WHO Drug Information Vol. 10, No. 2, 1996 Reports on Individual Drugs

22. Nosten, F., ter Kuile, F., Luxemburger, C. et al. factor determining the progression of ALS could be Cardiac effects of antimalarial treatment with halofantrine. overproduction or abnormal metabolism of glut­ Lancet, 341: 1054-56 (1993). amine resulting in toxic accumulation in presynaptic 23. Karbwang, J., Na-Bangchang, K., Thanavibul, A. et cells (2). al. Comparison of oral artesunate and quinine plus tetracycline in acute uncomplicated falciparum malaria. The scientific data on which the advisory group's Bulletin of the World Health Organization, 72: 233-38 decision was based have now been published. (1994). They derive from a double-blind, placebo­ controlled, multicentre study (4) and a smaller 24. Martin, G., Malone, J., Ross, E. Exfoliative dermatitis preliminary trial (5). The larger study involved some during malarial prophylaxis with mefloquine. Clinical and Infectious Diseases, 16:341-2 (1993). 950 patients with a disease history of less than 5 years' duration who were recruited from many 25. van den Enden, E., van Gompel, A., Colebunders, R. neurological clinics within seven countries in North et al. Mefloquine-induced Stevens-Johnson syndrome. America and Western Europe. These patients were Lancet, 337: 683 (1991). randomly assigned either to placebo or to 50 mg, 100 mg, or 200 mg riluzole daily. After treatment for 26. Shlim, D. Severe facial rash associated with meflo­ a median period of 18 months, the proportion of quine. Journal of the American Medical Association, 266: patients surviving without tracheostomy ranged in 2560 (1991 ). dose-related order from 50.4% (placebo) to 57.8% 27. Scerri, L., Pace J. Mefloquine-associated cutaneous (200 mg riluzole). After adjustment for pre­ vasculitis. International Journal of Dermatology, 32: 517- determined prognostic factors, the overall drug 518 (1993). effect was shown to be modest - but statistically significant- and stable throughout the period of 28. Danis, M., Nozais, J., Paris, L. et al. Fievre bilieuse follow-up. haemoglobinurique apres prise de mefloquine. 3 observations. Presse Medica/e. 22: 80 (1993). The marginal added benefit of the 200 mg dose was offset by a moderately increased incidence of dizziness, diarrhoea, anorexia, and also in oc­ Riluzole for amyotrophic casional rises in hepatic transaminases sufficient to lateral sclerosis warrant withdrawal of treatment. A tendency, seen in the preliminary trial, for riluzole to increase In September 1995, an advisory committee to the spasticity and to raise blood pressure, was not US Food and Drug Administration narrowly agreed evident, and no reason is offered to explain this. lt to recommend approval of riluzole- (Rilutek®, is notable that, in the initial study, weakness and Rhone-Poulenc Roher), a benzothiazole with anti­ debility was a principal reason for withdrawal of convulsant activity which is claimed to possess treatment (5). This adverse effect was anticipated "neuroprotective properties" (1)- in the manage­ since it has been claimed that antiglutamate ment of amyotrophic lateral sclerosis (ALS) (2). agents, as a class, have muscle-relaxant activity (6). The same effect occurred in the definitive study ALS is an insidious, progressive and ultimately fatal but on this occasion policy was changed "to disease of the central nervous system which occurs maintain patients on treatment and to continue typically in late middle age and with greater fre­ assessments even in the presence of asthenia". quency in men. lt results from degeneration of both upper and lower motor neurones, and it is charac­ Although increased survival was demonstrated terized clinically by a mixed picture of spasticity and within this study, the effect of treatment on the progressive muscular atrophy. In the United States, quality of life evidently remains uncertain. The the disease affects some 30 000 people at any one conclusion of the participating investigators is that time and, worldwide, the number of cases is "psychological well-being is enhanced by the claimed to be increasing (2). availability of a treatment that is safe and well­ tolerated, and has a proven effect on the disease, Various suggestions have been offered to explain, in contrast to many drugs (some of them unsafe) to in pharmacological terms, some of the experi­ which many thousands of patients have been mentally-induced central nervous effects of riluzole. exposed over the years". Riluzole, for instance, interferes with glutamate metabolism in laboratory animals (3), and it has The investigators also emphasize that the wide been suggested, without confirmation, that one variation in survival time among patients with ALS

