. Annals of Internal Medicine, 87: 582-590 (1977).

5. Jorkasky, D., Singer, I. Drug-induced tubulo-interstitial nephritis: special cases. Seminars in Nephrology, 8: 62-71 (1988).

6. Vanher Weghem, J., Even-Adin, D. Epidemiology of analgesic nephropathy in Belgium. Clinical Nephrology, 17: 129-133 (1982).

7. Elseviers, M., De Broe, M. Is analgesic nephropathy still a problem in Belgium? Nephrology, Dialysis and Trans­plantation, 2: 143-149 (1988).

8. Toto, R. Review: acute tubulo-interstitial nephritis. American Journal of Medical Science, 299: 392-410 (1990).

9. Vanher Weghem, J., Depierreux, M., Tielemans, C. et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet, 341: 387-391 (1993).

10. Segasothy, M., Samad, S. Illicit herbal preparation containing phenylbutazone causing analgesic neuropathy. Nephron, 59: 166-167 (1991).

11. Chang, H., But, P. Pharmacology and applications of Chinese materia medica. World Scientific Publications, Singapore, 1986. p.197.

12. Stefanovic, V., Pollenakovic, M. Balkan nephropathy; kidney disease beyond the Balkans? American Journal of Nephrology, 11: 1-11 (1991).

13. Atherton, D., Rustin, M., Brostoff, J. Need for correct identification of herbs in herbal poisoning. Lancet, 341: 637-638 (1993).

14. Huxtable, R. The myth of benificent nature: the risks of herbal preparations. Annals of Internal Medicine, 117: 165-166 (1992).

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General Information

HIV infection and drug-induced cutaneous reactions Skin disease is often the first clinical sign of infection caused by the human immunodeficiency virus (HIV) (1). In many instances, these diseases are more common (2), more persistent and more resistant to treatment than is the case in otherwise healthy patients. In some cases the disease is drug-induced. These reactions have been claimed to result in considerable morbidity (3) and — in the absence of effective alternative therapy — they sometimes result in the discontinuation of essential treatment. However, these generalizations were made largely on the basis of case reports and, to a lesser extent, on the results of small comparative cohort studies directed to special groups of patients or selected drugs (4-13).

Relevant data have now been published of a retrospective review (conducted in a way that assured anonymity) of health records generated over a 2.4-year period relating to all patients in a private US health plan who had been diagnosed as having HIV infection (14). Of 684 such patients identified, almost 80% were reported to have developed at least one skin disease during this period. The frequency was highest among those with symptomatic HIV infection. On average, these patients visited skin clinics about 15 times more frequently than others within the health plan and these diseases accounted for some 8% of hospital admissions within the group — one-third of which were for cutaneous drug reactions — and the incidence of newly-recorded skin diseases increased as immunodeficiency progressed.

Overall, almost 20% of the patients developed at least one presumed cutaneous reaction to drug treatment — and in one instance as many as five reactions — during the period of observation. No patient had multiple reactions to the same drug. Of some 100 reactions that were assessed in detail, only 5% were described as life-threatening, 10% as severe, 50% as moderate and the remainder as mild. Most common were morbilliform rashes and urticaria. Only one case of erythema multiforme (and no case of toxic epidermal necrolysis) was recorded, which suggests — notwithstanding the

attention attracted to such events in case reports (15) — that such reactions are infrequent.

Over 40% of the cohort experienced a cutaneous reaction associated with trimethoprim-sulfameth­oxazole either during or before the period of observation. It is estimated that these reactions occur in association with some 15 of every 100 courses of prescribed treatment. A similar incidence of reactions is estimated to be associated with other sulfonamides, including sulfadiazine and sulfa­salazine, and with trimethoprim administered either alone or in combination with dapsone. Reactions to aminopenicillins occurred in about 10% of the courses administered, and to a wide range of other antimicrobials with a somewhat lower incidence. In general, reactions tended to occur with frequencies some 10-fold higher than those previously recorded in the same population (19).

This study provides the first precise quantitative analysis of drug-induced cutaneous reactions among patients with HIV infection. It confirms they are frequent but, in most instances, relatively mild and that their incidence increases as immune function deteriorates. The previously-suspected high incidence of reactions associated with trimethoprim-sulfamethoxazole has been confirmed. However, since a high incidence of reactions has also been associated with a wide range of other antimicrobials, the report provides no grounds for any important change in policy for managing infections in HIV-positive patients.

References

1. Revision of the CDC surveillance case definition for the acquired human immunodeficiency syndrome. Morbidity and Mortality Weekly Report, 36 (suppl I): 1-15 (1987).

2. Dover, J., Johnson, R. Cutaneous manifestations of human immunodeficiency virus infection. Archives of Dermatology, 127: 1383-1391 & 1549-1558 (1991).

3. Coopman, S., Stern, R. Cutaneous drug reactions in human immunodeficiency virus infection. Archives of Dermatology, 127: 714-717 (1991).

4. Jaffe, H., Abrams, D., Ammann, A. et al. Complications of co-trimoxazole in treatment of AIDS-associated Pneumocystis carinii pneumonia in homosexual men. Lancet, 2: 1109-1111 (1983).

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5. Mitsuyasu, R., Groopman, J., Volberding, P. Cutaneous reaction to trimethoprim-sulfamethoxazole in patients with AIDS and Kaposi's sarcoma. New England Journal of Medicine, 308: 1535-1536 (1983).

6. Gordin, F., Simon, G., Wofsy, C, Mills, J. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Annals of Internal Medicine, 100: 495-499 (1984).

7. Leoung, G., Mills, J., Hopewell, P. et al. Dapsone-trimethoprim for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Annals of Internal Medicine, 105: 45-48 (1986).

8. Fischl, M., Dickinson, G., La Voie, L. Safety and efficacy of sulfamethoxazole and trimethoprim chemo¬ prophylaxis for Pneumocystis carinii pneumonia in AIDS. Journal of the American Medical Association, 259: 1185-1189 (1988).

9. Battegay, M., Opravil, M., Wüthrich, B., Lüthy, R. Rash with amoxycillin clavulanate therapy in HIV-infected patients. Lancet, 2: 1100 (1989).

10. Saiag, P., Caumes, E., Chosidow, O et al. Drug-induced toxic epidermal necrolysis (Lyell syndrome) in patients infected with the human immunodeficiency virus. Journal of the American Academy of Dermatology, 26: 567-574 (1992).

11. Kovacs, J., Hiemenz, J., Macher, A. et al. Pneumo­cystis carinii pneumonia: a comparison between patients with acquired immunodeficiency syndrome and patients with other immunodeficiencies. Annals of Internal Medicine, 100: 663 671 (1984).

12. Hira, S., Wadhawan, D., Kamanga, J. et al. Cutaneous manifestations of human immunodeficiency virus in Lusaka, Zambia. Journal of the American Academy of Dermatology, 19: 451-457 (1988).

13. McNeely, M., Yarchoan, R., Broder, S., Lawley, T. Dermatologic complications associated with administration of 2', 3'-dideoxycitidine in patients with human immunod­eficiency virus infection. Journal of the American Acad­emy of Dermatology, 21: 13213-1217 (1989).

14. Coopman, S., Johnson, R., Platt, R., Stem, R. Cutaneous disease and drug reactions in HIV infection. New England Journal of Medicine, 328: 1670-1674 (1993).

15. Raviglione, M., Dinan, W., Pablos-Mendez, A. et al. Fatal toxic epidermal necrolysis during prophylaxis with pyrimethamine and sulfadoxine in a human immuno­deficiency virus-infected person. Archives of Internal Medicine, 148: 2683-2685 (1988).

16. Chan, H., Stem, R., Amdt, K. et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: a population_based study with

particular reference to reactions caused by drugs among outpatients. Archives of Dermatology, 126: 43-47 (1990).

17. Roujeau, J., Guillaume, J., Fabre, J., Penso, D. et al. Toxic epidermal necrolysis (Lyell syndrome): incidence and drug etiology in France, 1981-1985. Archives of Dermatology, 126: 37-42 (1990).

18. Porteus, D., Berger, T. Severe cutaneous drug reactions (Stevens-Johnson syndrome and toxic epider­mal necrolysis) in human immunodeficiency virus infection. Archives of Dermatology, 127: 740-741 (1991).

19. Bigby, M., Jick, S., Jick, H., Amdt, K. Drug-induced cutaneous reactions: a report from the Boston Collabora­tive Drug Surveillance Programme on 15 438 consecutive inpatients, 1975 to 1982. Journal of the American Medical Association, 256: 3358-3363 (1986).

Mucosal immunity re-evaluated: a new departure in vaccine development When a vaccine is injected, it is reliably adminis­tered, and its immunogenicity can be readily assessed from measurements of antibody titres in plasma samples. However, injections are costly to administer, they carry a tangible risk of trans­mission of pathogenic organisms and, rarely, of serious local reactions.

Orally-administered vaccines, which generate antibodies within the intestinal mucosa, avert these disadvantages and they have proven prophylactic potential. Oral polio vaccine has provided durable protection against infection for generations of children, yet it remains the only widely-used mucosal vaccine. It would seem that the dominance of injectable vaccines owes much to conservatism and tradition.

The potential of oral vaccination is clearly worth examining on a broader front. Most pathogens targeted by vaccines normally invade the body by penetrating mucosal surfaces, and the submucosal lymphoid tissues constitute the largest immuno­logical structure in the body. Until recently, little interest has been directed to boosting natural mucosal immunity. This situation has now changed. An important aim of the World Health Organi­zation's Childhood Vaccine Initiative is to produce lasting immunity against several infectious diseases with a single dose of an orally-administered product. Much of the basic research needed to explore the feasibility of this objective is already well in hand. In large measure this work has been

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either supported or undertaken by the United States Institutes of Health, and it has been described in outline in a recent issue of the Journal of the American Medical Association (1).

Recombinant DNA technology has given vital impetus to the development of both systemic and mucosal vaccines. It is now possible to isolate genes that code for immunologically-important epitopes in selected pathogens and to create candidate vaccines by inserting these genes into attenuated strains of carrier bacteria — usually either Shigella or Salmonella. Two such prototype oral vaccines — one aimed at Plasmodium falciparum, the other at Escherichia coli— are already in phase I clinical trial.

Optimism regarding the potential for oral vaccination has been supported by two lines of fundamental research. Firstly, it has been shown that antibody generated by mucosal immunization — immunoglobulin A (IgA) — not only combines with target antigens on mucosal surfaces to prevent their absorption, it also neutralizes those that penetrate into the deeper mucosal layers by forming immune complexes that are ultimately excreted back into the lumen by the epithelial cells (2). Secondly, it seems that IgA antibody does not necessarily remain localized within the originally activated mucosal structure. Evidence that activated cells are disseminated in the blood and that they retain their immune competence after migration to distant structures has raised the prospect that, if mucosal vaccines can be made to boost IgA output, they may be superior in their immunogenicity to injectable preparations.

Important challenges still need to be resolved. Firstly, because intense antigenic stimuli must be applied to induce and sustain mucosal immunity, novel adjuvants must be developed. Alum, the only adjuvant currently approved for use within the USA, lacks the necessary potency. Secondly, orally-administered mucosal vaccines must be protected from degradation by stomach acid and digestive enzymes.

The first difficulty, it is hoped, may be overcome by replacing the alum adjuvant with an innocuous subunit of cholera toxin which, by clinging to the mucosal wall while coupled with the antigenic epitope, reinforces the immunogenic stimulus. Approaches are also being explored of using specific RNA fragments to amplify the production of IgA by mature B lymphocytes through activation of

the responsible gene. It remains possible, however, that a sufficiently strong antigenic stimulus might be obtained simply by assuring efficient transportation of the ingested antigen to the intestinal mucosa. Pilot studies in animals of a vaccine in which the antigen is encapsulated in biodegradable polymer microspheres have been sufficiently encouraging to engender hope that "a mix of fast and slow-release capsules may make booster doses unnecessary, render any adjuvant superfluous, and even make concurrent induction of mucosal and systemic immunity a reality".

References

1. Healy, B. Mucosal immunity, vaccine development's new frontier. Journal of the American Medical Association, 269: 1612 (1993).

2. Kaetzel, C.S., Robinson, J.K., Koteswara, R.C. et al. The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA. Proceedings of the National Academy of Sciences, 88: 8796-8800 (1991).

Peptic ulcer: a definitive cure emerges The long-held assumption that peptic ulceration is essentially due to gastric hypersecretion is now recognized to be simplistic. The essential role of gastric acid in ulcer formation and the existence of hyper-secretory states (represented in an extreme form by the Zollinger-Ellison syndrome) is not contested. However, other factors are involved which have important implications for therapeutic management.

Drugs which reduce gastric acidity both relieve dyspepsia and, when used regularly, promote healing of duodenal ulcer. These include antacids (1, 2), which not only neutralize gastric acid but which appear to have a cytoprotective effect (3); H2 receptor antagonists (4, 5) which inhibit acid secretion; and omeprazole (6, 7) a substituted benzimidazole which inhibits the H+/K+ proton pump (8, 9). The prostaglandin analogue misoprostol also merits listing (10, 11) since it has been shown to protect against the risk of peptic ulceration associated with the use of nonsteroidal anti­inflammatory agents (11-16).

Healing of an ulcer can usually be achieved with any of these drugs. However, in the absence of continued treatment, some 85% of patients relapse

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within one year (17-19). Maintenance therapy with cimetidine or ranitidine for up to 6 years has been reported to be safe and effective (20, 21). In particular, there is no evidence that prolonged drug-induced reduction of gastric acidity is associated with N-nitrosamine formation or gastric carcinoma (22-24), hypergastrinaemia (25, 26) or proliferation of the histamine-producing enterochromaffin cells (27, 28). However, maintenance therapy is far from ideal, if only because of its expense and incon­venience and a cursative approach to treatment has now become practicable. A Gram-negative, spiral, flagellate bacillus, Helicobacter pylori (formerly known as Campylobacter pylon), is found in the gastric epithelium of over 90% of patients with duodenal ulcer or chronic antral gastritis, and in 70% of those with gastric ulcer (29, 30). If this organism is eradicated during therapy of duodenal ulcer, the rate of relapse has been reported in various studies to fall from 50-70% to 0-20% (31-36). Patients who have no infection one month after discontinuation of treatment appear to be at low risk of reinfection for at least several years (37). Less information is available to establish whether the same effect is obtained in gastric ulcer (38), but a recent trial gives cause for optimism (39).

