Metabolism of praziquantel in man

A rational strategy for chemotherapy demands that dosage schedules be based on an adequate knowledge of clinical and biochemical pharmacology. Many anthelmintic drugs (e.g. suramin, diethylcarbamazine, hycanthone) were introduced before modern techniques for drug evaluation (controlled clinical trials) and before the development of specific and sensitive analytical methods for the assay of drugs and metabolites in biological fluids. Thus, many of the regimens used today for the treatment of parasitic diseases are largely empirically derived. By means of specific analytical methodology (high performance liquid chromatography, gas chromatography and mass-spectrometry) introduced in the 1960s, it is now possible to measure drugs and their metabolites with specificity and sensitivity. Much of this review deals with compounds which are active against the major systemic helminths, i.e., filariae (diethylcarbamazine, ivermectin and suramin) and schistosomes (niridazole, metrifonate, oxamniquine and praziquantel), but recent advances in the treatment of hydatid disease involving the benzimidazole carbamates albendazole and mebendazole are also discussed. Among the imidazole derivatives, mebendazole, a broad-spectrum anthelmintic, is poorly absorbed from the gastrointestinal tract after a therapeutic dose, but that fraction which is absorbed and escapes hepatic first-pass extraction is pharmacologically active against systemic helminths. Albendazole is more completely absorbed, but is almost undetectable in plasma due to its rapid conversion to an active sulphoxide metabolite. This compound may well become the drug of choice for the chemotherapy of echinococcosis. Levamisole, the 1-isomer of tetramisole, is rapidly and completely absorbed, but has not been widely used in systemic helminthiases because of severe side effects associated with prolonged dosage. Diethylcarbamazine is microfilaricidal against Onchocerca volvulus, but its use has been associated with major adverse effects resulting from its action on the microfilariae. These effects are related to the concentration of the drug in the plasma which, in turn, is influenced by urinary pH. The elimination half-life of diethylcarbamazine is prolonged and renal clearance reduced in alkaline urine. Under these conditions the microfilaricidal effect is enhanced, but the adverse reactions to treatment are more severe. Suramin is the only available antifilarial agent with macrofilaricidal activity. It has a long elimination half-life (36 to 54 days), and is highly (99.7%) bound to plasma protein which limits its removal from the blood.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Metabolism produces mono-and polyhydroxylated products (Buhring et al 1979), the major metabolite in humans being the monohydroxylated compound.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Clinical Pharmacokinetics of Anthelmintic Drugs

Edwards

Breckenridge

1988

Clinical Pharmacokinetics

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“…Among these variants, however, PZQ1 presents other disadvantages, such as decreased or complete absence of activity against juvenile schistosomes (32,33). Accordingly, a complete cure is not reliably achieved with a single dose of PZQ1, particularly given that reinfection is routine (8,34). Despite decades of extensive use, much remains unknown about PZQ1, in particular, its exact mode of action, its in vivo metabolism, and its molecular target(s).…”

Section: A Single Drug For Treatment and Control Of Schistosomiasismentioning

confidence: 99%

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Vale

Gouveia

Rinaldi

et al. 2017

Antimicrob Agents Chemother

292

244

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Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drugresistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes.

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“…It is marketed as a racemate, although only one enantiomer is biologically active. [5] Since its discovery by E. Merck (Darmstadt) and Bayer (Leverkusen) in the mid-1970s, [6] its safety, efficacy, and low cost (7 US cents per 600 mg tablet) have ensured its widespread use. The drug is usually administered at a single oral dose of 40 mg kg -1 of bodyweight; it reliably cures 60-90 % of patients and substantially decreases the worm burden and egg production in those who are not cured.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of “Trioxaquantel”^® Derivatives as Potential New Antischistosomal Drugs

et al. 2008

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Over the past 20 years, praziquantel, a pyrazinoisoquinoline derivative, has become the mainstay for morbidity control of human and animal schistosomiasis. From early in their lives in vertebrate hosts, schistosomes ingest hemoglobin and aggregate the released heme as a dark pigment very similar to the hemozoin produced by Plasmodium in malaria infection. The antimalarial artemisinin derivatives have real, though low, schistosomicide activity. Because of the complementarity of the two drug classes – praziquantel and artemisinin derivatives – we designed new molecules, named trioxaquantels®, that combine the 1,2,4‐trioxane unit responsible for the activity of artemisinin, and the pyrazinoisoquinoline moiety of praziquantel within a single drug. The synthesis of these new drugs and their preliminary evaluation in mice infected with Schistosoma mansoni is reported here.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

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Metabolism of praziquantel in man

Cited by 52 publications

References 8 publications

Clinical Pharmacokinetics of Anthelmintic Drugs

Clinical Pharmacokinetics of Anthelmintic Drugs

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Synthesis of “Trioxaquantel”^® Derivatives as Potential New Antischistosomal Drugs

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Metabolism of praziquantel in man

Cited by 52 publications

References 8 publications

Clinical Pharmacokinetics of Anthelmintic Drugs

Clinical Pharmacokinetics of Anthelmintic Drugs

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

Synthesis of “Trioxaquantel”® Derivatives as Potential New Antischistosomal Drugs

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Product

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Synthesis of “Trioxaquantel”^® Derivatives as Potential New Antischistosomal Drugs