Evaluation of amidoxime derivatives as prodrug candidates of potent bis-cationic antimalarials.

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.

A Novel Methodology to Estimate the Treatment Effect in Presence of Highly Variable Placebo Response.

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.

Structural characterization of in vitro metabolites of the new anticancer agent EAPB0503 by liquid chromatography-tandem mass spectrometry.

EAPB0503, 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.

Characterization of a new anticancer agent, EAPB0203, and its main metabolites: nuclear magnetic resonance and liquid chromatography-mass spectrometry studies.

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.

Stability of the ready-to-use solutions of eribulin for intravenous infusion.

A simple HPLC-UV method was developed to determine the stability of ready-to-use eribulin solutions under different storage conditions. The developed method was validated with respect to linearity, accuracy, precision and ruggedness. The following admixtures were prepared: 3-mL polypropylene syringes at concentration of 440 μg/mL and multilayer laminate polyolefin containers containing 0.

A quantitative liquid chromatography tandem mass spectrometry method for metabolomic analysis of Plasmodium falciparum lipid related metabolites.

Plasmodium falciparum is the causative agent of malaria, a deadly infectious disease for which treatments are scarce and drug-resistant parasites are now increasingly found. A comprehensive method of identifying and quantifying metabolites of this intracellular parasite could expand the arsenal of tools to understand its biology, and be used to develop new treatments against the disease. Here, we present two methods based on liquid chromatography tandem mass spectrometry for reliable measurement of water-soluble metabolites involved in phospholipid biosynthesis, as well as several other metabolites that reflect the metabolic status of the parasite including amino acids, carboxylic acids, energy-related carbohydrates, and nucleotides.

Stability of ready-to-use temsirolimus infusion solution (100mg/L) in polypropylene containers under different storage conditions.

The aim of this study was to determine the stability of ready-to-use temsirolimus infusion solutions under different storage conditions. Solutions were prepared in polypropylene containers by adding temsirolimus injection to 0.9% sodium chloride infusion to reach a final concentration of 100mg/L.

Intraperitoneal administration of novel doxorubicin loaded polymeric delivery systems against peritoneal carcinomatosis: experimental study in a murine model of ovarian cancer.

Objective: Peritoneal spread is an adverse outcome in ovarian cancer. Despite clinical efficiency, intraperitoneal (i.p.

Methotrexate pharmacokinetics in childhood acute lymphoblastic leukaemia: a prognostic value?

What Is Known And Objective: In industrialized countries, acute lymphoblastic leukaemia (ALL) is the most frequent cancer in children aged less than 15 years. High-dose methotrexate is a common component of many chemotherapeutic protocols for childhood with ALL. Our objective was to retrospectively evaluate the pharmacokinetics and plasma levels of high-dose methotrexate as it relates to event-free survival (EFS) in children with ALL.

Population pharmacokinetics of nalbuphine after surgery in children.

Background: Nalbuphine is an opioid analgesic agent widely used for control of mild-to-severe pain. However, limited data are available on the pharmacokinetics of this drug in children. The aim of this study was to characterize the population pharmacokinetics of nalbuphine in patients with ages ranging from 1 to 11 yr and to identify patient characteristics partially explaining inter-individual variability in nalbuphine pharmacokinetic parameters.

Pharmacokinetic properties and metabolism of a new potent antimalarial N-alkylamidine compound, M64, and its corresponding bioprecursors.

Antimalarial 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).

Metabolism and pharmacokinetics of EAPB0203 and EAPB0503, two imidazoquinoxaline compounds previously shown to have antitumoral activity on melanoma and T-lymphomas.

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.

Clinical impact of intesified 5-Fluorouracil-based chemotherapy using a prospective pharmacokinetically-guided dosing approach: comparative study in elderly and non-elderly patients with metastatic colorectal cancer.

We compared clinical outcome and pharmacokinetic (pK) parameters of a new pharmacokinetically-guided dosing strategy in two groups of patients (age < or >65 years) with metastatic colorectal cancer (mCRC). We retrospectively analyzed all the patients with mCRC, receiving standard LV5FU2 regimen during cycle-1, intensified from cycle-2 onwards according to an adaptation schedule based on the area under the concentration-time curve (AUC) value (mg.h/l.

Pharmacology of EAPB0203, a novel imidazo[1,2-a]quinoxaline derivative with anti-tumoral activity on melanoma.

In 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.

Quantitation of SAR97276 in mouse tissues by rapid resolution liquid chromatography-mass spectrometry.

1,12-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.

Quantitation of imidazo[1,2-a]quinoxaline derivatives in human and rat plasma using LC/ESI-MS.

Since 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.

Rapid resolution liquid chromatography-mass spectrometry determination of SAR97276 in monkey matrices. Pharmacokinetics in rhesus monkey infected by Plasmodium cynomolgi.

Since several years, we developed a new class of antimalarial drugs targeting the phospholipid metabolism of the Plasmodium falciparum malaria parasite. The bis-thiazolium compound, SAR97276, is the lead compound and is now in clinical development. In this paper, we applied the fast rapid resolution liquid chromatography-mass spectrometry technique to the analysis of SAR97276 in monkey matrices.

New imidazo[1,2-a]quinoxaline derivatives: synthesis and in vitro activity against human melanoma.

New 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.

Population pharmacokinetics of the two enantiomers of tramadol and O-demethyl tramadol after surgery in children.

Background: Few data are available on the stereoselective pharmacokinetics of tramadol in children. The aim of this study was to develop a population pharmacokinetic model for the (+)- and (-)-enantiomers of tramadol and its O-demethyl tramadol metabolite (M1) in children.

Methods: Twenty-five children (1-8 yr) were included in this study.

A liquid chromatography-mass spectrometry assay for simultaneous determination of two antimalarial thiazolium compounds in human and rat matrices.

A new class of antimalarial drugs targeting phospholipid metabolism of the malarial parasite is now in development. In the strategy of this development, two mono-thiazolium salts, T1 and T2, need to be monitored. A liquid chromatography-mass spectrometry (LC-MS) method has been developed and validated according to FDA guidelines for simultaneous determination of T1 and T2 in plasma, whole blood and red blood cells (RBCs) from human and rat.

Ibogaine, an anti-addictive drug: pharmacology and time to go further in development. A narrative review.

Ibogaine is an indole alkaloid derived from the bark of the root of the African shrub Tabernanthe iboga. Psychoactive properties of ibogaine have been known for decades. More recently, based on experimental data from animals and anectodal reports in human, it has been found that this drug has anti-addictive effects.

HPLC with UV or mass spectrometric detection for quantifying endogenous uracil and dihydrouracil in human plasma.

Background: 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.

Pharmacokinetics of artesunate in the domestic pig.

Objectives: 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).

In vitro and in vivo anti-tumoral activities of imidazo[1,2-a]quinoxaline, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline derivatives.

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.

A Kinetic Model for Simultaneous Fit of Clozapine and Norclozapine Concentrations in Chronic Schizophrenic Patients during Long-Term Treatment.

Objective: The pharmacokinetic profiles of clozapine and its main metabolite, norclozapine, were investigated in 18 chronic schizophrenic inpatients during long-term treatment.

Patients: Patients received stable daily doses (between 300 and 900mg) for at least 1 month. Plasma drug concentrations were determined by high performance liquid chromatography.