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suggests that multiple factors are involved in deter­ 9. Harrington, C., Louwagie, J., Rossau, R. et al. Influence mining the disease and its clinical course. lt has of apolipoprotein E genotype on senile dementia of the been proposed that the premature decline in Alzheimer and Lewy body types. American Journal of neuronal function which characterizes all the Pathology, 145: 1472-1484 (1994). common neurodegenerative diseases­ 10. AI-Chalabi, A., Enayat, Z., Bakker, M. et al. Associa­ Parkinson's disease, Alzheimer's disease, and tion of apoprotein E e4 allele with bulbar-onset rnotor motor-neurone disease- results from interplay neurone disease. Lancet, 347: 159-160 (1996). between environmental insults (such as infections or neurotoxins) and the normal ageing process (7). 11. Rempfer, R., Crook, R., Houlden, H. et al. Parkinson's Alternatively, it has been suggested that these disease, but not Alzheimer's disease, Lewy body variant conditions represent different phenotypic associated with mutant alleles at cytochrome P450 gene. expressions of an underlying genetic variant (8). Lancet, 344:815 (1994). That such genetic defects exist has recently been demonstrated (9-11 ), but it now seems that 12. Yoav, B-S., Whitehead, A., Davey-Smith, G. Parkin­ son's, Alzheimer's and motor-neurone disease: clinical variants at multiple sites are implicated (12). and pathological overlap may suggest common genetic If an association is eventually found between the and environmental factors. British Medical Journal, 312: metabolic functions that these genes control and 724 (1966). one or more of the metabolic effects of riluzole within the central nervous system, a lead might well Calcium channel blockers be created that could result in more profound therapeutic gains. as antihypertensive agents: a need for caution References 1. Couratier, P., Sindou, P., Esclaire, F. et al. Neuro­ Over the past year, several non-randomized out­ protective effects of riluzole in ALS CSF toxicity. come studies have raised concern about the safety Neuroreport, 5: 1012-1014 (1994). and efficacy of calcium channel blockers in the management of hypertension and ischaemic heart 2. Barnett, A. ALS drug squeaks through FDA panel. disease. Two of these studies, both of which were Lancet, 346: 897 (1995). conducted in the United States, suggest that hypertensive patients treated with a calcium 3. Martin, D., Thompson, M., Nadler, J. The neuro­ channel blocker are at greater risk of heart attack protective agent riluzole inhibits release of glutamine and than those treated with a beta-adrenoreceptor aspartate from slices of hippocampal area CAI. European Journal of Pharmacology, 250: 473-476 (1993). antagonist (1, 2). This risk is plausible in that pro­ ischaemic effects of calcium channel blockers have 4. Lacomblez, L., Bensimon, G., Leigh, N. for the ALS I previously been ascribed to a "coronary steal" Riluzole Study Group. Dose-ranging study of riluzole in phenomenon (a redistribution of coronary blood amyotrophic lateral sclerosis. Lancet, 347: 1425-1431 flow resulting from vasodilatation within an (1996). atheromatous coronary arterial system) (3). As a class, calcium channel blockers inhibit the cellular 5. Bensirnon, G., Lacomblez, L., Meininger, V. for the influx of calcium ions into the smooth muscle of ALS /Riluzole Study Group. A controlled trial of riluzole in blood vessels and into myocardial cells. This action amyotrophic lateral scerosis. New England Journal of Medicine, 330: 585-591 (1994). reduces myocardial contractility, impairs the generation and propagation of the conduction 6. Woods, J., Koek, W., France, C., Moerschbaecher, M. impulse, and decreases vascular tone within the In: Excitatory amino acid antagonists. Ed. Medrum, B. coronary arteries. In other respects, the three most Blackwell Scientific Publications, Oxford, 1991, pp. 237- widely used calcium channel blockers differ both in 264. their chemical configurations and their pharma­ cological profiles. Most importantly, nifedipine (a 7. Calne, D., McGeer, E., Eisen, A., Spencer, P. Alzheim­ dihydropyridine) acts predominantly on vascular er's disease, Parkinson's disease, and motor neurone smooth muscle and dilates coronary and peripheral disease: abiotrophic interactions between ageing and the environment. Lancet, 2: 1067-1070 (1986). arteries; while both nifedipine and diltiazem (a benzothiazepine) depress the myocardium to a 8. Appel, S. A unifying hypothesis for the cause of ALS, lesser degree than verapamil (a phenylalkylamine). parkinsonism and Alzheimer's disease. Annals of In a retrospective case-control study (1 ), no Neurology, 10: 499-503 ( 1981). significant difference in this risk of myocardial

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