PubMed Health⌕ Search

PubMed · 10560606

Antiparasitic agents.

Abstract

Several important developments have occurred in recent years in the chemotherapy for and prophylaxis of parasitic infections. Although mefloquine is clearly the most effective agent for prevention of chloroquine-resistant falciparum malaria, its use has been compromised by side effects, both real and imagined. Well-designed studies have shown that side effects occur no more frequently with low-dose mefloquine than with chloroquine. Use of mefloquine in pregnant women has not been associated with birth defects, but the incidence of stillbirths may be increased. Malarone is a new agent that combines atovaquone and proguanil, and it may be as effective as mefloquine; however, it is not yet available in the United States. Several newer agents have appeared in response to the development of multidrug resistant Plasmodium falciparum, especially in Southeast Asia. Halofantrine is available for the treatment of mild to moderate malaria due to P. falciparum and for P. vivax infections. Because of severe toxic effects, use of halofantrine should be restricted to only those unusual and rare situations in which other agents cannot be used. Artemisinin (an extract of the Chinese herbal remedy qinghaosu) and two derivatives, artesunate and artemether, are active against multidrug resistant P. falciparum and are widely used in Asia in oral, parenteral, and rectal forms. The antibacterial azithromycin in combination with atovaquone or quinine has now been reported to treat babesiosis effectively in experimental animals and in a few patients. Azithromycin in combination with paromomycin has also shown promise in the treatment of cryptosporidiosis (and toxoplasmosis when combined with pyrimethamine) in patients with the acquired immunodeficiency syndrome (AIDS). Albendazole is currently the only systemic agent available for treatment of microsporidiosis, an infection primarily of patients with AIDS. In addition, albendazole and ivermectin have emerged as effective broad-spectrum antihelminthics, with albendazole becoming the drug of choice for hydatid disease (echinococcosis), neurocysticercosis, and most intestinal nematode infections (except strongyloidiasis and trichuriasis). Liposomal amphotericin B is the first drug approved by the Food and Drug Administration for the treatment of visceral leishmaniasis.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

J E Rosenblatt. 1999. Antiparasitic agents.. https://doi.org/10.4065/74.11.1161

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

The effect of silicon on the infection by and spread of Pythium aphanidermatum in single roots of tomato and bitter gourd.

The effect of silicon (Si) supply on the infection and spread of Pythium aphanidermatum was studied in the roots of tomato [Lycopersicon esculentum (=Solanum lycopersicum), an Si excluder] and bitter gourd (Mormodica charantia, an Si intermediate accumulator). Individual roots were mounted into PVC compartmented boxes which allowed the application of Si and zoospores to defined root zones. Two days after inoculation, root growth was recorded, and P. aphanidermatum colonization of individual root sections was determined by ELISA. In tomato as well as in bitter gourd the root tip was the root section most sensitive to P. aphanidermatum infection. Application of Si did not affect severe root-growth inhibition by P. aphanidermatum in either species. However, continuous Si supply significantly inhibited the basipetal spread of the pathogen from the infected root apex in bitter gourd but not in tomato. Si application to the roots only during pretreatment or only during/after the infection of the roots failed to inhibit the spread of P. aphanidermatum. Determination and compartmentation of Si in the roots of bitter gourd revealed that apoplastic Si was not, but symplastic Si was, associated with the ability of the plant to reduce the spread of the fungus in roots. It is concluded that accumulation of Si in the root cell walls does not represent a physical barrier to the spread of P. aphanidermatum in bitter gourd and tomato roots. The maintenance of elevated symplastic Si contents is a prerequisite for Si-enhanced resistance against P. aphanidermatum.

Antiparasitic Agents↗

CYP4F enzymes are the major enzymes in human liver microsomes that catalyze the O-demethylation of the antiparasitic prodrug DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime].

DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime] is biotransformed to the potent antiparasitic diamidine DB75 [2,5-bis(4-amidinophenyl) furan] by sequential oxidative O-demethylation and reductive N-dehydroxylation reactions. Previous work demonstrated that the N-dehydroxylation reactions are catalyzed by cytochrome b5/NADH-cytochrome b5 reductase. Enzymes responsible for catalyzing the DB289 O-demethylation pathway have not been identified. We report an in vitro metabolism study to characterize enzymes in human liver microsomes (HLMs) that catalyze the initial O-demethylation of DB289 (M1 formation). Potent inhibition by 1-aminobenzotriazole confirmed that M1 formation is catalyzed by P450 enzymes. M1 formation by HLMs was NADPH-dependent, with a Km and Vmax of 0.5 microM and 3.8 nmol/min/mg protein, respectively. Initial screening showed that recombinant CYP1A1, CYP1A2, and CYP1B1 were efficient catalysts of M1 formation. However, none of these three enzymes was responsible for M1 formation by HLMs. Further screening showed that recombinant CYP2J2, CYP4F2, and CYP4F3B could also catalyze M1 formation. An antibody against CYP4F2, which inhibited both CYP4F2 and CYP4F3B, inhibited 91% of M1 formation by HLMs. Two inhibitors of P450-mediated arachidonic acid metabolism, HET0016 (N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine) and 17-octadecynoic acid, effectively inhibited M1 formation by HLMs. Inhibition studies with ebastine and antibodies against CYP2J2 suggested that CYP2J2 was not involved in M1 formation by HLMs. Additionally, ketoconazole preferentially inhibited CYP4F2, but not CYP4F3B, and partially inhibited M1 formation by HLMs. We conclude that CYP4F enzymes (e.g., CYP4F2, CYP4F3B) are the major enzymes responsible for M1 formation by HLMs. These findings indicate that, in human liver, members of the CYP4F subfamily biotransform not only endogenous compounds but also xenobiotics.

Antiparasitic Agents↗