Biomedical subjects
Publications and source records attributed to B O Duke.
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The effects of the arsenical drug melarsonyl potassium on Onchocerca volvulus were investigated in patients in Cameroon infected with the Cameroon forest and Sudan savanna strains of the parasite. Two intramuscular dosage schedules were tested: the first comprised 4 consecutive daily doses of 200 mg repeated once after a 10-14 day interval, i.e., 2 (4x200 mg). The second was a single dose schedule at 7.1 mg/kg-10 mg/kg, with a maximum of 500 mg.In most trials the drug had no immediate action on microfilarial concentrations. Only after the 2(4x200 mg) melarsonyl course against the Sudan savanna strain was a slight microfilaricidal action detected.The 2(4x200 mg) course of melarsonyl apparently killed or sterilized most or all of the adult female worms in the patients tested, leaving the residual population of microfilariae to decline gradually, from natural mortality, over the ensuing 2 years. These residual microfilariae could be killed with diethylcarbamazine.Single doses of melarsonyl at 7.1 mg/kg-10 mg/kg were somewhat less effective in killing or sterilizing adult worms, but it is suggested that if doses at the higher end of this range were to be repeated annually patients could be rendered free from microfilariae by the end of 3 years.It is emphasized that the risks of arsenical encephalopathy should at present preclude the use of melarsonyl potassium in the treatment of onchocerciasis, but that if this danger could be avoided the drug might prove to be of considerable use for mass therapy in control campaigns.
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It is important to standardize quantitative methods for assessing the action of drugs on Onchocerca volvulus in man. There are certain disadvantages to making observations on adult worms removed from excised nodules in treated patients, but a great deal of information on drug action can be obtained by making a careful study of the concentrations of microfilariae in multiple weighed skin snips taken before treatment and at intervals after treatment.Before drug trials can be carried out intelligently by this method it is necessary to know the normal length of life of the various stages of the parasite in man. By a variety of experimental methods the life-spans of the adult worms and the microfilariae have been determined, as well as the duration of the prepatent interval.Diethylcarbamazine can be used at doses that are effectively microfilaricidal but have no action on the adult worms. This drug can therefore be used to eliminate any residual microfilariae that remain after treatment with a new drug under trial, thus permitting a more rapid assessment of the latter's action on adult worms.
Antimonial preparations (Pentostam, Neostibosan, stibophen, and tartar emetic) have occasionally been used in the treatment of onchocerciasis without very promising results. The advent of the preparations TWSb (stibocaptate) and MSbE (Friedheim) of allegedly reduced toxicity made it desirable to test them against Onchocerca volvulus.The action of both preparations on the parasites was found to vary from one patient to another, ranging from complete elimination of all parasites in a few cases to no detectable action in others. A microfilaricidal action was detectable in many patients, particularly after treatment with TWSb, which was used at higher doses than MSbE. A lethal or sterilizing action on some or all adult female worms was observed in some patients. However, toxic reactions to the drugs were common and distressing, and often it was necessary to stop treatment on this account. Anorexia, nausea, vomiting and prostration were the most common manifestations, and there was one fatality from coincident yellow fever, which may well have been aggravated by antimony treatment.The uncertain action of these preparations on O. volvulus and the toxic manifestations that accompany their use render them unsuitable for the treatment of onchocerciasis, and it is probable that the effects of antimony on O. volvulus are produced only at or above the normal level of human tolerance.
Suramin and Mel W are the only two drugs at present known to be effective against the adult worms of Onchocerca volvulus, but in view of the unpredictable occurrence of fatal arsenical encephalopathy in a small proportion of patients receiving Mel W, suramin remains the preferred macrofilaricide in the treatment of onchocerciasis. It is therefore important to determine the suramin dosage schedules that will produce parasitological cures with minimal concomitant risks of toxic reactions. The criteria by which cures should be judged must also be appreciated.Courses of different duration and employing doses of 1.0 g, 0.5 g and 0.25 g suramin have been investigated for their action on adult worms and microfilariae, for the toxic reactions which they produce on the kidney, and for the level of suramin reached in the serum during treatment. A course of 5 or 6 weekly doses of 1.0 g has been shown to be the optimum for adults.It is sometimes stated without good foundation that different brands of suramin differ in their purity and chemical composition, thus producing inconsistent effects on the parasites and grave risks of toxic manifestations. The three main brands in current use in Africa (Antrypol, Moranyl and Naganol) have therefore been compared in a group of patients, using the same optimum dosage schedule for each preparation and recording the action of the various brands on the parasites, as well as their comparative toxicities and the serum suramin levels achieved. No significant differences between the brands were recorded.
The best hope for the control of transmission of Onchocerca volvulus over much of Africa lies in combining larvicidal measures directed against the Simulium vectors with chemotherapeutic measures designed to reduce the reservoir of transmissible microfilariae in man.There are few drugs effective against O. volvulus. Diethylcarbamazine kills the microfilariae but has virtually no effect on the adult worms. Suramin kills adult worms and many, but not all, of the microfilariae. Mel W kills adult worms but has little or no action on microfilariae. All these drugs suffer at present from disadvantages of toxicity, which tend to limit their use on a mass scale in the field. Nevertheless, before they, or indeed any new drugs with similar actions on the parasites, can be used intelligently for the control of onchocerciasis transmission, it is necessary to have accurate quantitative information on the effect that each of them has on the microfilarial population available for intake by Simulium, as well as on their actions on the developmental potential of those microfilariae ingested by the flies.The present paper describes the effects of treatment with various courses of diethylcarbamazine, suramin or Mel W on the numbers of microfilariae ingested by groups of S. damnosum and on the numbers of infective larvae developing therefrom.
Previous work on monkeys and on human volunteers led to the development of a schedule of diethylcarbamazine dosage suitable for the chemoprophylaxis of loiasis. In several parts of Africa where this chemoprophylaxis is practised against Loa loa, infections with Onchocerca volvulus are also common. Attempts were therefore made to determine whether diethylcarbamazine has any prophylactic action against the latter parasite by making use of chimpanzees exposed to experimental infections, and also by using biopsy techniques to study the fate of infective larvae inoculated into volunteers.Both experimental methods proved more difficult to apply in O. volvulus infections than had been the case with L. loa, but evidence was obtained that diethylcarbamazine is not an effective chemoprophylactic for O. volvulus.Further experiments were then carried out with suramin and with melarsonyl potassium (Mel W). Although both gave some evidence of partial prophylactic activity, their use for this purpose is at present neither practical nor safe.
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