[Mechanisms of pharmacokinetic drug-drug interactions]. / Mécanismes des interactions médicamenteuses d'origine pharmacocinétique.

Pharmacokinetic drug-drug interactions occur when a drug alters the disposition (absorption, distribution, elimination) of a coadministered agent. Pharmacokinetic interactions may result in the increase or the decrease of plasma drug concentrations. These modifications are variable in intensity but can lead to contraindications of the association. The mechanisms of pharmacokinetic interactions involve drug metabolizing enzymes, drug transporters and orphan nuclear receptors that regulate at the transcriptional level the expression of enzymes and transporters. The increase of drug plasma concentrations is generally related to the inhibition of enzymes and/or drug transport. The decrease of drug concentrations reflects the activation of orphan nuclear receptors by inducers that lead to the increase of the expression of enzymes and drug transporters. Inhibition of drug metabolism or transport is quite immediate (24-48h) while induction is a slower process (7-10 days). Complex situations may be observed with drugs that are both inducers and inhibitors (rifampin, ritonavir). They can cause the decrease and the increase of the exposure of the combined agent depending on the duration of the association.

[First-line treatment with pemetrexed in association with cisplatin in patients with non-operable malignant pleural mesothelioma]. / Association pemetrexed-cisplatine en première ligne dans le mésothéliome pleural malin non opérable.

Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. The optimal treatment of MPM was not clearly defined, until the publication of the multicentre, controlled and randomized phase III trial by Vogelzang et al. in 2003, which made the pemetrexed-cisplatin association the gold standard for the non-operable stages. Eleven patients with histologically proven pleural mesothelioma, not candidates for curative surgery, were assessed for eligibility and treated in our hospital. The response rate was similar to the reference study and the toxicity was acceptable. The median survival time was 12.7 months with an objective response rate of 45.5%. The median time to progression was 7.7 months. Neutropenia (all grades included) was the most common haematological toxicity (42.1%) although only one grade 3/4 was noted. Grade 3/4 anaemia and thrombocytopenia were not reported. Nausea and vomiting were the most commonly reported clinical toxicities with 81.8% reported (all grades included). One cutaneous allergic reaction was reported. The combination of pemetrexed and cisplatin chemotherapy provided the best objectives responses, but new therapeutic regimens are still warranted for these patients with a poor prognosis. The results were similar to those obtained in the Vogelzang et al.'s trial despite a selection bias because they correspond to 36.7% of the total recruitment in the unit.

[Use of linezolid for the treatment of lung infections in adults with cystic fibrosis]. / Utilisation du linézolide dans le traitement des infections broncho-pulmonaires du patient adulte atteint par la mucoviscidose.

INTRODUCTION: Linezolid, a new antistaphylococcal agent for oral or intravenous administration is active against Staphylococcus aureus with limited sensitivity to glycopeptides. The purpose of the present work was to compare data in the literature with practical clinical experience with the use of linezolid for lung infections in adult cystic fibrosis patients with the objective of developing local guidelines for use. MATERIAL AND METHODS: This retrospective clinical study was conducted in the adult pneumology department of a university hospital. RESULTS: The main clinical signs leading to prescription of linezolid were aggravating cough, bronchial obstruction, and exercise-induced fatigue. Among 42 cystic fibrosis patients, six aged 24+/-3 years were given 22 treatments of linezolid. Two patients were given the drug once and the others 2, 4, 5, and 9 times, 600 mg b.i.d. Mean duration of treatment with linezolid was 16+/-5 days. Among the six patients, two presented meti-R S. aureus infection. For twelve cases, clinical improvement was observed; and in two others the situation worsened leading to interruption of linezolid. CONCLUSIONS: There are few reports in the literature on use of linezolid in cystic fibrosis patients. Writing internal guidelines for our department has enabled standardized use: 600 mg b.i.d. p.o. for 14 days as second-line treatment for bronchial exacerbation of S. aureus infection.