The eradication of H. pylori requires multidrug therapy over a period of at least 12 days. The organism is sensitive to a wide variety of anti­microbials (40) which include amoxicillin, tetra­cycline and metronidazole. Colloidal bismuth subcitrate, which binds to the base of the ulcer (41) and protects against erosion by acid and pepsin (42), has also been shown to be bactericidal to H. pylori (43, 44). When any of these agents is used alone in an attempt at eradication, acquired drug resistance rapidly supervenes (45). The most effective regimen, which has been recommended by a working party of the World Congresses of Gastroenterology (46), is a 2-week course of triple therapy with colloidal bismuth salts (120 mg 4 times daily), metronidazole (400 mg 3 times daily) and tetracycline (500 mg 4 times daily). Unfortunately, however, about half the patients complain of gastrointestinal symptoms including a metallic taste, nausea, vomiting and diarrhoea to an extent that impairs compliance (47). Meta-analysis has indicated that regimens containing tetracycline are more effective than those containing amoxicillin (48), and a recent study has indicated that, administered concurrently with ranitidine, a double combination of amoxicillin and metronidazole may be better tolerated and highly effective in preventing relapse (49).

When treatment is inadequate, success can be compromised by pre-existing resistance to one or more of the selected drugs, or by emergence of resistance — most commonly to metronidazole (50). Where metronidazole is widely used for treating gastrointestinal infections such as giardiasis, amoebiasis, and non-specific diarrhoea, up to 80% of pretreatment isolates are resistant (50). As yet, there is no generally-accepted approach to treatment of patients with a metronidazole-resistant organism (38). Double therapy in which omeprazole is given with amoxicillin has been tried with variable results (38). Otherwise, use of bismuth becomes vitally important in these circumstances in reducing emergence of resistance during treatment: it is reported that infection was eradicated in up to 70% of patients with primary resistance to metronidazole when bismuth compounds were added to a combination of metronidazole and ampicillin (50).

The criteria for treating H. pylori infections will become better defined with the passage of time. Opinions currently differ even on the management of infected patients presenting with active duodenal ulceration. It has been proposed that all such patients should be treated on first presentation (51). However, a more conservative approach in which eradication is reserved for patients in whom duodenal ulceration presents a management problem, is more widely advocated (28). The patients most likely to benefit are those with persistently recurrent duodenal ulceration who would otherwise require maintenance treatment with an H2 antagonist or proton pump inhibitor; those who are being considered for elective surgery; and those who have bled or perforated in the past (38). The diagnosis of H. pylori infection will already have been confirmed by endoscopic mucosal biopsy in many such cases. Those with active duodenal ulceration, it is suggested, should receive a standard course of antisecretory treat­ment accompanied or followed by a 2-week course of triple antimicrobial therapy (38).

It is important to appreciate that H. pylori infection is common even in healthy adults (52). It is generally agreed that treatment is not warranted in patients without symptoms or with dyspepsia unaccom­panied by ulceration. It is possible, none the less, that a case may be made in the future for treating asymptomatic infections to reduce the risk of gastric cancer. A statistically significant relationship has recently been demonstrated between the pre­valence of seropositivity for H. pylori within the

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community and cumulative rates for the incidence of gastric cancer (regression coefficient 2.68, p=0.001) (53). It is not yet known whether eradication of H. pylori will reduce this risk. The investigation of the implications of H. pylori infection is now clearly entering another and even more challenging phase.

References

1. Tarnawski, A., Hollander, D., Cummings, D. et al. Are antacids acid neutralizes only? Histologic, ultrastructural and functional changes in normal gastric mucosa induced by antacids. Gastroenterology, 86: 1276 (1984).

2. Peterson, W., Sturdevant, R., Frankl, H. et al. Healing of duodenal ulcer with an antacid regimen. New England Journal of Medicine, 297: 341-345 (1977).

3. Lam, S., Lam, K., Lai, C. et al. Treatment of duodenal ulcer with antacid and sulpiride. Gastroenterology, 76: 315-322 (1979).

4. Meyrick-Thomas, J., Misiewicz, G. Histamine H2

receptor antagonists in the short- and long-term treatment of duodenal ulcer. Journal of Clinical Gastroenterology, 13:501-541 (1984).

5. Jones, D., Howden, C, Burget, D et al. Acid suppres­sion in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut, 28: 1120-1127 (1987).

6. Lauritsen, K.. Rune, S., Byster, P. et al. Effect of omeprazole and cimetidine on duodenal ulcer. New England Journal of Medicine, 312: 958-961 (1985).

7. Bardhan, K., Bianchi Porro G., Bose, K. et al. A comparison of two diffent doses of omeprazole versus ranitidine in the treatment of duodenal ulcers. Journal of Clinical Gastroenterology, 8: 408-413 (1986).

8. Larrson, H., Carlsson, E., Junggren, U. et al. Inhibition of gastric acid secretion by omeprazole in the dog and rat. Gastroenterology, 85: 900-907 (1983).

9. Lanzon-Miller, S., Pounder, R., Hamilton, M. et al. Twenty-four hour intragastric acidity and plasma gastrin concentration before and during treatment with either ranitidine or omeprazole. Alimentary Pharmacology and Therapeutics, 1: 239-251 (1987).

10. Roth, S., Agrawal, N., Mahowald, M. et al. Misoprostol heals gastrointestinal injury in patients with rheumatoid arthritis receiving aspirin. Archives of Internal Medicine, 149: 775-779 (1989).

11. Graham, D., Agrawal, N., Roth, S. Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet, 2: 1277-1280 (1988).

12. Somerville, K., Faulkner, G., Langman, M. Non­steroidal anti-inflammatory drugs and bleeding peptic ulcer. Lancet, 1: 462-464 (1986).

13. Armstrong, C, Blower, A. Non-steroidal anti­inflammatory drugs and life-threatening complications of peptic ulceration. Gut, 28: 527-532 (1987).

14. Griffin, M., Piper, J., Daugherty, J., Snowden, M., Ray, W. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Annals of Internal Medicine, 114: 257-263 (1991).

15. Holvoet, J., Terriere, L, van Hee, W. et al. Relation of upper gastrointestinal bleeding to non-steroidal anti­inflammatory drugs and aspirin: a case-control study. Gut, 32:730-734 (1991).

16. Soll, A. Nonsteroidal antiinflammatory drugs and peptic ulcer disease. Annals of Internal Medicine, 114: 307-319 (1991).

17. Martin, D., Hollanders, D., May, S. et al. Difference in relapse rates of duodenal ulcer after healing with cimetidine or tripotassium dicitratobismuthate. Lancet, 1: 7-10 (1984).

18. Lee, F., Samloff, I., Hardman, M. Comparison of tripotassium dicitratobismuthate tablets with ranitidine in healing and relapse of duodenal ulcers. Lancet, 1: 1291 -1303 (1985).

19. Hui, W., Lam, S., Lau, W. et al. Omeprazole and ranitidine in duodenal ulcer healing and subsequent relapse: randomized double-blind study with weekly endoscopic assessment. European Journal of Gastro­enterology and Hepatology, 2 (suppl): 35-43 (1989).

20. Walan, A., Bianchi Porro, G., Hentschel, E. et al. Maintenance treatment with cimetidine in peptic ulcer disease for up to 4 years. Scandinavian Journal of Gastroenterology, 22: 397-405 (1987).

21. Bardhan, K., Hinchliffe, R., Bose, K. et al. Six years of continuous cimetidine treatment in peptic ulcer disease: efficacy and safety. The Anglo-Irish cimetidine long-term study group. Alimentary Pharmacology and Therapeutics, 2:395-405 (1988).

22. Reed, P., Smith, P., Haines, K. et al. Effect of cimetidine on gastric juice N-nitrosamine concentration. Lancet, 2: 553-555 (1981).

23. Milton-Thompson, G., Ahmet, Z., Lightfoot, N. et al. Intragastric acidity, bacteria, nitrite and N-nitroso-componds before, during or after cimeticdine treatment. Lancet, 2: 1091-1095 (1982).

24. Hui, W. Update on treatment of duodenal ulcer disease. Drugs of Today, 27: 55-63 (1991).

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25. Hansky, J., Stem, A., Korman, M., Waugh, J. Effects of long-term cimetidine on serum gastrin in duodenal ulcer. Digestive Disease Science, 24: 468-470 (1979).

26. Fessten, H., Thijs, J., Lamers, C. et al. The effect of oral omeprazole on serum gastrin and serum pepsino-gen levels. Gastroenterology, 78: 1030-1034 (1984).

27. Hakanson, R., Bottcher, G., Ekblad, E. et al. Hista­mine in endocrine cells in the stomach. A survey of several species using a panel of histamine antibodies. Histochemistry, 86: 5-17 (1986)

28. Hui, W., Liu, H., Lam, S. Enterochromaffin-like cells of the human stomach: demonstration of histamine content and cholinergic nerve supply. Cellular and Molecular Biology, 34: 303-309 (1988).

29. Marshall, B., Warren, J. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulcer­ation. Lancet, 1: 1311-1314 (1984).

30. Heatley, R. Review article: the treatment of Helico­bacter pylori infection. Alimentary Pharmacology and Therapeutics, 6: 291-303 (1992).

31. Coghlan, J., Gilligan, D., Humphries, H. et al. Campylobacter pylori and recurrence of duodenal ulcers: a 12-month study. Lancet, 2: 1109-1111 (1987).

32. Marshall, B., Goodwin, C, Warren, J. et al. Prospec­tive doubl- blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet, 2: 1437-1442 (1988).

33. Isakov, V., Grigoriev, P., Yakovenko, E. Treatment of Helcobacter pylori-positive duodenal ulcers. Lancet, 336: 755-756 (1990).

34. Rauws, E., Tytgat, G. Eradication of Helicobacter pylori cures duodenal ulcer. Lancet, 1: 1233-1235 (1990).

35. Graham, D., Ginger, M., Lew, P. et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. Annals of Internal Medicine, 116: 705-708 (1992).

36. Fiocca, R., Solcia, E., Santoro, B. Duodenal ulcer relapse after eradication of Helicobacter pylori. Lancet, 337: 1614 (1991).

37. Borody, T., Andrews, P., Mancuso, N. et al. Helicobacter pylori reinfection 4 years post-eradication. Lancet, 339: 1295 (1992).

38. Helicobacter pylori infection: when and how to treat. Drug and Therapeutics Bulletin, 31: 15 February 1993.

39. Graham, D., Lew, G., Klein, P. et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer a randomized, controlled study. Annals of Internal Medicine, 116: 705-708 (1992).

40. Brogden, R., Pinder, R., Sawyer, P. et al. Tripotassium dicitratobismuthate: a report of its pharmacological properties and therapeutic efficacy in peptic ulcer. Drugs, 12:401-411 (1976).

41. Rauws, E. Therapeutic attempts at eradication of Campylobacter pylori. European Journal of Gastroenterol­ogy and Hepatology, 1: 34-41 (1989).

42. Lee, S. A potential mechanism of action of colloidal bismuth subcitrate: diffusion barrier to hydrochloric acid. Scandinavian Journal of Gastroenterology, 17: 17-21 (1982).

43. Marshall, B., Hislop, I., Glancy, R., Armstrong, J. Histological improvement of active chronic gastritis in patients treated with Denol. Australian and New Zealand Journal of Medicine, 14 (suppl 4): 907 (1984).

44. McNulty, C , Gearty, J., Grump, B. et al. Campylobacter pylori and associated gastritis: investiga­tor-blind, placebo-controlled trial of bismuth subsalicylate and erythromycin ethylsuccinate. British Medical Journal, 293: 645-649 (1986).

45. Rauws, E., Langenberg, W., Houthoff, H. et al. Campylobacter pylori-associated chronic antral gastritis. Gastroenterology, 94: 33-40 (1988).

46. Tytgat, G., Axon, A., Dixon, M. et al. Helicobacter pylori: causal agent in peptic ulcer disease? Working Party Reports, World Congresses of Gastroenterology. Sydney, Australia. Oxford: Blackwell, 36-45 (1990).

47. Bell, G., Powell, K., Burridge, S et al. Experience with anti-Heliobacter pylori eradication therapy: side effects and the importance of testing the pre-treatment bacterial isolate for metronidazole resistance. Alimentary Pharma­cology and Therapeutics, 6: 427-435 (1992).

48. Chiba, N., Rademaker, J., Rao, B., Hunt, R. Eradica­tion of Helicobacter pylori: meta-analysis to determine optimal therapy (abstract). Gut, 32 (10): A1220-A1221.

49. Hentschel, E., Brandstätter, G., Dragosics, B. et al. Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. New England Journal of Medicine, 328: 308-312 (1993).

50. Glupcznski, Y., Burette, A. Eradicating Helicobacter pylori. Lancet, 335: 976-977 (1990).

51. Graham, D. Treatment of peptic ulcers caused by Helicobacter pylori. New England Journal of Medicine, 328: 349-350 (1993).

52. McKinley, A., Upadhyay, R., Gemmell, C , Russell, R. Helicobacter pylori, bridging the credibility gap. Gut, 31 : 940-945 (1990).

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53. The Eurogast Study Group. An international associa­tion between Helicobacter pylori infection and gastric cancer. Lancet, 341: 1359-1362 (1993).

New threats from streptococci: the re-emergence of suppurative disease and rheumatic fever Throughout the early decades of the present century the acute pyogenic infections caused by group A beta-haemolytic streptococci — strepto­coccal gangrene, streptococcal sepsis, myositis, puerperal sepsis, erysipelas, scarlet fever — were feared illnesses. Death rates associated with these diseases at that time have been estimated to range from 20% to over 50% in industrialized countries (1). For many years afterwards the non-suppurative complications of these diseases, including rheumatic heart disease and glomerulonephritis, left a substantial legacy of chronic illness and premature death.

