Evaluation of the pharmacokinetic-pharmacodynamic relationship of praziquantel in the Schistosoma mansoni mouse model was written by Abla, Nada;Keiser, Jennifer;Vargas, Mireille;Reimers, Natalie;Haas, Helmut;Spangenberg, Thomas. And the article was included in PLoS Neglected Tropical Diseases in 2017.Computed Properties of C6H6N4 This article mentions the following:
After more than 40 years of use, Praziquantel (PZQ) still remains the drug of choice for the treatment of intestinal and urogenital schistosomiasis. Its anti-parasitic activity resides primarily in the (R)-enantiomer. Hitherto neither the mol. target nor the pharmacokinetic-pharmacodynamic relationship have been fully elucidated. Here we investigated the efficacy and pharmacokinetics of PZQ in the Schistosoma mansoni mouse model to determine the key factors that drive its efficacy. Dose-response studies with racemic PZQ with or without addition of an irreversible pan-cytochrome P 450 (CYP) inhibitor, 1-aminobenzotriazole (ABT), were performed. In addition, efficacy of PZQ in the presence of the CYP inducer, dexamethasone (DEX), was determined Plasma samples were obtained by tail vein bleeding at 4 time points. The (R)-PZQ levels were determined using a LC-MS/MS method. Non-compartmental pharmacokinetic anal. was performed using PKsolver. In addition, experiments using an enhanced in vitro assay were conducted. We found that the use of ABT increased (R)-PZQ plasma exposures in the systemic circulation by ∼10 to 20 fold but the latter were not predictive of efficacy. The use of DEX decreased plasma exposures of (R)-PZQ in the systemic circulation by ∼10 fold without reducing efficacy. We extrapolated the (R)-PZQ concentrations in mouse portal vein / mesenteric veins from the systemic exposures and found that a free exposure of (R)-PZQ of ∼ 20 μM*h in the portal vein was needed to obtain a worm burden reduction >60%. It is suggested that the high (R)-PZQ concentrations available before the hepatic first pass metabolism drive the efficacy against S. mansoni adult worms residing in the mesenteric veins. It is then possible that the current dosing regimen of 40 mg/kg in preventive chemotherapy programs may provide suboptimal concentrations in low-weight patients such as children, due to smaller total amounts of drug administered, and may consequently result in lower cure rates. In the experiment, the researchers used many compounds, for example, 1H-Benzo[d][1,2,3]triazol-1-amine (cas: 1614-12-6Computed Properties of C6H6N4).
1H-Benzo[d][1,2,3]triazol-1-amine (cas: 1614-12-6) belongs to triazole derivatives. Many triazoles are versatile, biologically active compounds commonly used as fungicides and plant retardants. 1,2,3-Triazoles are usually prepared following (3+2) cycloaddition protocols. A common technique for unsubstituted triazoles is the Huisgen azide-alkyne 1,3-dipolar cycloaddition: a azide and an alkyne react at high temperature to form a ring. However, the Huisgen strategy produces a mixture of isomers (typically 1,4- and 1,5-disubstituted) when used to produce substituted triazoles.Computed Properties of C6H6N4
Referemce:
1,2,3-Triazole – Wikipedia,
Triazoles – an overview | ScienceDirect Topics