A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia.

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m(-2) day(-1) was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m(-2) day(-1). Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m(-2) day(-1) for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m(-2), and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m(-2) day(-1). The mean half-life of ssHHT was 11.01+/-3.4 h, the volume of distribution at steady state was 2+/-1.4 l kg(-1) and the plasma clearance was 11.6+/-10.4 l h(-1). Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m(-2) day(-1).

[Assessment of compliance with ARV treatment in Africa]. / Bilan de quelques études sur l'observance aux ARV en Afrique.

This study was conducted in health facilities in the capitals of five sub-Saharan African countries (Cotonou, Benin; Bangui, Central African Republic; Libreville, Gabon; Yaoundé, Cameroon; and Casablanca, Morocco). The purpose was to investigate factors promoting and impeding compliance with antiretroviral therapy (ART) and cotrimoxazole (CTX) prophylaxis in adult patients. Patients were interviewed immediately after follow-up examination to identify the problems that they encountered and the solutions that they proposed to improve compliance. Compliance was assessed based on three measurement modalities, i.e. skipping medication during the four days prior to attendance, counting the number of remaining tablets, and attendance assiduity. Compliance scores varied according to measurement modality from 65% to 90%. All patients underlined the impact of treatment on their daily life and the difficulty of following the prescribed regimen properly. Impeding factors for compliance were treatment-related hunger, lack of information, out-of-pocket expenses (including laboratory tests, transportation, and loss of income), side effects, long waiting time at the treatment centers, and fear stigma and discrimination. Efforts to increase access to treatment can only be successful if accompanied by measures to promote compliance.

[Plasma assay of methadone enantiomers with high performance liquid chromatography]. / Dosage plasmatique des énantiomères de la méthadone par chromatographie liquide à haute performance.

6-Dimethylamino-4,4-diphenylheptane-3-one (methadone) is a synthetic opioid. Presence of an assymetrical carbon in its structure explains existence of two enantiomers. Levogyral enantiomer or R-methadone exhibits an 25 fold superior analgesic activity to the dextrogyral enantiomer S-methadone. In order to run separately a plasma assay of these two enantiomers, a chromatographic chiral separation method coupled with an ultraviolet detection has been performed. It allows selective assay of each enantiomer. This method, although an analytical interference with d-propoxyphene, is sensitive, reproductible, specific and shows a convenient resolution for the analysis of both the stereospecific and racemic forms. This method can be applied for pharmacokinetic study of the drug in patients treated by methadone.

Sensitive determination of tenofovir in human plasma samples using reversed-phase liquid chromatography.

A new high-performance liquid chromatography assay was developed for the determination of tenofovir, a nucleotide analogue, in plasma. A solid-liquid extraction procedure was coupled with a reversed-phase HPLC system. The system requires a mobile phase containing Na(2)HPO(4) buffer, tetrabutylammonium hydrogen sulfate and acetonitrile for different elution through a C(18) column with UV detection. The method proved to be accurate, precise and linear between 10 and 4000 ng/ml. The method was applied to determine trough levels of tenofovir in 11 HIV-infected patients with virologic failure under multiple antiretroviral therapy. This method was also successfully applied to a pharmacokinetic study in an HIV infected patient with renal failure.