Antimicrobial therapy, initially involving sulfon­amides and later penicillin dramatically relieved the situation. But, even before these agents became generally available, the incidence and severity of these infections had begun to decline (2). By the 1970s acute rheumatic fever had virtually disappeared from developed countries — although not from Africa and Asia where rheumatic fever remains one of the main causes of disability and premature death (3, 4) — and debate was engaged as to whether in more affluent countries acute streptococcal pharyngitis was being overtreated (5).

From the late 1980s, however, limited outbreaks of systemic pyogenic disease (6-8) and acute rheumatic fever (9) have again been reported, most extensively — but not exclusively —from North America. Some of the characteristics of these outbreaks are unexpected having regard to previous experience. Invasive pyogenic disease is now occurring in previously healthy children and adults and is no longer restricted largely to infants and the elderly (8,10-13). Osteomyelitis, septic arthritis, pneumonia and empyema, endocarditis, peritonitis, sinusitis, mastoiditis and meningitis have all been described. Reported death rates in patients with bacteraemia have ranged from 7% to 35% (14). Similarly, small focal outbreaks of rheumatic fever have recently been reported in communities of high socioeconomic status (9), and a new condition, streptococcal toxic shock syndrome, has emerged (13, 15-17).

The shock-like syndrome associated with staphylococcal and streptococcal infection are virtually identical. Both are characterized by the occurrence of shock and multiorgan failure early in the course of infection (18). The primary site of infection is often apparent but rash, hypotension, shock, myositis, necrotising fasciitis and disseminated intravascular coagulation and multiorgan failure rapidly supervene. Death rates as high as 30% have been reported even when patients have received appropriate antimicrobial therapy, supportive care and, when necessary, surgical debridement (17).

These changes in the clinical sequelae of strepto­coccal infection are compatible with a change in the virulence of the pathogen (19). Indeed, a shift has been described in serotypes common in North America towards those containing specific M-type antigens (11, 12, 17, 20-22) and towards those producing a hitherto unusual exotoxin, strepto­coccal pyrogenic exotoxin A (17, 23-27) and proteinase substances (8). These organisms also produce considerable amounts of capsular hyaluronic acid (28) and the risk of fulminating invasive disease and toxic shock is exacerbated in patients with neither serotype nor antitoxin anti­body.

Prevention of these serious complications of streptococcal disease is dependent upon effective treatment of the initial focal infection, and parti­cularly of streptococcal pharyngitis. Fortunately, thus far, group A streptococci have remained sensitive to penicillins (29), although disquieting reports have recently been published of organisms resistant to erythromycin (30, 31). It has recently been claimed that amoxicillin administered once daily is as effective as a course of phenoxy¬ methylpenicillin in the treatment of streptococcal pharyngitis (32). This has been contested, however, both on grounds of cost (33) and because use of broad-spectrum penicillins in the blind treatment of sore throats may exacerbate rashes in patients with glandular fever (34).

The Canadian Paediatric Society in a recent statement (35) does not recommend any change in routine penicillin therapy of streptococcal pharyngitis and impetigo. It notes, however, that the clinical response to penicillin is now sometimes relatively slow (13), that cefalosporins are also effective (36), and that clindamycin, by inhibiting protein synthesis and interfering with M-protein and toxin production (37), may potentiate the effect of penicillin. The statement, less predictably, places

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emphasis on the need for microbiological confirma­tion of streptococcal pharyngitis. This fails to address the problematic aspects both of case finding and of establishing the diagnosis (33). Even in the most highly developed countries only a small minority of patients with sore throat ever attend their doctor (38); f irm evidence is still lacking as to whether treatment with antibiotics reduces the risk of subsequent development of rheumatic fever (39); the throat swab has a low sensitivity and specificity (40) — although results obtained with polyclonal antibody-based immunoassays and liposome technology are promising for use in developed and developing countries alike (41, 42, 43); and false-positive throat swabs and even rising antistrepto­lysin O titres have been recorded in asymptomatic patients (44).

Given the concerns over the possible re-emergence of rheumatic fever, management of streptococcal sore throat and the criteria for prophylactic use of penicillin need careful re-examination at national level.

References

1. Stevens, D. Invasive group A Streptococcus infections. Clinical Infectious Disease, 14: 2-11 (1992).

2. Dajani, A. Current status of nonsuppurative complica­tions of group A streptococci. Pediatric Infectious Diseases Journal, 10 (suppt 10): 25-27 (1991).

3. Ekra, A., Bertrand, E. Rheumatic heart disease in Africa. World Health Forum, 13: 331-333 (1992).

4. Al-Sekait, M., Al-Sweilem, A., Tahir, M. Rheumatic fever and chronic rheumatic disease in the school children in Saudi Arabia. Saudi Medical Journal, 8:245-247 (1988).

5. Gerber, M., Markowitz, M. Management of streptococ­cal pharyngitis reconsidered. Pediatric Infectious Diseases Journal, 4:518-526 (1985).

6. Christie, C , Havens, P., Shapiro, E. Bacteremia with group A streptococci in childhood. American Journal of Diseases of Childhood, 142: 559-561 (1988).

7. Givner, L, Abramson, J., Wasilaukas, B. Apparent increase in the incidence of invasive group A beta¬ hemolytic streptococcal disease in children. Journal of Pediatrics, 118: 341-346 (1991).

8. Wheeler, M., Roe, M., Kaplan, E. et al. Outbreak of group A Streptococcus septicemia in children: clinical, epidemiologic, and microbiological correlates. Journal of the American Medical Association, 266: 533-537 (1991).

9. Taubert, K., Rowley, A., Shulman, S. Nationwide survey of Kawasaki disease and acute rheumatic fever. Journal of Pediatrics, 119: 2179-282 (1991).

10. Hamden, A., Lennon, D. Serious suppurative group A streptococcal infections in previously well children. Pediatric Infectious Diseases Journal, 7: 714-718 (1988).

11. Martin, P., Hoiby, E. Streptococcal serogroup A epidemic in Norway 1987-1988. Scandinavian Journal of Infectious Diseases, 22:421-429 (1990).

12. Schwartz, B., Facklam, R., Breiman, R., Changing epidemiology of group A streptococcal infection in the USA. Lancet, 336: 1167-1171 (1990).

13. Hoge, C, Schwartz, B., Talkington, D. et al. The changing epidemiology of invasive group A streptococcal infections and the emergence of streptococcal toxic shock-like syndrome: a retrospective population-based study. Journal of the American Medical Association, 269: 384389 (1993).

14. Infectious Diseases and Immunization Committee, Canadian Paediatric Society. Group A Streptococcus: a re-emergent pathogen. Canadian Medical Association Journal, 148: 1909-1911 (1993).

15. Cone, L, Woodward, D., Schlievert, P. et al. Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. New England Journal of Medicine, 317:146-149 (1987).

16. Bartter, T., Dascal, A., Carroll, K. et al. 'Toxic strep syndrome': a manifestation of group A streptococcal infection. Archives of Internal Medicine, 148: 1421-1424 (1988).

17. Stevens, D., Tanner, M., Winship, J et al. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. New England Journal of Medicine, 321: 1-7 (1989).

18. The Working Group on Severe Streptococcal Infections. Defining the group A streptococcal toxic shock syndrome. Journal of the American Medical Association, 269: 390-391 (1993).

19. Ferreri, P. Microbiological features of current virulent strains of group A streptococci. Pediatric Infectious Diseases Journal, 10 (suppl 10): 20-24 (1991).

20. Gaworzewska, E., Colman, G. Changes in the pattern of infection caused by Streptococcus pyogenes. Epidemiology of Infections, 100: 257-269 (1988).

21. Kaplan, E., Johnson, D., Cleary, P. Group A strepto­coccal serotypes isolated from patients and sibling contacts during the resurgence of rheumatic fever in the United States in the mid-1980s. Journal of Infectious Diseases, 259: 101-103 (1989).

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22. Cleary, P., Kaplan, E., Handley, J. et al. Clonal basis for resurgence of serious Streptococcus pyogenes disease in the 1980s. Lancet, 339: 518-521 (1992).

23. Bohach, G., Fast, D., Nelson, R. Schlievert, P. Staphylococcal and streptylococcal pyrogenic toxins involved in toxic shock syndrome and related illnesses. Critical Reviews in Microbiology, 17: 251-272 (1990).

24. Hauser, A., Stevens, D., Kaplan, E., Schlievert, P. Molecular analysis of pyrogenig exotoxins from Strepto­coccus pyogenes isolates associated with the toxic shock­like syndrome. Journal of Clinical Microbiology, 29: 1562-1567 (1991).

25. Belani, K., Schlievert, P., Kaplan, E., et al. Association of exotoxin-producing group A streptococci and severe disease in children. Pediatric Infectious Diseases Journal, 10:351-354 (1991).

26. Musser, J., Hauser, A., Kim, M., et al. Streptococcus pyogenes causing toxic-shock-like syndrome and other invasive diseases: clonal diversity and pyrogenic exotoxin expression. Proceedings of the National Academy of Sciences, USA, 88: 2668-2672 (1991).

27. Shulman, S. Invasive and toxin-related diseases caused by group A streptococci. Pediatric Infectious Diseases Journal, 10 (suppl 10): 28-31 (1991).

28. Burrows, K., Halperin, S., Swift, M. et al. Changing pattern of group A streptococcal (GAS) bacteremia in children. Presented at the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 23, 1990.

29. Klein, J. Re-emergence of virulent group A streptococ­cal infections. Pediatric Infectious Diseases Journal, 10 (suppl 10): 3-6 (1991).

30. Scott, R., Naidoo, J., Lightfoot, N. et al. A community outbreak of group A beta haemolytic streptococci with transferable resistance to erythromycin. Epidemiology of Infections, 102: 85-91 (1989).

31. Seppälä, H., Nissinan, A., Jävinen, H. et al. Resis­tance to erythromycin in group A streptococci. New England Journal of Medicine, 326: 292-297 (1992).

32. Shvartzman, P., Tabenkin, H., Rosenzwaig, A., Dolginov, F. Treatment of streptococcal pharyngitis with amoxicillin once a day. British Medical Journal, 306: 1170-1172 (1993).

33. Little, P., Morgan, S., Williamson, I. Treatment of streptococcal sore throat: stick to penicillin or nothing. British Medical Journal, 306: 1611-1622 (1993).

34. Airey, N. Treatment of streptococcal sore throat: beware glandular fever trap. British Medical Journal, 306: 1611 (1993).

35. Wittier, R., Yamada, S., Bass, J. et al. Penicillin tolerance and erythromycin resistance of group A beta-haemolytic streptococci in Hawaii and the Philippines. American Journal of Diseases of Childhood, 144: 587-589 (1990)

36. Pichichero, M. The rising incidence of penicillin treatment failures in group A streptococcal tonsillophaiyn¬ gitis: an emerging case for the cephalosporins? Pediatric Infectious Diseases Journal, 10: 550-555 (1991).

37. Gemmel, C, Peterson, P., Schmeling, D. et al. Potentiation of opsonization and phagocytosis of Streptococcus pyogenes following growth in the presence of clindamycin. Journal of Clinical Investigation, 67: 1249-1256 (1981).

38. Banks, M., Beresford, S., Morrell, D. et al. Factors influencing the demand for primary health care in women aged 20-64 years: a preliminary report. International Journal of Epidemiology, 4: 189-195 (1975).

39. Howie, J., Foggo, B. Antibiotics, sore throats and rheumatic fever. Journal of the Royal College of General Practitioners, 35: 223-224 (1985).

40. Del Mar, C. Managing sore throat: a literature review. I. Making the diagnosis. Medical Journal of Australia, 156: 572-575 (1992).

41. Dobkin, D., Shulman, S. Evaluation of an ELISA for group" A streptococcus antigen for diagnosis of phayngitis. Journal of Pediatrics, 110: 566-568 (1987).

42. Gerber, M., Randolph, M., DeMeo, K. Liposome immunoassay for rapid identification of group A strepto­cocci directly from throat swab. Journal of Clinical Microbiology, 28: 1463-1464 (1990).

43. Arya, S. Immunoassays for rapid diagnosis. British Medical Journal, 306:1612 (1993).

44. Haverkom, M., Valkenburg, H., Goslings, W. A controlled study of streptococcal pharyngitis and its implications in the Netherlands. Journal of Infectious Diseases, 124: 339 (1971).

.... And the widening spectrum of group B streptococcal disease Group B beta-haemolytic streptococci, or S. agalactiae, were initially distinguished from group A streptococci on serological grounds. Their pathological potential was first recognized in the 1930s when they were implicated in cases of puerperal sepsis (1). By the mid-1970s they had become the leading cause of neonatal sepsis and meningitis in the United States and an important

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cause of maternal peripartum infections (2). Within the USA it is estimated that these infections afflict about 1 in 500 infants during their first three months of life (3) and cause as many as 50 000 maternal pregnancy-related infections each year (4, 5).

Within the past decade, several small surveys have suggested that non-pregnant adults are also now vulnerable to group B streptococcal disease (6-9). One localized survey undertaken in the USA during 1989 and 1990 indicated that these diseases were occurring as frequently in adults as in infants, and that infections among men and non-pregnant women outnumbered the number of cases related to pregnancy (10). Almost all of the non-pregnant adult patients had serious underlying medical conditions — including diabetes mellitus, neuro­logical disease, renal failure, cancer, alcohol abuse, and hepatic, pulmonary or renal insufficiency — and over 20% of these died from invasive strepto­coccal infection. Older patients, and patients with diabetes or cancer were at particular risk. About one-third of the infections involved skin, soft tissues or bone. Another third presented as bacteraemia with no identified primary focus, and the remainder were diagnosed as urinary infections, pneumonia and peritonitis.

