Pharmacological Reviews, Vol 7, 279-299, Copyright © 1955 by the American Society for Pharmacology and Experimental Therapeutics

THE CHEMOTHERAPY OF FILARIAL INFECTIONS

¹ National Institute for Medical Research, London

It is interesting to compare the chemotherapeutic reactions of filarial worms with those of other parasites and micro-organisms. The nematodes of the intestine live in an environment too different from the tissues to permit a close comparison; as mentioned above, many intestinal round worms seem to be expelled (but not killed) by piperazine compounds, many compounds of this type being more active than diethylcarbamazine in this respect. Most of the compounds which are effective on the intestinal nematodes, e.g., hexylresorcinol, carbon tetrachloride, etc., are too toxic for the tissues to permit them having a useful action on filariae. The other important class of worms invading the body itself is that of the trematodes, especially the schistosomes. Both filariae and schistosomes are sensitive to antimonials, although their relative sensitivities to the different compounds are not quite the same. Diethylcarbamazine has a slight therapeutic action in human schistosomiasis which is of theoretical interest but not of practical importance (7, 81). Otherwise there is little resemblance between these two types of parasite. Leucanthone (miracil, nilodin), which acts on schistosomes, has no action upon filariae (Litomosoides). The bacteria seem to have no chemotherapeutic resemblances to filariae; sulphonamides, antibiotics, isoniazide etc. all have no action upon filariae. Similarly, malaria parasites show no resemblances; none of the well-known antimalarial compounds has been found to possess antifilarial activity (apart from the slight action exhibited by proguanil).

With the trypanosomes, however, there are many remarkable similarities. Thus filariae are very sensitive to arsenicals and also to antimonials. Litomosoides is sensitive to phenanthridinium and styrylquinoline compounds, which destroy Trypanosoma congolense; and Onchocerca responds to suramin. On the other hand, Litomosoides does not respond to diamidine compounds, to antrycide, or to acriflavine, all of which are trypanocidal, while trypanosomes do not respond to diethylcarbamazine, or to cyanine 863.

Finally, consideration may be given to the further requirements of chemotherapeutic research in this field. From a clinical point of view the chief requirement is a drug to kill Onchocerca volvulus. At present diethylcarbamazine does not kill the adult worms, and suramin is potentially toxic. In filariasis due to Wuchereria or to Loa, diethylcarbamazine is so active that it seems unreasonable to ask for greater activity; but it would be valuable if some means could be discovered of avoiding the minor toxic effects which are such a handicap to mass treatments. This might be achieved by discovering a completely new compound, or by modifying the molecule or the pharmaceutical vehicle of diethylcarbamazine so that its effects were exerted more slowly. It would be advantageous to have a preparation of diethylcarbamazine which could be administered on fewer occasions while exerting an equally prolonged action in the body. There is no compound known at present which will kill Dracunculus (apart from the doubtful action of diethylcarbamazine), and it would be valuable to find one. The search would be much facilitated by obtaining an analogous helminthic infection in a laboratory animal (similar to Litomosoides in cotton rats which made possible the discovery of diethylcarbamazine). All new knowledge of the biology and biochemistry of filarial worms will assist in the provision of a rational chemotherapy, while the discovery of new chemotherapeutic agents will probably throw new light on the metabolism of the worms.

Note:

Grateful acknowledgments are due to Dr. D. R. Bangham for allowing reference to be made to unpublished work, and to Dr. J. W. Walker for assistance with chemical nomenclature.