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22. Nosten, F., ter Kuile, F., Luxemburger, C. et al.
Cardiac effects of antimalarial treatment with halofantrine.
Lancet, 341: 1054-56 (1993).
23. Karbwang, J., Na-Bangchang, K., Thanavibul, A. et al. Comparison of oral artesunate and quinine plus tetracycline in acute uncomplicated falciparum malaria.
Bulletin of the World Health Organization, 72: 233-38 (1994).
24. Martin, G., Malone, J., Ross, E. Exfoliative dermatitis during malarial prophylaxis with mefloquine. Clinical and Infectious Diseases, 16:341-2 (1993).
25. van den Enden, E., van Gompel, A., Colebunders, R.
et al. Mefloquine-induced Stevens-Johnson syndrome.
Lancet, 337: 683 (1991).
26. Shlim, D. Severe facial rash associated with meflo- quine. Journal of the American Medical Association, 266:
2560 (1991 ).
27. Scerri, L., Pace J. Mefloquine-associated cutaneous vasculitis. International Journal of Dermatology, 32: 517- 518 (1993).
28. Danis, M., Nozais, J., Paris, L. et al. Fievre bilieuse haemoglobinurique apres prise de mefloquine. 3 observations. Presse Medica/e. 22: 80 (1993).
Riluzole for amyotrophic lateral sclerosis
In September 1995, an advisory committee to the US Food and Drug Administration narrowly agreed to recommend approval of riluzole- (Rilutek®, Rhone-Poulenc Roher), a benzothiazole with anti- convulsant activity which is claimed to possess
"neuroprotective properties" (1)- in the manage- ment of amyotrophic lateral sclerosis (ALS) (2).
ALS is an insidious, progressive and ultimately fatal disease of the central nervous system which occurs typically in late middle age and with greater fre- quency in men. lt results from degeneration of both upper and lower motor neurones, and it is charac- terized clinically by a mixed picture of spasticity and progressive muscular atrophy. In the United States, the disease affects some 30 000 people at any one time and, worldwide, the number of cases is claimed to be increasing (2).
Various suggestions have been offered to explain, in pharmacological terms, some of the experi- mentally-induced central nervous effects of riluzole.
Riluzole, for instance, interferes with glutamate metabolism in laboratory animals (3), and it has been suggested, without confirmation, that one
Reports on Individual Drugs
factor determining the progression of ALS could be overproduction or abnormal metabolism of glut- amine resulting in toxic accumulation in presynaptic cells (2).
The scientific data on which the advisory group's decision was based have now been published.
They derive from a double-blind, placebo- controlled, multicentre study (4) and a smaller preliminary trial (5). The larger study involved some 950 patients with a disease history of less than 5 years' duration who were recruited from many neurological clinics within seven countries in North America and Western Europe. These patients were randomly assigned either to placebo or to 50 mg, 100 mg, or 200 mg riluzole daily. After treatment for a median period of 18 months, the proportion of patients surviving without tracheostomy ranged in dose-related order from 50.4% (placebo) to 57.8%
(200 mg riluzole). After adjustment for pre- determined prognostic factors, the overall drug effect was shown to be modest - but statistically significant- and stable throughout the period of follow-up.
The marginal added benefit of the 200 mg dose was offset by a moderately increased incidence of dizziness, diarrhoea, anorexia, and also in oc- casional rises in hepatic transaminases sufficient to warrant withdrawal of treatment. A tendency, seen in the preliminary trial, for riluzole to increase spasticity and to raise blood pressure, was not evident, and no reason is offered to explain this. lt is notable that, in the initial study, weakness and debility was a principal reason for withdrawal of treatment (5). This adverse effect was anticipated since it has been claimed that antiglutamate agents, as a class, have muscle-relaxant activity (6). The same effect occurred in the definitive study but on this occasion policy was changed "to maintain patients on treatment and to continue assessments even in the presence of asthenia".
Although increased survival was demonstrated within this study, the effect of treatment on the quality of life evidently remains uncertain. The conclusion of the participating investigators is that
"psychological well-being is enhanced by the availability of a treatment that is safe and well- tolerated, and has a proven effect on the disease, in contrast to many drugs (some of them unsafe) to which many thousands of patients have been exposed over the years".