Among infants, there are indications that the mortality associated with these infections has regressed over the past 20 years from between 30 and 50% to its current level of 5 to 15% (11). How­ever, the costs incurred for acute care and the long-term morbidity resulting from meningitis remain considerable. Ampicillin, 2 g administered intra­venously every 4 hours to a maternal carrier throughout labour prevents colonization and infection of the infant during delivery. Since up to a quarter of all women are carriers, preventive treatment is usually only practicable on a selective basis and particularly when the infant is at increased risk. Preterm labour, early rupture of membranes, fever, multiple gestation, or a history of infection during a previous pregnancy are considered to comprise the most important indica­tions for treatment (2).

Immunization, if it proves feasible, will provide a more practicable preventive strategy. Administra­tion of a specific capsular polysaccharide has elicited a detectable IgG antibody response in some two-thirds of vaccinated pregnant women (12). Work is now in hand to develop a multivalent polysaccharide-protein conjugate vaccine in the expectation that this will increase both the rate and the intensity of the antibody response, and

encouraging results have already been reported in animal models (13).

References

1. Fry, R. Fatal infections by haemolytic streptococcus group B. Lancet, 1: 199-201 (1938).

2. Wessels, M., Kaspar, D. The changing spectrum of group B streptococcal disease. New England Journal of Medicine, 328: 1843-1844 (1993).

3. Zangwill, K., Schuchat, A., Wenger, J. Group B streptococcal disease in the United States, 1990: report for a multistats active surveillance system. Morbidity and Mortality Weekly Report, 41 (SS-6): 25-32 (1992).

4. Dillon, H., Khare, S., Gray, B. Group B streptococcal carriage and disease: a 6-year prospective study. Journal of Pediatrics, 110: 31-36 (1987).

5. Baker, C, Flench, M., Kasper, D. Response to type III polysaccharide in women whose infants have had invasive group streptococcal infection, New England Journal of Medicine, 322: 1857-1860 (1990).

6. Gallagher, P., Watanakunakom, C. Group B streptococ­cal bacteremia in a community teaching hospital. American Journal of Medicine, 78: 795-800 (1985).

7. Verghese, A., Mireault, K., Arbeit, R. Group B strepto­coccal bacteremia in men. Reviews of Infectious Dis­eases, 8: 912-917 (1986).

8. Opal, S., Cross, A., Palmer, M., Almazan, R. Group B streptococcal sepsis in adults and infants: contrasts and comparisons. Archives of Internal Medicine, 148: 641-645 (1988).

9. Schwartz. B., Schuchat, A., Oxtoby, M. et al. Invasive group B streptococcal disease in adults: a population-based study in metropolitan Atlanta. Journal of the American Medical Association, 266: 1112-1114 (1991).

10. Farley, M., Harvey, C, Stull, T. et al. A population-based assessment of invasive disease due to group B streptococcus in nonpregnant adults. New England Journal of Medicine, 328: 1807-1811 (1993).

11. Group B streptococcal disease in the United States, 1990: report from a multistate active surveillance system. CDC surveillance summary 1992. Morbidity and Mortality Weekly Report, 41: 25-32 (1992).

12. Baker, C, Rench, M., Edwards, M. et al. Immunization of pregnant women with a polysaccharide vaccine of group B streptococcus. New England Journal of Medicine, 319: 1180-1185 (1988).

13. Paoletti, L., Wessels, M., Michon, F. et al. Group B streptococcus type II polysaccharide-tetanus toxoid conjugate vaccine. Infection and Immunity, 60: 4009-4014 (1992).

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WHO Drug Information Vol. 7, No. 2, 1993

Regulatory Matters

Reporting reactions to biotechnology products United Kingdom — When reporting suspected adverse reactions associated with products generated by biological synthesis, doctors have been requested to ensure that they cite the full approved name or the brand name. These products, which include human insulins, growth hormones, erythropoietins, recombinant tissue plasminogen activators, growth factors, interferons and vaccines, closely resemble their naturally-occurring counterpart. But as they almost always have a slightly different amino-acid sequence or different glycosylation, it is impossible to exclude the possibility that these differences will have significant influence on the adverse reaction profile of the product.

Source: Committee on Safety of Medicines. Current Problems, Vol. 19, June 1993.

Ketorolac: restrictions on parenteral dosage United Kingdom — The Committee on Safety of Medicines has concluded that parenteral administration of ketorolac, a nonsteroidal anti­inflammatory agent (NSAID) indicated for short-term management of moderate to severe post­operative pain, should not be sustained for more than two days and that dosage should not exceed 90 mg daily for younger adults or 60 mg daily for elderly patients. Oral dosage recommendations remain unchanged. This action has stemmed from a review of adverse reaction reports notified both in the USA, where most experience with ketorolac has been obtained, and in the UK.

Since it was first launched in the USA in 1990, ketorolac is estimated to have been prescribed for some 16 million patients and it has been associated with 97 deaths. Whereas other risk factors undoubtedly contributed to these deaths, their pattern is consistent with the typical adverse reaction profile of NSAIDs. Almost half resulted from gastrointestinal bleeding or perforation, some 20% from renal insufficiency, and a smaller propor­tion from anaphylaxis and asthma.

Interim information on the use of ketorolac to control post-operative pain has been generated in a cohort study still ongoing in the USA. This indicates that risk of gastrointestinal bleeding during treat­ment is correlated with increasing age (over 65); previous peptic ulceration; concomitant treatment with anti-coagulants and other nonsteroidal anti­inflammatory drugs; increasing dosage and increasing duration of treatment (beyond 2 days).

Doctors in the UK have been reminded that contra­indications to treatment with ketorolac and other NSAIDs include a history of peptic ulceration, gastrointestinal bleeding, haemorrhagic diathesis or cerebrovascular bleeding; a history of asthma; a recent surgical intervention with a high risk of bleeding; moderate to severe renal impairment (serum creatinine greater than 160 µmol/l); hypo­v o l e m i a or dehydration from any cause; hyper­sensitivity to other drugs of this class or to acetyl¬ salicylic acid.

Source:- Committee on Safety of Medicines. Current Problems in Pharmacovigilance, Vol. 19, June 1993.

Paroxetine: dystonia and withdrawal symptoms United Kingdom— Paroxetine, an antidepressant that selectively inhibits reuptake of serotonin by central nerve cells, has been associated with occasional cases of dystonia and withdrawal symptoms.

The Committee on Safety of Medicines has received 39 reports of extrapyramidal reactions among patients receiving the product, only two of whom were also taking a neuroleptic drug. The reporting rate is of the order of one case for every 10 000 prescriptions issued. Fifteen of the reports describe acute dystonia affecting the face or mouth and, among these, one patient experienced an oculogyric crisis. The reaction typically occurred within 3 days of starting treatment and was rapidly self-limiting. However, in one instance the signs persisted for 3 days and 2 patients were treated with an anti-cholinergic drug. Only 9 similar reactions have been reported among patients receiving other drugs of this class and, in 6 of

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these, other possible predisposing factors were identified.

Twice as many reports have been received of withdrawal symptoms, including dizziness, sweating, nausea, insomnia, tremor and confusion. Typically, these symptoms became apparent within 1-4 days of stopping treatment and they resolved whenever treatment was reinstated. Such reactions have been less frequently associated with other drugs of this class, and doctors have been advised to avoid abrupt discontinuation of treatment.

Source: Committee on Safety of Medicines. Current Problems, Vol 19, February 1993.

Quinolone antibiotics: serious adverse reactions The quinolone antibiotic, temafloxacin, was with­drawn worldwide in June 1992 within months of its initial registration as a result of an unacceptably high association in the United States with a variety of serious adverse effects reported which have been postulated to have an immunological basis. These included haemolytic anaemia, hypo¬ glycaemia, renal failure, hepatic dysfunction and anaphylaxis. During the first 3 months after its introduction to the market in the USA, the reporting rate for such reactions was estimated as 28 per 100 000 prescriptions. Comparable rates for ofloxacin, norfloxacin and ciprofloxacin were between 5 and 10-fold less.

Within the UK, in contrast, only 39 reports citing temafloxacin were submitted to the Committee on Safety of Medicines. None of these was serious in its outcome. For other widely-used quinolines, the patterns of adverse reaction reporting in the United Kingdom and the USA has been remarkably similar.

The Committee does not consider that these different experiences can be attributed solely to lower usage of temafloxacin in the UK. It suggests that the higher incidence of reactions notified in the USA reflects the higher dosages recommended in the product labelling.

Source: Committee on Safety of Medicines. Current Problems, Vol. 19, February 1993.

Sotalol: approved for life-threatening arrhythmias United States of America — The Food and Drug Administration has approved the use of sotalol hydrochloride to treat life-threatening arrhythmias. It is not recommended for the treatment of less severe arrhythmias, including asymptomatic premature ventricular contractions.

This restriction is important since sotalol, like other antiarrhythmic agents can exacerbate potentially fatal ventricular arrhythmias, including sustained ventricular tachycardia and ventricular fibrillation, in vulnerable individuals. Other significant adverse effects include prolongation of the QT interval and dose-related "torsades de pointes". Sotalol should not be administered to patients in whom the QT interval is already prolonged as a result of electro­lyte imbalance.

Sotalol has performed well in comparison with other antiarrhythmic drugs in a comparative study involving some 1300 patients with life-threatening arrhythmias. There is no direct evidence, as yet, however, that it improves survival. Treatment should always be started, and doses increased, in a hospital with electrocardiographic facilities.

Source: Medical Bulletin. Food and Drug Administration, Vol 23, March 1993.

Stavudine: a new antiviral for HIV infection United States of America — The antiviral drug stavudine has now been made available to AIDS patients in the USA who have either been unable to tolerate other antiviral drugs or who have failed to respond satisfactorily to them.

It is not yet known whether stavudine can delay the onset of disease or extend life in HIV-positive patients. Early trials indicate that it may have beneficial effects on the immune system since it temporarily increases the CD4 cell count. In general, it is well tolerated, but some patients develop peripheral neuropathy which is commonly reversible on discontinuation of treatment or reduction of dosage.

Source: Medical Bulletin. Food and Drug Administration, Vol 23, March 1993.

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Sulfasalazine: fatal blood dyscrasias United Kingdom — The Committee on Safety of Medicines has reminded doctors that they should warn all patients receiving long-term sulfasalazine therapy for inflammatory bowel disease or rheumatoid arthritis to report promptly any un­explained fever, sore throat, malaise or other non­specific illness. In addition, they are advised that blood counts should be performed routinely before treatment is started and at monthly intervals during the first three months of therapy. Treatment should be discontinued immediately there is suspicion of a blood dyscrasia.

Such warnings have long been extant, but reports of deaths attributable to sulfasalazine-induced blood disorders continue to occur. In all, the Committee reports, blood disorders account for some 20% of all adverse effects associated with sulfasalazine. Among these are reports of 36 fatalities: 22 of these are ascribed to agranulo­cytosis, 13 to aplastic anaemia, and one to thrombocytopenia. The ages of these patients ranged from 10 to 84 years. The sample included more women than men, and most were being treated for inflammatory bowel disease. In some two-thirds of the cases the condition developed within 3 months of starting treatment, and in most of the remaining patients within a further period of three months.

Source: Committee on Safety of Medicines. Current Problems, Vol. 19, June 1993.

Sumatriptan: acute treatment of migraine

United States of America — The Food and Drug Administration has announced the registration of sumatriptan succinate for the acute treatment of migraine attacks. In clinical trials involving more than 1000 patients, approximately 82% improved within 2 hours of treatment, and 65% of all patients remained pain-free.

The maximum single dose recommended is 6 mg injected subcutaneously. Doses as low as 1 mg have been shown to be effective in some patients. Doctors are advised to give the first dose under supervision in order to monitor adverse effects and

to ensure that, if an auto-injector is used, it is employed properly. The most common systemic adverse effects are dizziness, drowsiness, anxiety and malaise. Atypical sensations including tingling, feelings of tightness or heaviness. Heat, cold or pressure are also frequently described. Less often, patients complain of musculoskeletal pain or discomfort in the throat, nose or ears. These effects are usually transient and without serious significance.

More importantly, sumatriptan has a potential to cause coronary artery constriction and to raise blood pressure. The FDA warns that it should not be used by patients with coronary artery disease and uncontrolled hypertension, and that use of ergot-containing drugs is contraindicated within 24 hours of its administration.

Source: Medical Bulletin. Food and Drug Administration, Vol 23, March 1993.

Halofantrine: revised data sheet Halofantrine (Halfan®: SmithKline Beecham Pharmaceuticals, UK) is a phenanthrene-methanol antimalarial which is effective against the asexual erythrocyte stage of malaria parasites. It is indicated for the treatment of acute malaria caused by single or mixed infections of Plasmodium falci­parum or P. vivax. It is administered in a total dosage of 24 mg/kg given as 8 mg/kg three times at six-hourly intervals. The majority of patients who have been treated with halofantrine have been infected with P. falciparum in areas where chloroquine or multidrug-resistant strains are common.

Recent research reports have alerted that the administration of halofantrine can result in prolongation of QTc intervals and ventricular dysrhythmias in susceptible individuals (1-3). There have also been some spontaneous reports of serious ventricular dysrhythmias, rarely associated with death. In total, eight cardiac arrests have been reported to the pharmaceutical company, leading to six deaths, some of which may have been associated with ventricular dysrhythmias. These cases have occurred particularly under certain conditions which include the use of doses higher than recommended, recent or concomitant treatment with mefloquine, the presence of pre­existing prolongation of QTc interval or in patients with thiamine deficiency.

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An analysis of available ECG data on patients with P. falciparum malaria and in healthy volunteers indicates that:

(i) halofantrine causes an increase in QTc interval at recommended doses.

(ii) the absorption of halofantrine is increased approximately six fold when taken with a fatty meal, with additional increases in the QTc interval.

SmithKline Beecham is consequently revising the data sheet for Halfan® (4). In advance of this revision WHO has been advised by the pharmaceutical company that halofantrine:

• is contraindicated in patients with a known family history of QTc prolongation;

• is not recommended for use in combination with drugs or clinical conditions known to prolong the QTc interval or in patients who may suffer from thiamine deficiency;

• should not be administered to patients with a severe electrolyte imbalance;

• treatment should not exceed the recommended total dosage of 24 mg/kg given as 8 mg/kg three times at 6-hourly intervals;

• should be administered on an empty stomach (i.e., not given with food);

• should only be used as an emergency self-medication for presumptive therapy in those patients known to have normal QTc intervals.

