Plasmodium falciparum is responsible for most of the cases of malaria and its resistance to established antimalarial drugs is a major issue. Thus, new chemotherapies are needed to fight the emerging multi-drug resistance of P. falciparum malaria, like choline analogues targeting plasmodial phospholipidic metabolism.
View Article and Find Full Text PDFMycophenolate mofetil (MMF) is an important immunosuppressant used in renal transplantation, and mycophenolic acid (MPA) is the active component released from the ester prodrug MMF. The objective of this study was to investigate the population pharmacokinetics of mycophenolic acid (MPA) following oral administration of MMF in Chinese adult renal transplant recipients and to identify factors that explain MPA pharmacokinetic variability. Pharmacokinetic data for MPA and covariate information were retrospectively collected from 118 patients (79 patients were assigned to the group for building the population pharmacokinetic model, while 39 patients were assigned to the validation group).
View Article and Find Full Text PDFNeuropsychopharmacology
October 2015
One of the main reasons for the inefficiency of multicenter randomized clinical trials (RCTs) in depression is the excessively high level of placebo response. The aim of this work was to propose a novel methodology to analyze RCTs based on the assumption that centers with high placebo response are less informative than the other centers for estimating the 'true' treatment effect (TE). A linear mixed-effect modeling approach for repeated measures (MMRM) was used as a reference approach.
View Article and Find Full Text PDFEAPB0503, belonging to the imidazo[1,2-a]quinoxaline series, is an anticancer drug with antitumoral activity against a variety of tumors. Previous studies have shown that this drug undergoes demethylation and oxygenation reactions. In this paper, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) was employed to assess the structures of unknown oxygenated metabolites of EAPB0503.
View Article and Find Full Text PDFAnal Chem
November 2012
The present study was conducted to assess the structures of the main unknown oxygenated metabolites of EAPB0203. The first step was to assign all the (1)H and (13)C NMR of both EAPB0203 and its demethylated metabolite (EAPB0202) to the corresponding atoms in their molecular structures and to elucidate the fragmentation pathways for the [M + H](+) ions of these compounds using high-resolution mass spectrometry (MS). MS/MS spectra showed that both protonated molecules possessing an even number of electrons were unexpectedly losing radicals such as H(•), CH(3)(•), or even C(7)H(7)(•) giving stable radical cations.
View Article and Find Full Text PDFObjective: Peritoneal spread is an adverse outcome in ovarian cancer. Despite clinical efficiency, intraperitoneal (i.p.
View Article and Find Full Text PDFAntimalarial activities and pharmacokinetics of the bis-alkylamidine, M64, and its amidoxime, M64-AH, and O-methylsulfonate, M64-S-Me, derivatives were investigated. M64 and M64-S-Me had the most potent activity against the Plasmodium falciparum growth (IC(50)<12nM). The three compounds can clear the Plasmodium vinckei infection in mice (ED(50)<10mg/kg).
View Article and Find Full Text PDFDrug Metab Dispos
October 2010
For several years, our group has been developing quinoxalinic compounds. Two of them, N-methyl-1-(2-phenethyl)imidazo[1,2-a]quinoxalin-4-amine (EAPB0203) and 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine (EAPB0503), have emerged as the most promising anticancer drugs. In the present work, we determined metabolism pathways using liver microsomes from four mammalian species including human.
View Article and Find Full Text PDFIn spite of the development of new anticancer drugs by the pharmaceutical industry, melanoma and T lymphomas are diseases for which medical advances remain limited. Thus, there was an urgent need of new therapeutics with an original mechanism of action. Since several years, our group develops quinoxalinic compounds.
View Article and Find Full Text PDF1,12-Bis[5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium]dodecane dibromide (SAR97276, T3) is a new antimalarial drug, which is currently being evaluated in clinical trials for severe malaria. Drug accumulation inside the parasite and a dual mechanism of action are a major strength of this compound, as it could help delay the development of resistance. The purpose of this article was to develop a rapid resolution LC-MS method for quantifying SAR97276 in mouse tissues.
View Article and Find Full Text PDFSince several years, our group developed quinoxalinic compounds. Among the synthesized compounds, in the imidazo[1,2-a]quinoxaline series, EAPB0203 has shown interesting activities both on melanoma and lymphoma. The structure of EAPB0203 has been modulated and a new compound, EAPB0503, exhibits an in vitro cytotoxic activity on melanoma cancer cell line 7-9 times higher than EAPB0203.
View Article and Find Full Text PDFNew imidazo[1,2-a]quinoxaline analogues have been synthesized in good yields via a bimolecular condensation of 2-imidazole carboxylic acid, followed by a coupling with ortho-fluoroaniline and subsequent substitution on the imidazole ring by Suzuki Cross-coupling reaction using microwave assistance. Antitumor activities of these derivatives were evaluated by growth inhibition of A375 cells in vitro. All compounds exhibited high activities compared to imiquimod and fotemustine used as references.
