Pyrimethamine Resistance Research Articles

Drug resistance in malaria—A perspective

One of the major technical problems facing malaria eradication in certain areas is the development of drug resistance. Resistance presents difficulties mainly in relation to P. falciparum infection. Proguanil and pyrimethamine resistance have seldom been reported in other species in the field and chloroquine resistance so far is restricted to P. falciparum malaria. The distribution of chloroquine resistance and multiple resistance in P. falciparum in South America and South-east Asia is reviewed and figured in two maps. The history of the development of resistance is discussed. The main predisposing conditions to resistance appear to be the influx of people with low levels of immunity into an area of continuing transmission, the presence there of resistant mutant parasites and free availability of the respective antimalarials. It is suggested that the underlying mechanisms by which resistant strains emerge are essentially the same for chloroquine as for folic reductase inhibitors. It is suggested moreover that chloroquine resistance may emerge in time in Africa where, until now, no proved foci of such strains have been recorded. The main weapon against drug resistance is the interruption of malaria transmission by residual spraying but in certain problem areas this is not possible. In these areas little can be done when multiple-resistant parasites are present until better drugs are available. A brief reference is made to the treatment of chloroquine-resistant P. falciparum malaria.

The use of long acting sulfonamides, alone or with pyrimethamine, in malaria (with special reference to sulformetoxine)

Review of the early literature as well as more recent results show that sulfonamides possess a distinct antimalarial activity. However, when give alone, their action is less marked and slower than that of the antimalarials commonly used in the treatment of the acute attack. Combinations with pyrimethamine provide better results, even in cases of pyrimethamine and chloroquine resistance. This warrants further investigations in an attempt to develop a therapeutic agent suitable for the treatment of such resistant cases. It may also be possible with an appropriate combination of pyrimethamine with a sulfonamide to achieve a satisfactory method for suppressive treatment both in areas with and without pyrimethamine resistance. Three main points must still be carefully studied: 1) the risk of developing malaria resistance against one or both of the components of the combination. 2) The risk of developing bacterial resistance to sulfonamides if these substances are used on a large scale in too low doses. It seems indeed that antimalarial effect with the combination of sufonamides + pyrimethamine can be obtained with doses of sulfonamides which are below those usually employed in bacterial diseases. Since the range of the ratios providing potentiation is rather large, only ratios of the combination sulfonamides: pyrimethamine should be chosen in which an antfbacterial sulfonamidemia is guaranteed. 3) It goes without sayinq that, although both pyrimethamine and modem sulfonamides, when given by themselves, have proved tc possess a large margin of safety, long term administration of their combination should be careful studied from the point of view of possible side effects. Substantial evidence has already been produced to show that the long acting sulfonamide Fanasil (Ro 4-4393) given once or once weekly possesses marked schizonticidal activity against P. falciparum. Although its action is slower than that of 4-aminoquinolines, it may be useful as a second choice drug in semi-immune subjects for the therapy of falciparum malaria. Preliminary results show that, when combined with pyrimethamine, Fanasil is highly effective in suppressing fever and asexual parasitemia due to P. falciparum. Single doses of 1 g Fanasil together with 50 mg pyrimethamine seem to be adequate for the treatment of acute falciparum malaria in semi-immune patients. The onset of action of the combination is much more rapid than that of the single components. Weekly doses of 500 mg Fanasil and 25 mg pyrimeihamine appear to provide satisfactory suppressive effects against P. falciparum at least in East Africa. This combination is active on strains which do not respond satisfactorily to the standard doses of pyrimethamine and/or chloroquine and seems to have a satisfactory sporontocidal effect. Preliminary results indicate that Fanasil alone cannot be recommended for use against the other human malaria parasites. The combination with pyrimethamine appears to be much more effective. East African strains of P. malariae seem to respond better to the combination than do Malayan strains of P. vivax but further trials are required before definite assessment can be made. Fanasil by itself has no gametocytoddal or sporontocidal action but seems to potentiate the effect of pyrimethamine at least on sporogony of P. falciparum.

Mixed lethal strains of Plasmodium gallinaceum: Drug-sensitive, transferable (SP) × drug-resistant, non-transferable (BI)

Mosquitoes were fed on chicks simultaneously inoculated with lethal, transferable, drug sensitive SP strain P. gallinaceum and (1) the lethal, BI strain, 800-fold resistant to pyrimethamine or (2) the BI-strain, 64-fold resistant to pyrimethamine and 32-fold resistant to metachloridine. In subsequent mosquito transfers, where no selection was made for pyrimethamine resistance, drug resistance disappeared, and the mortality rate averaged 90% over 8 to 9 transfers. Where selection was made for pyrimethamine resistance after the first mosquito transfer, drug resistance persisted, and the average mortality rate was 33%. Where the BI-pyrimethamine-metachloridine-resistant strain was used, metachloridine resistance could not be demonstrated after 8 transfers, during which selection was made for pyrimethamine resistance.