The pharmaceutical company recommends a second therapeutic course one week following the initial treatment of patients who have had no previous exposure to malaria, such as travellers from non-endemic areas.

References

1. Nosten, S., ter Kuile, F., Luxemburger, C. et al. Cardiac effects of antimalarial treatment with halofantrine, Lancet, 341: 1054-1056 (1993).

2. Castot, A., Rapoport, P., Le Coz, P. Prolonged QT interval with halofantrine. Lancet, 341: 1541 (1993).

3. Monlun, E., Pillet, O., Cochard, J.F. et al. Prolonged QT interval with halofantrine. Lancet, 341: 1541-2 (1993).

4. Communication to WHO from SmithKline Beecham Pharmaceuticals, 24 August 1993.

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WHO Drug Information Vol. 7, No. 2, 1993

Essential Drugs

Guidelines for antimicrobial susceptibility testing (intermediate laboratories)

Introduction

Although many communicable diseases have been effectively contained, bacterial infections remain a major cause of morbidity and mortality particularly in developing countries.

It has been stressed repeatedly that the increas­ing prevalence of strains of common pathogenic bacteria resistant to widely-available, relatively-cheap antimicrobials such as those included in WHO's Model List of Essential Drugs (1) is dangerously eroding their effectiveness not only for the treatment of individual patients but also for the community at large.

Whenever one such drug or class of drugs is used excessively, genetic changes favouring the emergence of antimicrobial-resistant bacteria tend to supervene. Although this can occur after only a single exposure in an individual patient, it usually emerges after a sustained period of use. Resistance is generally stable and passed on for several generations of bacteria. The spread of anti­microbial-resistant clones of bacteria within a host population or environment is also important. This is most noticeable in hospitals where certain resistant organisms can become endemic and may infect many patients. The danger is intensified by poor hygienic practices in the hospital and/or lack of adequate training in control and containment of nosocomial and other infections. The spread of resistant bacteria within the community is of even greater importance. This seriously compromises presumptive initial therapy of common bacterial infections and requires revision of routine anti­microbial strategies.

The need for more systematic and coordinated international approaches to laboratory monitoring of antimicrobial sensitivity has become important and urgent. Microbiological laboratories including national reference laboratories need to be established in developing as well as developed

countries if the resistance of important bacterial pathogens is to be monitored. In response to this need, the WHONET (2, 3) programme was developed by the WHO Collaborating Centre for Surveillance of Antimicrobial Resistance. It is now operating in some 100 hospitals, mostly in the United States, and it is expanding in South America and the western Pacific region. The system will not be fully effective, however, until every country has a national reference laboratory that is actively reporting to this network.

The concept of "reserve antimicrobials" was introduced to WHO's Model List of Essential Drugs in 1989 (4). This resulted from increasing concern about the emergence of important pathogens that have developed resistance to all "essential" antimicrobials. A reserve antimicrobial was defined as "an antimicrobial which is useful for a wide range of infections but, because of the need to reduce the risk of development of resistance and because of its relatively high cost, it would be inappropriate to recommend its unrestricted use". This concept becomes tangible, however, only when means exist of demonstrating prevailing sensitivity patterns. This implies a need for precise laboratory investigation. Without these facilities seriously-ill patients are endangered.

If antimicrobial resistance is to be controlled, sev­eral independent measures need to be undertaken:

1. Routine surveillance of antimicrobial-resistant bacteria using standardized, predictive test methods must be introduced in hospital and community settings.

2. Antimicrobial prescribing guidelines must be developed that will assure effective treatment and not encourage the emergence and spread of antimicrobial-resistant bacteria.

3. Comprehensive national programmes must be implemented that respect standards of good laboratory practice, with the objective of assuring quality and availability of antimicrobials.

4. Adequate training of technical personnel must be assured.

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5. Systems must be developed within the context of WHONET whereby each country can collate and disseminate information on antimicrobial resistance to hospitals and health workers.

The following guidelines concern routine surveil­lance of antimicrobial-resistant bacteria using tests which can be undertaken in intermediate level laboratories.

Susceptibility testing

Since the majority of infections which arise in man are not investigated by microbiological methods, antimicrobial treatment is usually administered on the basis of a presumptive etiological diagnosis determined by the clinical history and findings. Microbiological investigations are carried out where the etiology is uncertain, in severe infections when patients fail to respond to empiric therapy or develop a new infection during the course of therapy, or for public health purposes. Additionally, in vitro susceptibility tests are performed when an organism is known to have unpredictable sensitivity.

Susceptibility tests are carried out on antimicrobials to which the organism is normally susceptible in order to determine whether resistance has emerged. Demonstration of a prevalence of resistant strains could influence recommendations for presumptive antimicrobial therapy.

Clinically and epidemiologically important bacteria and essential antimicrobials for susceptibility testing

General principles

i) The antimicrobial substances listed in these guidelines are commonly used in presumptive therapy. This list is illustrative rather than comprehensive; other drugs may be important in various countries or regions.

ii) Some of the drugs listed are index compounds representative of a defined group of drugs, e.g.; oxacillin resistance in staphylococci indicates resistance to other beta-lactams.

iii) The most important types of resistance are easy to detect in rapidly-growing organisms. In contrast, detection of resistance in fastidious and anaerobic bacteria requires a high degree of technical expertise. In such circumstances, testing should be carried out in central reference laboratories, wherever possible.

1. Community-acquired infections

These infections are caused by organisms highly prevalent in the community. Some can be treated on an outpatient basis and others are severe enough to require hospital admission for diagnosis and therapy.

Causative organisms

Drugs used as markers of antimicrobial resistance

Staphylococcus aureus benzylpenicillin, oxacillin erythromycin, gentamicin

Streptococcus pneumoniae

benzylpenicillin as predicted by the oxacillin disc test

erythromycin chloramphenicol, sulfamethoxazole

trimethoprim

Streptococcus pyogenes

(benzylpenicillin)2

erythromycin

Haemophilus influenzae

ampicillin, chloramphenicol sulfamethoxazole, trimethoprim

by estimating beta-lactamase production

Neisseria gonorrhoeae

benzylpenicillin, tetracycline (ciprofloxacin1, ceftriaxone1)2

by estimating beta-lactamase production

Escherichia coli (UTI)

ampicillin, sulfamethoxazole trimethoprim, nitrofurantoin nalidixic acid, sulfonamide

(gentamicin))2

(fluoroquinolone)2, (cefalosporin)3 2

Salmonella typhi and other invasive Salmonella

ampicillin chloramphenicol

sulfamethoxazole, trimethoprim (fluoroquinolone)2, (cefotaxime)2

Shigella spp. ampicillin, sulfamethoxazole trimethoprim, tetracycline

(chloramphenicol)2, nalidixic acid4

(fluoroquinolone)2

Vibrio cholerae tetracyclines, sulfamethoxazole trimethoprim, nitrofurantoin

(erythromycin)2, (chloramphenicol)2

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Essential Drugs WHO Drug Information Vol. 7, No. 2, 1993

2. Hospital-acquired infections

These infections arise in patients who are either in hospital or who have recently been discharged from hospital. The causative organism is derived either from the patient's endogenous flora or from the flora which are endemic in the hospital.

Causative organisms

Drugs used as markers of antimicrobial resistance

Staphylococcus aureus

Coagulase-negative staphylococci

Enterococci

benzylpenicillin erythromycin, oxacillin

gentamicin, (vancomycin)2

benzylpenicillin erythromycin, oxacillin

gentamicin, (vancomycin)2

ampicillin, gentamicin (vancomycin)2

Pathogenic Gram-negative bacilli epidemic or endemic in hospitals including E. coli, Klebsiella spp., Salmonella, Enterobacter

Pseudomonas aeruginosa

ampicillin chloramphenicol

sulfamethoxazole trimethoprim

gentamicin, (fluoroquinolone)2

(cefalosporin3)

gentamicin, piperacillin, (fluoroquinolone)2

(ceftazidime)2

3. Laboratory facilities required

In most developing countries health laboratory services are generally organized at three levels:

1. Peripheral laboratories including those attached to health centres and first referral hospitals (district hospitals).

2. Intermediate level laboratories, situated in regional or provincial hospitals.

3. Central reference laboratories usually located in the capital city or in a university hospital. Facilities for bacteriological culture and suscepti­bility testing are generally not available at the peripheral level. Laboratory support in microbiology will be limited to microscopy and to some simple and rapid tests for the detection of antibodies (typhoid, syphilis) or antigens (meningitis, Chlamydia).

Most intermediate laboratories should have the facilities to culture, identify and establish the susceptibility of common pathogens such as Shigella, Salmonella spp., Vibrio cholerae, staphylococci, nosocomial Gram-negative bacilli, streptococci, meningococci, gonococci, pneumo¬ cocci and Haemophilus influenzae. Susceptibility testing should also be routinely performed at least for rapidly-growing pathogens. For fastidious bacteria, testing may be limited to rapid, inexpen­sive methods notably beta-lactamase testing of Haemophilus and gonococci and elementary or disc-test screening, using for instance oxacillin as a marker for penicillin resistance in pneumococci.

All isolates of Shigella, Salmonella and Vibrio spp. and representative isolates of pneumococci, H. influenzae, meningococci and gonococci should be forwarded to a central reference laboratory using an appropriate transport medium. Monitoring of Shigella, which should be undertaken on the basis of periodic epidemiological studies, necessitates equipment for refrigeration, confirmatory identifi­cation, and susceptibility testing.

4. Laboratory requirements at the

intermediate level

A special room should be available for bacterio­logical procedures. It should include a simple safety cabinet for handling cultures of dangerous patho­gens (e.g., S. typhi), and facilities for safe disposal of specimens and cultures.

The standard equipment should include:

• an autoclave;

1. Ciprofloxacin and ceftriaxone are reserve antimicrobials that are recommended for single-dose therapy of N. gonor­rhoeae infections where there is a high prevalence of resistance to first-line antimicrobials. 2. Compounds in parentheses indicate that results need to be reported to the clinician only when resistance is discov­ered in the listed antimicrobials. 3. Cefalosporin signifies a so-called "first-generation" cefalosporin such as: cefalotin to represent cefalotin, cefalexin and cefadroxil; or cefazolin to represent cefazolin, cefaclor. Use of wide-spectrum cefalosporin (ceftazidime) may be considered to assure recognition of an extended range of beta-lactamase mediated resistance. 4. Nalidixic acid is a reserve antimicrobial recommended for the treatment of shigellosis

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• an incubator thermostat regulated at 35 °C; • Bunsen burners or spirit lamps; • a refrigerator with freezer-compartment adequate

for correct storage of discs, prepared media, and some delicate reagents. Opened discs will retain potency for one month at 4-8 °C, while unopened disc stocks should be stored at below 8 °C.

In addition to the standard routine culture media needed for isolation and identification, the following media and materials are needed for disc diffusion testing:

• Mueller-Hinton agar from a reputable manufacturer;

• antimicrobial discs of the recommended potency; • barium chloride standard (0.5 McFarland, for

preparation of the inoculum); • sterile swabs for application of the inoculum; • ruler or calipers for measuring zone diameters of

inhibition; • standard bacterial strains for internal quality

control.

The following are additionally needed for testing fastidious organisms:

• a candle-jar; • blood, and XV or IsoVitaleX supplement for

preparation of Mueller-Hinton chocolate agar (for testing Haemophilus);

• GC agar, haemoglobin, XV or IsoVitaleX supplement for testing gonococci;

• blood agar (5% blood in Mueller-Hinton agar) for testing pneumococci;

• discs or other reagents for beta-lactamase testing.

5. Recommended testing method

Strict adherence to well-established techniques (Annex I) and regular quality control of media and reagents are necessary if reproducible and reliable results are to be assured. An unusual or unex­pected susceptibility result requires confirmation within a central reference laboratory.

The laboratory must be able to identify bacteria correctly and consistently (Annex IV) before undertaking susceptibility testing. This applies to common Gram-positive and Gram-negative bacteria, as well as more technically-demanding species.

Disc diffusion tests, which are both economical and simple to use (5), are widely employed for testing individual isolates of pathogens. Standardized

procedures must be carefully followed if tests are to hold comparative value. The refined Kirby-Bauer disc method has been carefully monitored by the United States National Committee for Clinical Labo­ratory Standards (NCCLS) and is widely used. It is satisfactory provided it is rigorously standardized. Several other methods have been described involving the use of controlled media, standard disc concentrations and strict compliance with agreed guidelines.

6. Methods of testing

Screening methods described in depth in other WHO publications (6), are recommended for susceptibility testing in intermediate laboratories. These involve inoculating standardized media with a lawn culture of a standardized inoculum of bacteria, followed by incubation in the presence of standardized antimicrobial discs, at 35 °C. The zone of inhibition around the antimicrobial disc is inversely proportional to the minimal inhibitory concentrations of the antimicrobial to the organism.

7. Pathogens to be tested

Most rapidly-growing aerobic bacteria of a non-fastidious nature can grow on Mueller-Hinton agar or other recommended susceptibility-test agars. For these organisms disc susceptibility testing is the most practical method. Other pathogens which could be considered for testing include the Enterobacteriaceae, Pseudomonas spp., enterococci, Neisseria meningitidis for penicillin resistance, and Streptococcus pyogenes for erythromycin resistance. The choice of other organisms for susceptibility testing is influenced by local factors. In serious invasive infections such as pneumococcal septicaemia or H. influenzae meningitis a test to confirm susceptibility to penicillin or ampicillin may avert the need to use expensive broad-spectrum antimicrobials.

Susceptibility testing of the following organisms should be undertaken in either an intermediate or central reference laboratory on the basis of their importance to the individual patient or to the region.

Salmonella typhi: All isolates should be identified and tested for antimicrobial susceptibility.

