Dihydrofolate Reductases in Parasitic Protozoa and Helminths

Jaffe, Julian J.

doi:10.1016/b978-0-12-711050-9.50020-8

Cited by 6 publications

(5 citation statements)

References 37 publications

(4 reference statements)

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“…In addition to the potential role of suramin in the blockade of glycolysis in filarial worms, folate metabolism has also been identified as sensitive to inhibition by the drug. Inhibition of 50 % of the activity of 0. volvulus dihydrofolate reductase (DHFR) was obtained with 2 x 10~6 M suramin whereas rat liver DHFR activity was 50% inhibited by suramin at 7 x 10~5 M (Jaffe, 1972). The NADP-dependent 10 formyltetrahydrofolate dehydrogenase of B. pahangi was also 50% inhibited by 5 x 10~6 M suramin (Jaffe, 1980).…”

Section: Discussionmentioning

confidence: 99%

“…A review of the extensive literature on suramin has been provided by Hawking (1978), and biochemical studies by Jaffe (1972Jaffe ( , 1980, Walter (1979), Walter & Schulz Key (1980 a, b) and Walter & Albiez (1981) have examined the suceptibility to suramin of various enzymes from Brugia pahangi, Dirofilaria immitis and Onchocerca volvulus. These biochemical studies have demonstrated that if the concentration of suramin in the worm tissues reached 1 x 10~6-l x 10~5 M a diverse range of filarial enzymes could be inhibited.…”

Section: Introductionmentioning

confidence: 99%

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The mode of action of suramin on the filarial worm Brugia pahangi

1983

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The mode of action of suramin upon Brugia pahangi has been investigated in vivo and in vitro. The drug was without effect on the glycolytic activity of worms in vitro at 2 X 10(-4) M. The lack of effect was correlated with the failure of [14C]suramin to penetrate the worms in vitro. Suramin bound to the surface of worms in vitro presumably by virtue of its polyanionic nature. B. pahangi adults ingested [14C]suramin in vivo but no reduction in the rate of lactate production, of glucose utilization or in the rates of uptake of [14C]glucose, [14C]leucine or [14C]adenosine was observed in worms recovered from jirds between weeks 1 and 5 following 4 daily doses of suramin at 50 mg/kg given intraperitoneally. Worm death occurred between weeks 5 and 7 but this delayed drug effect was not the result of a progressive accumulation of suramin in the worms. Ultrastructural changes were observed in the intestinal epithelium of worms from suramin-treated jirds and parallel observations on worms exposed to Trypan blue in vivo suggest that both polyanionic compounds are restricted to the intestinal lumen of the worms. The evidence presented is consistent with the concept that, in B. pahangi, suramin acts at the surface of the intestinal epithelium and not by primarily inhibiting glucose catabolism or inhibiting phagosome and lysosome fusion as previously demonstrated for bloodstream trypanosomes and mammalian macrophages, respectively.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The mode of action of suramin on the filarial worm Brugia pahangi

1983

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“…A similar enzyme, of lower molecular weight, is used by the mammalian host to produce tetrahydrofolate, and the basis of selective toxicity for the parasite here is the affinity of pyrimethamine and cycloguanil for the plasmodial enzyme which is 1000 times higher than for the mammalian enzyme (Jaffe 1972). A similar enzyme, of lower molecular weight, is used by the mammalian host to produce tetrahydrofolate, and the basis of selective toxicity for the parasite here is the affinity of pyrimethamine and cycloguanil for the plasmodial enzyme which is 1000 times higher than for the mammalian enzyme (Jaffe 1972).…”