View Article and Find Full Text PDFBackground: We developed and compared 2 different methods for quantifying uracil (U) and dihydrouracil (UH(2)) in BSA and human plasma. Special attention was paid to the selectivity/specificity and the absence of a matrix effect. The UH(2)/U ratio is intended as a biomarker to identify patients with deficiency in 5-fluorouracil metabolism.
View Article and Find Full Text PDFObjectives: The aim was to study the pharmacokinetic profile of artesunate and its metabolite dihydroartemisinin (DHA) in a pig model.
Methods: Thirteen pigs received either intravenous (iv) or intramuscular (im) artesunate (60 mg), with the alternative preparation given 24 h later in an open crossover design. Five of them also received an additional intra-arterial (ia) artesunate dose (60 mg).
Imidazoquinoxaline and pyrazoloquinoxaline derivatives, analogues of imiquimod, were synthesized, and their in vitro cytotoxic and pharmacodynamic activities were evaluated. In vitro cytotoxicity studies were assessed against melanoma (A375, M4Be, RPMI-7591), colon (LS174T), breast (MCF7), and lymphoma (Raji) human cancer cell lines. In vivo studies were carried out in M4Be xenografted athymic mice.
View Article and Find Full Text PDFOncol Rep
December 2007
In this study we propose for the first time a limited sampling strategy to estimate the individual pharmacokinetic parameters of both irinotecan and SN-38 in patients treated with the irinotecan plus 5-fluorouracil (FOLFIRI) regimen. The pharmacokinetics of irinotecan and SN-38 were studied in 74 patients with advanced inoperable digestive cancer. Plasma concentrations were taken during and up to the 42 h following a 90-min infusion of irinotecan (180-225 mg/m(2)).
View Article and Find Full Text PDFEur J Pharm Sci
May 2007
Peritoneal spread is a common manifestation in ovarian and gastrointestinal cancer. Intraperitoneal (i.p.
View Article and Find Full Text PDFTherapeutic drug monitoring of factor VIII is well established in the treatment of patients with hemophilia attributable to important interindividual variability. The individual initial factor VIII dosage is usually calculated according to individual pharmacokinetic parameters obtained after a dose test administered before the surgery, using at least five-concentration data. The authors proposed a limited sampling strategy to estimate individual pharmacokinetic parameters from one- or two-concentration data in patients with hemophilia A before surgery.
View Article and Find Full Text PDFPurpose: The objectives of this study were to characterize the population pharmacokinetics of MTX in patients with acute lymphoblastic leukemia (ALL) with ages ranging from 2 to 16 years and to propose a limited sampling strategy to estimate individual pharmacokinetic parameters.
Methods: Seventy-nine children were enrolled in this study; they received 1-4 courses of chemotherapy. MTX was administered at a dose of 5 g/m2.
In the present paper, we report for the first time the tissue distribution of ibogaine and noribogaine, the main metabolite of ibogaine, in a 48-year-old Caucasian male, with a history of drug abuse, found dead at his home after a poisoning involving the ingestion of root bark from the shrub Tabernanthe iboga. Ibogaine and noribogaine were quantified in tissues and fluids using a fully validated liquid chromatography-electrospray mass spectrometry method. Apart from cardiac tissue, ibogaine and noribogaine were identified in all matrices investigated.
View Article and Find Full Text PDFThe objective of this study was to determine the impact of single versus sequential exposure to melphalan on the proliferation of an androgen-independent prostate cell line, PC-3, and to report the results of a pilot phase II study. For exposure to a single bolus dose, the doses were added at the start of the study and cell culture was continued for 96 h. For sequential exposure, 1/9 of the dose was added every 1.
View Article and Find Full Text PDFJ Chromatogr B Analyt Technol Biomed Life Sci
November 2006
A liquid chromatography/electrospray ionization mass spectrometry (LC-ESI-MS) method was developed for the first time for the determination of ibogaine and noribogaine in human plasma and whole blood. The method involved solid phase extraction of the compounds and the internal standard (fluorescein) from the two matrices using OasisHLB columns. LC separation was performed on a Zorbax eclipse XD8 C8 column (5 microm) with a mobile phase of acetonitrile containing 0.
View Article and Find Full Text PDFPurpose: Irinotecan is extensively metabolized into at least four compounds and previous pharmacokinetic-pharmacodynamic studies have given varying results. We hypothesized that saliva, a noninvasive, safe and painless biological sampling process, could be a good predictor of the behavior of irinotecan and its metabolites.
Methods: Thirty-five patients with metastatic digestive cancer were treated with a Folfiri regimen every 2 weeks.
J Chromatogr B Analyt Technol Biomed Life Sci
February 2006
A specific and sensitive liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) method was developed for the determination of free and total ropivacaine in human plasma. The work-up procedure involved a simple precipitation of plasma proteins with methanol. Etidocaine served as the internal standard.
View Article and Find Full Text PDF