Salmonella (other than S. typhi): Isolates should be derived from specimens other than faeces. In addition, the susceptibility of faecal isolates should be monitored periodically.

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Shigella: Except in epidemic situations in which the causative organism has been confirmed, all isolates should be identified and tested for antimicrobial susceptibility.

Streptococcus pneumoniae: All invasive isolates and a selection of respiratory isolates should be identified and tested. Penicillin resistance may be moderate (0.12 to 1 mg/L) or high (>1 mg/L), and can be detected using 1µg oxacillin disc for screening. Penicillin resistance should be confirmed quantitatively in a central reference laboratory.

Staphylococcus aureus and coagulase-negative staphylococci: All isolates from wounds, pus or exudates should be identified and tested. Routine testing using oxacillin as the index drug is per­formed by a disc diffusion test on Mueller-Hinton agar. This requires:

(a) full 24-hour incubation;

(b) an ambient temperature not in excess of 35 °C;

(c) careful reading of colonies growing within the inhibition zone;

d) confirmation of methicillin resistance using Mueller-Hinton agar supplemented with 4% NaCI and 6 µg oxacillin.

Enterococci: Both E. faecalis and E. faecium can be identified to genus level by bile esculin. Both show some natural low-level resistance to amino­glycosides and a higher level of resistance to several other antimicrobials. Discs containing ≥120 µg gentamicin are required to detect the important strains exhibiting high-level gentamicin resistance (>500 mg/L MICs). Standard discs are available from several sources and the criteria for interpretation vary with the supplier.

Haemophilus influenzae: All invasive strains isolated from CSF or blood and a proportion of respiratory isolates should be tested. Special media are required. At intermediate level laboratories, tests for beta-lactamase can be performed to predict ampicillin resistance using either nitrocefin discs, a starch-iodine procedure or an acidimetric method. Chloramphenicol and sulfamethoxazole/ trimethoprim resistance is best detected by disc diffusion tests. These tests are best performed in central reference laboratories. The break point for chloramphenicol resistance is set at ≤ 2 mg chloramphenicol/l which is lower than that applied to other bacteria (≤ 8 mg/L).

N. gonorrhoeae: A sample of isolates should be tested annually, preferably in central reference laboratories. Testing should be conducted under atmospheric conditions using defined enrichment media. Beta-lactamase production can be detected using nitrocefin discs, starch-iodine procedure or an acidimetric method. Non-enzymic penicillin, tetra­cycline, ceftriaxone and fluoroquinolone-resistance can be detected by the disc-diffusion method.

Mycobacterium tuberculosis: Testing should be performed in a central reference laboratory with technical expertise in the identification and culture of mycobacterial species.

8. Guidelines for scoring bacterial susceptibility and resistance

There is no formal international agreement, as yet, on scoring for bacterial susceptibility or resistance. However, many countries have developed national standards based on a uniform methodology. In particular, NCCLS guidelines are in general use throughout the USA and in individual laboratories in some other countries. Other standards have been developed by Japan, Germany, Sweden and the United Kingdom. These standards demand the precise adoption of a specific method, including adherence to the prescribed medium, the antimicrobial content in the disc, the density of the inoculum, and the guidelines for interpreting the results.

At the present time, NCCLS methodologies, standards and guidelines (7) are the most extensively used and are regularly updated. For countries where standardized methods are not in use, they provide a suitable framework for implementation. In countries where other methods for detecting resistance are already well established and are known to be reliable, the applied disc methods can be supplemented by the tests listed in Annexes I and III. The interpretive criteria for the essential drugs indicated for resistance pattern monitoring are found in Annex II.

9. Quality assurance

Each laboratory performing antimicrobial susceptibility tests should have an internal, self-administered quality control procedure which should be followed, if possible, on a weekly basis. The selection of the strain will depend upon the organisms and antimicrobials tested, e.g., S. aureus

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ATCC 25923 should be selected when testing Gram-positive clinical isolates and E. coli ATCC 25922 should be selected when testing non-fastidious Gram-negative bacilli. The test results should be carefully recorded and possible causes for values outside prescribed limits should be investigated.

Some countries now additionally require labora­tories to submit to external proficiency tests involving the identification of potential pathogens as well as an assessment of the accuracy of susceptibility tests. These provide inter-laboratory comparison of organism identification as well as antimicrobial susceptibility-testing accuracy. All laboratories are encouraged to participate in such programmes.

References

1. WHO Technical Report Series No. 825. The use of essential drugs. Geneva, 1992.

2. WHO Technical Report Series No. 624. Surveillance for the prevention and control of health hazards due to antimicrobial-resistant enterobacterial report of a WHO meeting. Geneva, 1978.

3. Antimicrobial resistance. WHO Scientific Working Group. Bulletin of the World Health Organization, 61: 383-394 (1983).

4. WHO Technical Report Series No. 796. The use of essential drugs. Geneva, 1990.

5. WHO Technical Report Series No. 610. Twenty-eighth Report of the WHO Expert Committee on Biological Standardization, Annex 5. Geneva, 1977.

6. Vandepitte J. et al. Basic laboratory procedures in clinical bacteriology. WHO, Geneva, 1991.

7. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disc susceptibility tests - fourth edition: Approved Standard. NCCLS document M2-A5 and M100-S4. Villanova, PA: NCCLS, 1992 and 1993.

These proposed guidelines have been developed on the basis of an informal consultation convened by WHO involving the following participants:

Professor K. Engbaek, State Serum Institute, Copenhagen, Denmark Dr R. N. Jones (Rapporteur), University of Iowa, United States Professor Li Jia-Tai, Beijing Medical University, Beijing, China Dr F. Moosdeen, Universiti Kebangsaan, Bangi, Selangor, Malaysia Professor J.-C. Pechère, Centre Medical Universitaire, Geneva, Switzerland Dr Mrs Kunti Prakash, Lady Harding Medical College, New Delhi, India Professor K. Rahal, Institut Pasteur d'Algérie, Algiers, Algeria Professor J. Vandepitte, St Rafäel Academic Hospital, Leuven, Belgium Professor J. D. Williams (Chairperson), London Hospital Medical College, London, United Kingdom

Comments on this consultative document should be addressed to: Division of Drug Management and Policies

World Health Organization 1211 Geneva 27, Switzerland

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Essential Drugs WHO Drug Information Vol. 7, No. 2, 1993

Annex I: Disc diffusion method (brief outline)

I. Background, selective reporting, interpretive category definitions and media selection (see text and appropriate Annex).

A. Refer to references listed below for more detailed description of the procedures.

II. Medium preparation

A. Prepare Mueller-Hinton agar medium from a performance-tested lot according to manufacturer's recommendations.

B. Pour in 9-cm plates (25 to 30 ml) or 14-cm plates (60 to 70 ml).

C. Store at 2 to 8 °C, medium at pH 7.2-7.4.

III. Disc reagents/inoculum turbidity standard

A. Utilize commercially-prepared discs, stored at 8 °C or below.

B. Allow discs to reach room temperature before use and avoid excessive moisture accumulation.

C. Use 0.5 McFarland turbidity standard (BaCI2) stored in the dark and dispensed in 4 to 6 ml tubes which should be shaken before use.

IV. Procedure steps

A. Select 4 or 5 well-isolated colonies and prepare the inoculum by direct colony-to-broth mixing method, to be equal to the BaSO4 standard turbidity (critical step).

B. Inoculum should be prepared in saline or a clear broth.

C. Use a sterile cotton swab for inoculum delivery, removing excess fluid by pressing swab against inner side of tube.

D. Swab the plate surface for even distribution (three directions), allow to dry.

E. Place disks on agar surface, no closer than 24 mm apart: 1. Two to 6 discs on a 9-cm plate 2. Five to 11 discs on a 14-cm plate (lower disc numbers for fastidious species).

F. Incubate at 35 °C as follows: 1. Staphylococci 24 hours. 2. Haemophilus and Neisseria: 20 to 24 hours in 3 to 5% CO2 or in a candle-jar. 3. All other species: 16 to 18 hours.

G. Measure zones of inhibition to nearest mm, and interpret results with the assistance of tables provided (Annex II).

H. Record test and quality control results.

References

1. Antimicrobial susceptibility testing. In: Vandepitte, J. et al. (Eds). Basic laboratory procedures in clinical bacteriology. pp. 78-95. World Health Organization, Geneva, 1991.

2. Performance standards for antimicrobial disc susceptibility tests. M2-A5 Approved Standard. NCCLS, Villanova, PA., USA, 1993.

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WHO Drug Information Vol. 7, No. 2, 1993 Essential Drugs

Annex II: Disc diffusion test criteria (NCCLS method)

Antimicrobial agent Zone diameter in mm

Disc Susceptible* Inter- Resistant* content mediate*

Beta-lactams

Ampicillin when testing Gram-negative enteric organisms when testing enterococci when testing haemophilus

Oxacillin when testing staphylococci when testing pneumococci

for penicillin susceptibilitya

Benzylpenicillin when testing staphylococci when testing streptococci when testing N. gonorrhoeae c,d

Piperacillin

when testing P. aeruginosa

Cefazoline

Cefotaximee

Ceftazidimee

Ceftriaxonee

when testing N. gonorrhoeaeb,f

Cefalotine

Quinolones

Ciprofloxacin when testing Gram-negative enteric bacilli when testing N. gonorrhoeae b,f

Nalidixic acid

Other drugs

Chloramphenicol when testing Gram-negative enteric bacilli when testing haemophilus and pneumococci b,h

10 µg 10 µg 10 µg

1 µg

1 µg

10 units 10 units 10 units

100 µg

30 µg

30 µg

30 µg

30 µg

30 µg

5 µg 5 µg

30 µg

30 µg 30 µg

≥17 ≥17 ≥22

≥13

≥20

≥29 ≥28 ≥47

≥18

≥18

≥23

≥18

≥35

≥18

≥21 ≥36

≥19

≥18 ≥26

14-16

19-21

11-12

20-27 27-46

15-17

15-22

15-17

15-17

16-20

14-18

13-17

≤13 ≤16 ≤18

≤10

≤19

≤28 ≤19 ≤26

≤17

≤ 14

≤ 14

≤ 14

≤ 14

≤ 15

≤13

≤12 ≤25

* See note 1 on next page.

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Essential Drugs WHO Drug Information Vol. 7, No. 2, 1993

Annex II: Disc diffusion test criteria (continued)

Zone diameter in mm Antimicrobial agent

Disc Susceptible* Inter- Resistant* content mediate*

Erythromycin

Gentamicing

Nitrofurantoini

Tetracycline when testing Gram-negative enteric bacilli when testing N. gonorrhoeae c,d

Trimethoprim

Sulfonamides

Trimethoprim/sulfamethoxazole j

Vancomycin when testing enterococci when testing other Gram-positives b

* Note 1 : The three categories of antimicrobial susceptibilty are as follows:

Susceptible: the infection caused by the tested strain would probably respond to appropriate doses of that anti­microbial.

Resistant: the infection caused by the tested strain would not respond to therapy.

Intermediate: the organism's response to therapy is unpredictable.

(a) Oxacillin (representative for methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin) is preferred because of its superior stability to degradation in storage and the application to S. pneumoniae testing. Oxacillin resistance among staphylococci implies resistance to all beta-lactams (penicillins, cefalosponns, carbapenems and beta-lactase inhibitor combinations).

(b) Strains yielding zone diameter results suggestive of a non-susceptible category should be submitted to a reference laboratory for further testing.

(c) An intermediate category indicates a lower patient infection cure rate (85-95%) compared to more than 95% cure rates for susceptible strains.

(d) Gonococci with 10 unit penicillin disc zones of ≤19 mm are likely to be beta-lactamase producers. Similarly, tetracycline 30 µg disc zone diameters of ≤19 mm usually

indicate a plasmid-mediated PRNG strain (MIC correlate, ≥16mg/L).

(e) Choices for cefalosporin surveillance testing: cefalotin represents cefalotin, cefalexin and cefadroxil; cefazolin represents cefazolin and cefaclor; ceftazidime maximizes recognition of extended spectrum beta-lactamase mediated resistance; ceftriaxone is a reserve antimicrobial used for gonococcal testing only; and cefotaxime should be tested against salmonellae.

(f) For these drugs, the current rarity of well-documented resistant strains precludes defining any category other than susceptible.

(g) Testing for high-level aminoglycoside resistance should be performed by the agar dilution method (BHI medium) with a screening concentration of 500 mg gentamicin/L. Alternative high-content gentamicin discs (>100 µg content) may be available for this purpose in some geographic areas. Local product criteria should be applied.

(h) These criteria were modified from those utilized by the NCCLS for use in laboratories in developing countries, i.e., no intermediate category.

(i) Used to predict susceptibility to furazolidone,

(j) Also designated co-trimoxazole.