Section: Antimetabolitesmentioning

confidence: 99%

Antimalarial Drugs

1987

Drugs

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Over the last decade, chloroquine-resistant falciparum malaria has spread to other areas from its original foci in Southeast Asia and South America. Additionally, new knowledge about the life-cycle of the malaria parasite, and about the pharmacokinetic properties of antimalarial drugs, has emerged. It is appropriate to reassess our approach to prevention and management of malaria with these factors in mind. Antimalarial drugs can be classified in two ways: biologically as tissue schizontocides, hypnozoitocides, blood schizontocides, gametocytocides or sporontocides; or by a mixed chemical/biological classification as 8-aminoquinolines, antimetabolites and (again) blood schizontocides. Chloroquine resistance in P. falciparum can now be found in most areas where malaria occurs. Malarial strains moderately resistant to the chloroquine group of drugs (chloroquine and mepacrine) are generally susceptible to the aryl amino alcohols such as quinine. Indeed, quinine is the most widely used drug for treating malaria due to chloroquine-resistant strains, followed by a 7-day course of tetracycline where some resistance to quinine is also found. Alternatively, the course of quinine may be followed by sulfadoxine/pyrimethamine or the newer quinoline derivative, mefloquine. Quinidine has also shown activity against quinine-resistant strains. Prophylaxis of chloroquine-resistant strains is best undertaken with daily proguanil (chloroguanide), and weekly chloroquine. In severe malaria, including cerebral malaria, an intravenous loading dose of quinine should be considered, and plasma concentration monitoring may be advisable to assist with dosage adjustment. In patients with severe renal insufficiency, there is evidence that the elimination of chloroquine is prolonged, and dosage adjustments may be necessary. Other recent findings on the pharmacodynamic properties, mechanisms of action and toxicity of antimalarial drugs are also discussed.

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“…Adult helminths appear to have minimal survival needs for nucleic acid synthesis because the adults d o not multiply in the final host. Results in studies by Jaffe, McCormack & Meymarian (1971) and Jaffe (1972), however have shown that suramin, which appears to be a dihydrofolate reductase inhibitor, and tubercidin, a nucleoside analog, are effective against Onchocerca and Schistosoma, respectively. These data would indicate that a more complete understanding of nucleic acid metabolism is essential if generalizations are t o be made on the lack of importance of nucleic acid metabolism.…”

Section: P R I N C I P L E S O F M O D E O F a C T I O Nmentioning

confidence: 99%

Mode of action of common anthelmintics

Rew

1978

Vet Pharm & Therapeutics

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The primary physiological mode of action of nearly all drugs used to control helminth parasites is not well understood. Examination of the general modes of action in terms of parasite requirements for survival may, however, provide guidelines to continue our present investigations and direct us for future research. Two general areas of drug activity are (1) interference with energy‐generating metabolism, and (2) interference with proper neuromuscular coordination. Few exceptions are found to these areas because the target organisms require little else for survival. The target of most previously effective and many presently effective anthelmintics is an adult parasite. Adult helminth parasites must maintain an advantageous feeding site and must transport and metabolize substrates (primarily glucose) to generate life‐maintaining energy. Adult worms have almost no other short‐term requirements for survival because they have little or no metabolic activity in either lipid synthesis or oxidation, nucleic acid synthesis, or protein synthesis (except egg‐laying). Examination of specifics of energy‐generating metabolism and putative neurochemical transmitters allows us certain predictions in relating a given drug activity to an individual species. These examinations indicate that such diversity exists among helminth metabolic or nervous systems that a broad‐spectrum anthelmintic would most likely inhibit at several sensitive points. Published information on drug action and differences in data interpretation are discussed. Two novel areas for future anthelmintic investigations may be (1) juvenile hormone or ecdysone analogs, and (2) pheromones. A combined empirical and rational approach to the development of new drugs may be the most efficient avenue of future research.

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Dihydrofolate Reductases in Parasitic Protozoa and Helminths

Cited by 6 publications

References 37 publications

The mode of action of suramin on the filarial worm Brugia pahangi

The mode of action of suramin on the filarial worm Brugia pahangi

Antimalarial Drugs

Mode of action of common anthelmintics

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