The investigators also emphasize that the wide variation in survival time among patients with ALS
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suggests that multiple factors are involved in deter- mining the disease and its clinical course. lt has been proposed that the premature decline in neuronal function which characterizes all the common neurodegenerative diseases- Parkinson's disease, Alzheimer's disease, and motor-neurone disease- results from interplay between environmental insults (such as infections or neurotoxins) and the normal ageing process (7).
Alternatively, it has been suggested that these conditions represent different phenotypic expressions of an underlying genetic variant (8).
That such genetic defects exist has recently been demonstrated (9-11 ), but it now seems that variants at multiple sites are implicated (12).
If an association is eventually found between the metabolic functions that these genes control and one or more of the metabolic effects of riluzole within the central nervous system, a lead might well be created that could result in more profound therapeutic gains.
References
1. Couratier, P., Sindou, P., Esclaire, F. et al. Neuro- protective effects of riluzole in ALS CSF toxicity.
Neuroreport, 5: 1012-1014 (1994).
2. Barnett, A. ALS drug squeaks through FDA panel.
Lancet, 346: 897 (1995).
3. Martin, D., Thompson, M., Nadler, J. The neuro- protective agent riluzole inhibits release of glutamine and aspartate from slices of hippocampal area CAI. European Journal of Pharmacology, 250: 473-476 (1993).
4. Lacomblez, L., Bensimon, G., Leigh, N. for the ALS I Riluzole Study Group. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet, 347: 1425-1431 (1996).
5. Bensirnon, G., Lacomblez, L., Meininger, V. for the ALS /Riluzole Study Group. A controlled trial of riluzole in amyotrophic lateral scerosis. New England Journal of Medicine, 330: 585-591 (1994).
6. Woods, J., Koek, W., France, C., Moerschbaecher, M.
In: Excitatory amino acid antagonists. Ed. Medrum, B.
Blackwell Scientific Publications, Oxford, 1991, pp. 237- 264.
7. Calne, D., McGeer, E., Eisen, A., Spencer, P. Alzheim- er's disease, Parkinson's disease, and motor neurone disease: abiotrophic interactions between ageing and the environment. Lancet, 2: 1067-1070 (1986).
8. Appel, S. A unifying hypothesis for the cause of ALS, parkinsonism and Alzheimer's disease. Annals of Neurology, 10: 499-503 ( 1981).
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9. Harrington, C., Louwagie, J., Rossau, R. et al. Influence of apolipoprotein E genotype on senile dementia of the Alzheimer and Lewy body types. American Journal of Pathology, 145: 1472-1484 (1994).
10. AI-Chalabi, A., Enayat, Z., Bakker, M. et al. Associa- tion of apoprotein E e4 allele with bulbar-onset rnotor neurone disease. Lancet, 347: 159-160 (1996).
11. Rempfer, R., Crook, R., Houlden, H. et al. Parkinson's disease, but not Alzheimer's disease, Lewy body variant associated with mutant alleles at cytochrome P450 gene.
Lancet, 344:815 (1994).
12. Yoav, B-S., Whitehead, A., Davey-Smith, G. Parkin- son's, Alzheimer's and motor-neurone disease: clinical and pathological overlap may suggest common genetic and environmental factors. British Medical Journal, 312:
724 (1966).
Calcium channel blockers as antihypertensive agents:
a need for caution
Over the past year, several non-randomized out- come studies have raised concern about the safety and efficacy of calcium channel blockers in the management of hypertension and ischaemic heart disease. Two of these studies, both of which were conducted in the United States, suggest that hypertensive patients treated with a calcium channel blocker are at greater risk of heart attack than those treated with a beta-adrenoreceptor antagonist (1, 2). This risk is plausible in that pro- ischaemic effects of calcium channel blockers have previously been ascribed to a "coronary steal"
phenomenon (a redistribution of coronary blood flow resulting from vasodilatation within an atheromatous coronary arterial system) (3). As a class, calcium channel blockers inhibit the cellular influx of calcium ions into the smooth muscle of blood vessels and into myocardial cells. This action reduces myocardial contractility, impairs the generation and propagation of the conduction impulse, and decreases vascular tone within the coronary arteries. In other respects, the three most widely used calcium channel blockers differ both in their chemical configurations and their pharma- cological profiles. Most importantly, nifedipine (a dihydropyridine) acts predominantly on vascular smooth muscle and dilates coronary and peripheral arteries; while both nifedipine and diltiazem (a benzothiazepine) depress the myocardium to a lesser degree than verapamil (a phenylalkylamine).
In a retrospective case-control study (1 ), no significant difference in this risk of myocardial