76

15µg

10 µg

300 µg

30 µg 30 µg

5 µg

300 µg

1.25 µg/ 23.75 µg

30 µg 30 µg

≥23

≥15

≥17

≥19 ≥38

≥16

≥17

≥16

≥17 ≥ 12

14-22

13-14

15-16

15-18 31-37

11-15

13-16

11-15

15-16 10-11

≤ 13

≤ 12

≤ 14

≤ 14 ≤30

≤10

≤ 12

≤ 10

≤ 14 ≤ 9

WHO Drug Information Vol. 7, No. 2, 1993 Essential Drugs

Annex III: Quality control guidelines for disc diffusion tests

Zone diameter limits for control strains

Disc E. coli S. aureus H. N. gonor- P. Antimicrobial agent content ATCC25922 ATCC25923 influenzae rhoeae aeruginosa

ATCC49247 ATCC35218 ATCC35218

Ampicillin

Oxacillin

Benzylpenicillin

Piperacillin

Cefazolin

Cefotaxime

Ceftazidime

Ceftriaxone

Cefalotin

Ciprofloxacin

Nalidixic acid

Chloramphenicol

Erythromycin

Gentamicin

Nitrofurantoin

Sulfonamides

Tetracycline

Trimethoprim

Trimethoprim/ sulfamethoxazole

Vancomycin

10 µg

1 µg

10 units

100µg

30 µg

30 µg

30 µg

30 µg

30 µg

5 µ g

30 µg

30 µg

15 µg

10 µg

300 µg

300 µg

30 µg

5 µ g

1.25 µg/ 23.75 µg

30 µg

16-22

24-30

23-29

29-35

25-32

29-35

17-22

30-40

22-28

21-27

19-26

20-25

18-26

18-25

21-28

24-32

27-35

18-24

26-37

29-35

25-31

16-20

22-28

29-37

22-30

19-26

22-30

19-27

18-22

24-34

19-28

19-26

24-32

15-19

13-21

31-39

27-35

31-39

34-42

31-40

24-32

26-34

34-38

39-51

48-58

30-42

25-33

18-22

22-29

17-23

25-33

16-21

Note 1 : Quality control tests should be performed at least weekly if organisms are processed on a daily basis. However, if testing is infrequent and/or irregularly performed, quality control strains (one or more) should be processed concur­rently with the clinical isolate tests. Note 2: These quality control ranges were suggested for use with Mueller-Hinton agar (E. coli and S. aureus preferred). Note 3: Quality control zone guidelines are listed to assist intermediate and central reference laboratories wishing to test Haemophilus and gonococci. The zone diameter ranges were derived for tests on Haemophilus test medium (HTM) and supplemented GC agar respectively.

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Essential Drugs WHO Drug Information Vol. 7, No. 2, 1993

Annex IV: Minimum identification features

Principal pathogens which require accurate identification to monitor the resulting antimicrobial susceptibility are listed below. The minimum identification characteristics and tests are also presented. These conform to those listed in WHO's Basic Laboratory Procedures in Clinical Bacteriology, and other widely-recognized reference material.

Organism Minimum identification features Organism Minimum identification features

Staphylococcus aureus

Coagulase-negative staphylococcus

Gram-positive cocci in clusters

catalase-positive coagulase-positive

Gram-positive cocci in clusters

catalase-positive coagulase-negative

S. pneumoniae Gram-positive oval-shaped cocci in diplo or short chains

alpha (green) haemolytic colonies catalase-negative

bile solubility or optochin disc susceptibility

S. pyogenes (group A) Gram-positive cocci in chains

beta-haemolytic colonies catalase-negative

bacitracin (0.04 µg) disc-susceptibile sulfamethoxazole/trimethoprim

(23.75 µg/1.25 µg) disc-resistant

Enterococci Gram-positive cocci in diplo or short chains

catalase-negative1

bile-esculin hydrolysis growth in 6.5% NaCI broth

H. influenzae Gram-negative, slender cocco-bacilli "satelliting" colonies

around colonies of Staphylococci

no growth on blood-free media

N. gonorrhoeae Oval Gram-negative diplococci with

concave opposing edges and long axes parallel

oxidase-positive growth on selective GC media

(Continued on next column)

no growth on nutrient agar maltose not fermented

(gamma-glutamyl-aminopeptidase negative)

N. meningitidis Oval Gram-negative diplococci with concave opposing edges

and long axes parallel oxidase-positive

growth on selective GC media no growth on nutrient agar

maltose fermented (gamma-glutamyl-

aminopeptidase positive)

E. coli Gram-negative, non-motile rods indole-positive

acid slant, gas is produced, H2S-negative (TSI)

[beta-glucuronidase-positive (PGUA)]

Klebsiella spp. Gram-negative, non-motile rods indole-negative (except K. oxytoca)

lysine-positive (LIA) acid slant, gas is produced,

H2S-negative (TSI)

Salmonella spp. Gram-negative motile rods acid butt, alkaline

or neutral slant, gas is produced except S typhi (TSI)

lysine-positive except S. paratyphi A (LIA slant)

H2S-positive except S. paratyphi A (TSI and LIA slant)

Shigella spp. Gram-negative non-motile rods lysine-negative

oxidase-negative acid butt, alkaline or neutral slant,

no gas production except some strains in a few serotypes,

no H2S production (TSI)

1. Some strains may produce a pseudocatalase.

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WHO Drug Information Vol. 7, No. 2, 1993

Recent Publications

Pharmacists in Europe The Council of Europe, which was founded in 1949, is a political organization that promotes collabora­tion between its 27 Member States* in the interest of greater European unity. Its aims are to uphold the principles of parliamentary democracy and human rights; and to improve living conditions and promote human values. It has a Committee of Ministers and an Assembly composed of members of national parliaments. Its decisions take the form either of policy statements proposing a common course of action to be followed, or of conventions and agreements which are binding on the states that ratify them. Its competence is very wide, covering practically all aspects of European affairs, with the exception of defence matters.

In 1959, a "partial agreement" was concluded between seven member states (Belgium, France, Federal Republic of Germany, Italy, Luxembourg, Netherlands, and the United Kingdom). This aims, inter alia, to protect public health, with particular respect to consumer health, and to harmonize national health legislation. This work is entrusted to committees consisting of members who are both expert in the field in question and responsible for the implementation of government policy in their national ministries. These bodies draw up statements of policy or common guidelines for national policy-makers which are adopted by a Committee of Ministers composed of represen­tatives of Member States participating in the particular activity. Each government is free to interpret these guidelines in accordance with its own law and practice but it is expected to report back periodically on its implementation of the measures recommended.

This procedure provides for considerable flexibility in two respects. Any state may reserve its position on a given point without impeding the others in what they consider to be appropriate; and recom-

* Austria, Belgium, Bulgaria, Cyprus, Denmark, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Liechtenstein, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, San Marino, Spain, Sweden, Switzerland, Czechoslovakia, Turkey and the United Kingdom

mendations may be readily amended in the light of technical evolution and scientific progress.

Among the longest established of these bodies is the Committee of Experts on Pharmaceutical Questions. Currently supported by 12 Member States, it has been influential since its inception in the classification and standardization of medicinal products, the control of narcotic substances, and the control of media advertising. Its latest report, which focuses on the role and training of com­munity pharmacists, is distilled from a seminar convened in 1991 in which over 200 pharmacists drawn from all Member States of the Council of Europe participated. Given the ubiquitous need to expand pharmacy services at community level in countries at all stages of development, the proposals for action that the Committee has identified have relevance far outside the European region. The following precis provides an indication of the scope and orientation of the document.

The aim of the basic course of education in pharmacy is to provide a durable foundation for a lifetime of practice directed to the effective and rational use of medicines. The professional value of an initial period of joint training with students of other health professions should be considered. Advances in knowledge and changes in practice across a broad technical front, both pharmaceutical and medical, creates a mandatory need for continued in-post training to assure efficient career development.

Community pharmacy, it is emphasized, should be structured to serve the needs of the consumer. Pharmacists should promote a healthy lifestyle, facilitate the treatment of minor ailments, dispense prescription medicines and advise patients on their appropriate use. Legal controls and ethical precepts should provide for the exercise of reasonable professional discretion, and remuneration should be arranged to preclude the interests of the consumer being compromised by financial considerations.

Community pharmacies constitute the channel through which medicines are distributed to the local community. Expensive hospital facilities and beds can be freed by organizing flexible delivery of services to patients at home. An integrated

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Recent Publications WHO Drug Information Vol. 7, No. 2, 1993

approach to primary and secondary care is needed to reflect and encourage this trend. Access to medicines should not be unduly restricted by legal classification. There should be good reasons — such as toxicity or potential for abuse — that are based on considerations of public health, for subjecting products to prescription control.

Self-medication is an integral part of health care. Resources need to be provided to develop the pharmacist's competence and facilities to deal with minor illness and to refer patients to medical practitioners as occasion demands. Collaboration and training involving all relevant groups of health professionals are needed to develop broad agreement on treatment strategies and protocols.

The community pharmacist is crucially placed both to provide and generate information about the rational use of drugs. The pharmacy should be a source for both health professionals and patients to obtain technical and economic information about medicinal products. Pharmacists need to reinforce the doctor's message by fostering understanding and encouraging a positive attitude in patients about their medicines. Good adherence to therapeutic regimens is crucial in maintaining many patients within the community rather than in institutional care. Pharmacists are well placed both

to ensure that patients make best use of prescribed medicines and to reduce wastage.

Trained pharmacists possess a potential for involvement in more sophisticated screening and counselling of patients, particularly in connection with drug abuse, HIV infection and other trans­missible diseases. Given the necessary initiative, they can also provide a natural focus for the conduct of drug monitoring studies and field research on drug use. A tradition of research in community practice has yet to become securely established.

Viewed in a global perspective, these are formidable objectives, particularly where the profession of pharmacy remains tenuously established. As the report emphasizes, wherever they are secured they must be retained in focus. Without a review framework established by the appropriate health authorities and professional bodies, and an audit process based on a range of performance indicators, there can be no lasting assurance that yesterday's goals meet contem­porary needs.

Council of Europe. Seminar on the role and training of community pharmacists. Council of Europe Press, 1993. ISBN 92 871 2296 2.

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WHO Drug Information, Vol. 7, No. 2, 1993

International Nonproprietary Names for Pharmaceutical Substances (INN)

Proposed International Nonproprietary Names: List 69 Lists of proposed (1-65) and recommended (1-31) international nonproprietary names can be found in Cumulative List No. 8, 1992.

*Action and Use: The statements in italics indicating the action and use are based largely on information supplied by the manufacturer. The information is meant to provide an indication of the potential use of new substances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors will be neither revised nor included in the Cumulative Lists of INNs.

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

Comments on, or formal objections to, the proposed names may be forwarded by any person to the INN Programme of the World Health Organization within four months of the date of their publication in WHO Drug Information, i.e., for List 69 Proposed INN not later than 31 January 1994.

Proposed International Nonproprietary Name (Latin, English)

Chemical Name or Description; Molecular and Graphic formulae Chemical Abstracts Service (CAS) registry number Action and Use*

alvirceptum sudotoxum alvircept sudotox

N2-L-methionyl-1-178-antigen CD 4 (human clone pT4B protein moiety reduced) (178-248')-protein with 248-L-histidine-249-L-methionine-250-L-alanine-251-L-glutamic acid-248-613-exotoxin A (Pseudomonas aeruginosa reduced) C2600H4130N748O812S10 137487-62-8 antiviral

aranidipinum aranidipine

(±)-acetonyl methyl 1,4-dihydro-2,6-dimethyl-4-(o-nitrophenyl)-3,5-pyridinedi= carboxylate C19H20N2O7 86780-90-7 calcium channel blocker

81

Proposed International Chemical Name or Description; Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

atevirdinum atevirdine

1-[3-(ethylamino)-2-pyridyl]-4-[(5-methoxyindol-2-yl)carbonyl]piperazine C21H25N5O2 136816-75-6 antiviral

azelnidipinum azelnidipine

3-[1 -(diphenylmethyl)-3-azetidinyl] 5-isopropyl (±)-2-amino-1,4-dihydro-6-methyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate C33H34N4O6 123524-52-7 calcium channel blocker

beciparcilum beciparcil

p-[(5-thio-β-D-xylopyranosyl)thio]benzonitrile C12H13NO3S2 130782-54-6 antithrombotic

biapenemum biapenem

6-[[(4R,5S,6S)-2-carboxy-6-[(1 R)-1 -hydroxyethyl]-4-methyl-7-oxo-1 -aza= bicyclo[3.2.0]hept-2-en-3-yl]thio]-6,7-dihydra-5H-pyrazolo[1,2-a]-s-triazol-4-ium hydroxide, inner salt C15H18N4O4S 120410-24-4 antibacterial

carvotrolinum carvotroline

8-fluoro-2,3,4,5-tetrahydro-2-[2-(4-pyridyl)ethyl]-1H-pyrido[4,3-bJ indole C18H18FN3 107266-08-0 antipsychotic

cedefingolum cedefingol

N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)heptadecyl]acetamide C20H41NO3 35301-24-7 antipsoriatic

82

Proposed International Chemical Name or Description; Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

ciprokirenum ciprokiren

darglitazonum darglitazone

(αS)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-a-[(αS)-α-[[[1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]melhyl]hydrocinnam= amido]imidazole-4-propionamide C37H55N5O8S 143631-62-3 renin inhibitor

(±)-5-[p-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]benzyl]-2,4-thiazolidinedione C23H20N2O4S 141200-24-0 hypoglycaemic

edobacomabum edobacomab

immunoglobulin M (mouse monoclonal XMMEN-0E5 anti-endotoxin), disulfide with mouse monoclonal XMMEN-0E5 light chain, pentameric dimer

141410-98-2 immunomodulator

epristeridum epristeride

17β-(tert-butylcarbamoyl)androsta-3,5-diene-3-carboxylic acid C25H37NO3 119169-78-7 testosterone reductase inhibitor

fananserinum fananserin

2-[3-[4-(p-fluorophenyl)-1-piperazinyl]propyl]-2H-naphth[1,8-cd]isothiazole 1,1-dioxide C23H24FN3O2S 127625-29-0 serotonin receptor antagonist

83

Proposed International Chemical Name or Description; Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

ferpifosatum natricum ferpifosate sodium

hexasodium tris[(4,5-dihydroxy-6-methyl-3-pyridinemethanol 3-phosphato)(3-)-O3,O3,O5]ferrate(6-) C21H21 FeNa6N3O18P3 138708-32-4 magnetic resonance contrast medium

flocalcitriolum flocalcitriol

(+)-(5Z,7E)-26,26,26,27,27,27-hexafluoro-9,10-secocholesta-5,7,10(19)-triene-1α,3β,25-triol C27H38F6O3 83805-11-2 vitamine D3 analogue

fosopaminum fosopamine

4-[2-(methylamino)ethyl]pyrocatechol 1-(dihydrogen phosphate) C9H14NO5P 103878-96-2 dopamine receptor agonist

fropenemum fropenem

(+)-(5R,6S)-6-[(1 R)-1 -hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furyl]-4-thia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid C12H15NO5S 106560-14-9 antibiotic

iliparcilum iliparcil

4-ethyl-7-[(5-thio-β-D-xylopyranosyl)oxy]coumarin C16H18O6S 137214-72-3 antithrombotic

84

Proposed International Chemical Name or Description; Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

iloperidonum iloperidone

4'-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3'-methoxyaceto= phenone C24H27FN2O4 133454-47-4 antipsychotic

lemildipinum lemildipine

3-isopropyl 5-methyl (±)-4-(2,3-dichlorophenyl)-1,4-dihydrc-2-(hydroxymethyl)-6-methyl-3,5-pyridinedicarboxylate, carbamate (ester) C20H22Cl2N2O6 125729-29-5 calcium channel blocker

lerisetronum lerisetron

1 -benzyl-2-(1 -piperazinyl)benzimidazole C18H20N4 143257-98-1 antiemetic

limazocicum limazocic

(-)-(R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid C8H13NO3S2 128620-82-6 hepatoprotective

linotrobanum linotroban

[[5-(2-benzenesulfonamidoethyl)-2-thienyl]oxy]aceticacid C14H15NO5S2 120824-08-0 antithrombotic

85

Proposed International Chemical Name or Description; Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

lurosetronum lurosetron

6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methylimidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1 -one C17H17FN4O 128486-54-4 antiemetic

merafloxacinum merafloxacin

(±)-1 -ethyl-7-[3-[(ethylamino)methyl]-1 -pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid C19H23F2N3O3 110013-21-3 antibacterial (veterinary)

mofegilinum mofegiline

(E)-2-(fluoromethylene)-4-(p-fluorophenyl)butyiamine C11H13F2N 119386-96-8 antiparkinsonian

naralriptanum naratriptan

N-methyl-3-(1-methyl-4-piperidyl)indole-5-ethanesulfonamide C17H25N3O2S 121679-13-8 antimigraine

olradipinum olradipine

3-ethyl 5-methyl (±)-2-[[2-(2-aminoethoxy)ethoxy]methyl]-4-(2,3-dichlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate C22H28CI2N2O6 115972-78-6 calcium channel inhibitor

86

Proposed International Chemical Name or Description; Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

ormeloxifenum ormeloxifene

(±)-1-[2-[p-(frans-7-methoxy-2,2-dimethyl-3-phenyl-4-chromanyl)phenoxy]ethyl]= pyrrolidine C30H35NO3 78994-24-8 oral contraceptive

and enantiomer

patamostatum patamostat

p-[(2-succinimidoethyl)thio]phenyl p-guanidinobenzoate C20H20N4O4S 114568-26-2 protease inhibitor

pimagedinum pimagedine

aminoguanidine CH6N4 79-17-4 aldose reductase inhibitor

rabeprazolum rabeprazole

2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]benzimidazole C18H21N3O3S 117976-89-3 antiulcer

reteplasum reteplase

173-L-serine-174-L-tyrosine-175-L-glutamine-173-527-plasminogen activator (human tissue-type) C1736H2653N499O522S22 133652-38-7 trombolytic

safingolum safingol

(2S,3S)-2-amino-1,3-octadecanediol C18H39NO2 15639-50-6 antipsoriatic

saquinavirum saquinavir

(S)-N-[(αS)-α-[(1R)-2-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydro-2(1R)-isoquinolyl]-1-hydroxyethyl]phenethyl]-2-quinaldamido succinamide C38H50N6O5 127779-20-8 antiviral

87

Proposed International Chemical Name or Description; Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

selfotelum selfotel

sibopirdinum sibopirdine

sirolimusum sirolimus

cis-4-(phosphonomethyl)pipecolic acid C7H14NO5P 110347-85-8 N-methyl-D-aspartate antagonist

5,5-bis(4-pyridylmethyl)-5H-cyclopenta[2,1 -b:3,4-b']dipyridine C23H18N4 122955-18-4 nootropic agent

(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13, 14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1 S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1 -methylelhyl]-10,21 -dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohen= triacontine-1,5,11,28,29(4H,6H,31 H)-pentone C51H79NO13 53123-88-9 immunosuppressant

somatosalmum somatosalm

somatotropin (Oncorhyncus mykiss clone ptGH-ll isoform II reduced) C952H1524N266O290S8 123212-08-8 growth hormone

suritozolum suritozole

3-(m-fluorophenyl)-1,4-dimethyl-A2-1,2,4-triazoline-5-thione C10H10FN3S 110623-33-1 antidepressant

88

Proposed International Chemical Name or Description; Molecular and Graphic formulae Nonproprietary Name Chemical Abstracts Service (CAS) registry number (Latin, English) Action and Use*

ularitidum ularitide

L-threonyl-L-aianyl-L-prolyl-L-arginyl-L-seryl-L-leucyl-L-arginyl-L-arginyl-L-seryl-L-seryl-L-cysteinyl-L-phenylalanylglycylglycyl-L-arginyl-L-methionyl-L-aspartyl-L-arginyl-L-isoleucylglycyl-L-alanyl-L-glutaminyl-L-serylglycyl-L-leucylglycyl-L-cysteinyl-L-asparaginyl-L-seryl-L-phenylalanyl-L-arginyl-L-tyrosine cyclic (11 -27)-disulfide C145H234N52O44S3 118812-69-4 diuretic

valaciclovirum valaciclovir

L-valine, ester with 9-[(2-hydroxyethoxy)methyl]guanine C13H20N6O4 124832-26-4 antiviral

vebufloxacinum vebufloxacin

(±)-9-fluoro-6,7-dihydro-5-methyl-8-(4-methyl-1 -piperazinyl)-1 -oxo-1 H, 5H-benzo[ij]quinolizine-2-carboxylic acid C19H22FN3O3 79644-90-9 antibacterial

zolimomabum aritoxum zolimomab aritox

immunoglobulin G 1 (mouse monoclonal H65-RTA anti-human antigen CD 5 heavy chain), disulfide with mouse monoclonal H65-RTA light chain, dimer, disulfide with ricin (castor-oil plant A-chain protein moiety)

141483-72-9 immunomodulator

Names for Radicals and Groups

Some substances for which a proposed international nonproprietary name has been established may be used in the form of salts or esters. The radicals or groups involved may be of complex composition and it is then inconvenient to refer to them in systematic chemical nomenclature. Consequently, shorter nonproprietary names for some radicals and groups have been devised or selected, and they are suggested for use with the proposed international nonproprietary names.

epolaminum epolamine

1-pyrrolidineethanol C6H13NO 2955-88-6

89

AMENDMENTS TO PREVIOUS LISTS

Supplement to WHO Chronicle Vol. 33, No. 3, 1979

Proposed International Nonproprietary Names (Prop. INN): List 41 p. 11 pipecuronii bromidum

pipecuronium bromide replace the chemical name, the graphic formula and the CAS registry number by the following: 4,4 '-(3α,17β-dihydroxy-5α-androstan-2β, 16β-ylene)bis[1,1 -dimethylpiperazinium] dibromide, diacetate (ester) C35H62Br2N4O4 52212-02-9

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

Proposed International Nonproprietary Names (Prop. INN): List 46 p. 2 adrafinilum

adrafinil replace the graphic formula by the following:

Supplement to WHO Chronicle Vol. 40, No. 1, 1986

Proposed International Nonproprietary Names (Prop. INN): List 55 p. 4 bropiriminum

bropirimine replace the chemical name and the graphic formula by the following: 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone

90

Supplement to WHO Chronicle Vol. 40, No. 5, 1986

Proposed International Nonproprietary Names (Prop. INN): List 56

p. 8 fosinoprilum fosinopril

replace the chemical name, the graphic formula and the CAS registry number by the following: (4S)-4-cyclohexyl-1-[[(R)-[(S)-1-hydroxy-2-methylpropoxy](4-phenylbutyl)= phosphinyl]acetyl]-L-proline propionate (ester) 98048-97-6

WHO Drug Information, Vol. 6, No. 2, 1992

Proposed International Nonproprietary Names (Prop. INN): List 67

p. 6 delete masnidipinum masnidipine

insert iercanidipinum lercanidipine

WHO Drug Information, Vol. 6, No. 4, 1992

Proposed International Nonproprietary Names (Prop. INN): List 68

p. 3

p. 6

p. 8

bizelesinum bizelesin

glemanserinum glemanserin

leminoprazolum leminoprazole

replace the molecular formula by the following: C43H36Cl2N8O5

replace the CAS registry number by the following: 132553-86-7

replace the graphic formula by the following:

p. 9 orbifloxacinum orbifloxacin

replace the graphic formula by the following:

91

p. 10 ramorelixum ramorelix

replace the CAS registry number and the graphic formula by the following:

127932-90-5

p. 14 troglitazonum troglitazone

replace the graphic formula by the following:

92

1:1 mixture of

and enantiomer

with

and enantiomer

WHO Drug Information, Vol. 7, No. 2, 1993

Annex 1

PROCEDURE FOR THE SELECTION OF RECOMMENDED INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES*

The following procedure shall be followed by the World Health Organization in the selection of recommended interna­tional nonproprietary names for pharmaceutical substances, in accordance with the World Health Assembly resolution WHA 3.11:

1. Proposals for recommended international nonproprietary names shall be submitted to the World Health Organization on the form provided therefor.

2. Such proposals shall be submitted by the Director-General of the World Health Organization to the members of the Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations designated for this purpose, for consideration in accordance with the "General principles for guidance in devising International Nonproprietary Names", appended to this procedure. The name used by the person discovering or first developing and marketing a pharmaceutical substance shall be accepted, unless there are compelling reasons to the contrary.

3. Subsequent to the examination provided for in article 2, the Director-General of the World Health Organization shall give notice that a proposed international nonproprietary name is being considered.

A. Such notice shall be given by publication in the Chronicle of the World Health Organization1 and by letter to Member States and to national pharmacopoeia commissions or other bodies designated by Member States.

(i) Notice may also be sent to specific persons known to be concerned with a name under consideration.

B. Such notice shall:

(i) set forth the name under consideration;

(ii) identify the person who submitted a proposal for naming the substance, if so requested by such person;

(iii) identify the substance for which a name is being considered;

(iv) set forth the time within which comments and objections will be received and the person and place to whom they should be directed;

(v) state the authority under which the World Health Organization is acting and refer to these rules of procedure.

C. In forwarding the notice, the Director-General of the World Health Organization shall request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the proposed name during the period it is under consideration by the World Health Organization.

4. Comments on the proposed name may be forwarded by any person to the World Health Organization within four months of the date of publication, under article 3, of the name in the Chronicle of the World Health Organization.1

5. A formal objection to a proposed name may be filed by any interested person within four months of the date of publication, under article 3, of the name in the Chronicle of the World Health Organization.1

A. Such objection shall:

(i) identify the person objecting;

* Text adopted by the Executive Board of WHO In resolution EB15.R7 (Off. Rec. Wld Health Org., 1955. 60, 3) and amended by the Board in resolution EB43.H9 (Off. Rec. Wld HIth Org., 1969,173,10). 1 The title of this publication was changed to WHO Chronicle In January 1959. From 1987 onwards lists of INNs are published In WHO Drug Information.

93

WHO Drug Information, Vol. 7, No. 2, 1993

6. The use of an isolated letter or number should be avoided; hyphenated construction is also undesirable.

7. To facilitate the translation and pronunciation of INN, "f" should be used instead of "ph", "t" instead of "th", "e" instead of "ae" or "oe", and " i " instead of "y"; the use of the letters "h" and "k" should be avoided.

8. Provided that the names suggested are in accordance with these principles, names proposed by the person discovering or first developing and marketing a pharmaceutical preparation, or names already officially in use in any country, should receive preferential consideration.

9. Group relationship in INN (see Guiding Principle 2) should if possible be shown by using a common stem. The following list contains examples of stems for groups of substances, particularly for new groups. There are many other stems in active use.1 Where a stem is shown without any hyphens it may be used anywhere in the name.

Latin English

-acum -actidum -adolum -adol--astum -astinum -azepamum -bactamum bol -buzonum -cain--cainum cef--cillinum -conazolum cort -dipinum -fibratum gest gli-io--ium -metacinum -mycinum -nidazolum -ololum -oxacinum -pridum -pril(at)um -profenum prost -relinum -terolum -tidinum -trexatum -verinum vin--vin-

-ac -actide -adol ) -adol- ) -ast -astine -azepam -bactam bol -buzone -cain--caine cef--cillin -conazole cort -dipine -fibrate gest gli-io--ium -metacin -mycin -nidazole -olol -oxacin -pride pril(at) -profen prost -relin -terol -tidine -trexate -verine vin- ) -vin- )

anti-inflammatory agents of the ibufenac group synthetic polypeptides with a corticotrophin-like action analgesics anti-asthmatic, anti-allergic substances not acting primarily as antihistaminics antihistaminics substances of the diazepam group β-lactamase inhibitors steroids, anabolic anti-inflammatory analgesics of the phenylbutazone group antifibrillant substances with local anaesthetic activity local anaesthetics antibiotics, derivatives of cefalosporanic acid antibiotics, derivatives of 6-aminopenicillanic acid systematic antifungal agents of the miconazole group corticosteroids, except those of the prednisolone group calcium antagonists of the nifedipine group substances of the clofibrate group steroids, progestogens sulfonamide hypoglycemics iodine-containing contrast media quaternary ammonium compounds anti-inflammatory substances of the indometacin group antibiotics, produced by Streptomycas strains antiprotozoal substances of the metronidazole group β-adrenergic blocking agents antibacterial agents of the nalidix acid group sulpiride derivatives angiotensin-converting enzyme inhibitors anti-inflammatory substances of the ibuprofen group prostaglandins hypophyseal hormone release-stimulating peptides bronchodilators, phenethylamine derivates H2-receptor antagonists folic acid antagonists spasmolytics with a papaverine-like action vinca type alkaloids

1 A more extensive listing of stems is contained in the working document Pharm. S/Nom.15 which is regularly updated and can be requested from Pharmaceuticals, WHO, Geneva.

95

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)

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

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

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

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

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

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

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

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

10.-

1 1 . -

2 1 . -

9. -

11 . -

24.-36.-64.-

34.-

24.-

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.