[Pregnancy in a patient with mitochondrial disease]. / Grossesse chez une patiente atteinte de cytopathie mitochondriale.

We report a case of a pregnant woman with a mitochondrial disorder affecting the energy-generating pathway of oxidative phosphorylation which was suggested when the patient presented the progressive clinical phenotype of a proximal tubular renal insufficiency, a muscular weakness of extremities, a bilateral optic neuropathy and a brain magnetic resonance imaging suggesting diffuse leucoencephalopathy. Her diagnosis was made on the basis of abnormal mitochondria on a muscle biopsy and of spectrophotometric deficiencies of the complexes I, II+III and IV of the respiratory chain. No specific molecular mutation could be detected. Her pregnancy was complicated by a severe preeclampsia, an insulin requiring gestational diabetes and a worrying renal failure which precipitated the premature delivery by cesarean section at 30 weeks gestation. The clinical course of the female neonate weighing 1030 grams was uneventful. At two Years of age she showed no sign of mitochondrial disease. But the postpartum course of the mother was complicated by seizures and a terminal renal failure leading presently to dialysis, but requiring a kidney transplantation in the near future.

Dose-finding and pharmacokinetic study of an all-oral combination regimen of oral vinorelbine and capecitabine for patients with metastatic breast cancer.

PURPOSE: A phase I study was performed to determine the maximal tolerated dose, recommended doses (RDs), safety and efficacy of oral vinorelbine when combined with capecitabine in an all-oral chemotherapy regimen in patients with metastatic breast cancer (MBC), with pharmacokinetic blood sampling to investigate potential drug-drug interactions. PATIENTS AND METHODS: Forty-four patients with MBC received as first- or second-line chemotherapy, oral vinorelbine at a dose of 60 or 80 mg/m2 on days 1 and 8 (and 15) with escalating doses of capecitabine from 1650 to 2500 mg/m2/day days 1-14 every 3 or 4 weeks. Three schedules were tested: day 1, day 8 and weekly regimens of oral vinorelbine with a 14-day course of capecitabine every 3 weeks; and a days 1 and 8 regimen of oral vinorelbine with a 14-day course of capecitabine every 4 weeks. RESULTS: With oral vinorelbine at 60 mg/m2, the RDs were established as oral vinorelbine 60 mg/m2 on days 1 and 8 plus capecitabine 2250 mg/m2/day days 1-14 and oral vinorelbine 60 mg/m2/week plus capecitabine 2000 mg/m2/day days 1-14. With oral vinorelbine at 80 mg/m2, the RD was oral vinorelbine 80 mg/m2 on days 1 and 8 plus capecitabine 2000 mg/m2/day days 1-14. Neutropenia was the main dose-limiting toxicity of the combination; it was reported in 40 patients (90.9%), with grade 3 in 14 patients (31.8%) and 6.2% of cycles, and grade 4 in 12 patients (27.3%) and 4.3% of cycles. Complications were rare with only three patients experiencing febrile neutropenia (one episode each). The most frequent non-haematological toxicity was gastrointestinal; however, the incidence of grade 3 was low, with no episode of grade 4. Hand-foot syndrome was reported in 14 patients (31.8%) and 22.6% of cycles, with grade 2 in two patients (4.5%) and 1.2% of cycles (two episodes each). No episode of grade 3 was observed. Objective responses were reported in 18 patients (three complete responses and 15 partial responses), yielding a response rate of 40.9% in the intention-to-treat population according to the investigator assessment. Results from the pharmacokinetic study demonstrated the absence of mutual pharmacokinetic interactions when both drugs were co-administered. CONCLUSIONS: The combination of oral vinorelbine and capecitabine is safe and easy to administer in an outpatient setting. This all-oral combination chemotherapy may offer a good alternative to the intravenous route for patients with MBC. Based on these promising results, a phase II study has started using oral vinorelbine 60 mg/m2/week with capecitabine 2000 mg/m2/day days 1-14 every 3 weeks as first-line chemotherapy in patients with MBC.

Liquid chromatographic analysis of propranolol enantiomers in human blood using precolumn derivatization with (+)-1-(9-fluorenyl)ethyl chloroformate.

A method for the determination of the R-(+) and S-(-) enantiomers of propranolol in blood was developed. After extraction with heptane-isopentanol and derivatization with (+)-1-(9-fluorenyl)ethyl chloroformate, excess reagent was removed using solid-phase extraction. The enantiomers were separated on an achiral, reversed-phase, radially compressed column, and detected by fluorescence with excitation and emission wavelengths of 260 and 340 nm, respectively. The limit of quantification was 0.5 ng/ml. This method was used for pharmacokinetic analysis of propranolol enantiomers after administration of immediate-release (80 mg) or sustained-release (160 mg) racemic propranolol.

Acebutolol and diacetolol plasma levels in patients undergoing myocardial revascularization with hypothermic cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) has been reported to alter the disposition of numerous drugs and consequently to modify their plasma levels. The present study was designed to delineate the time course of acebutolol (a cardioselective beta-blocker) and diacetolol (its main metabolite) plasma levels in seven patients undergoing myocardial revascularization with hypothermic CPB. All patients were given oral acebutolol twice daily until 3 hours before surgery. Initiation of CPB produced an immediate and significant, but transient, decrease in acebutolol and diacetolol plasma concentrations. Cessation of CPB was not associated with an increase in plasma beta-blocker levels. It is concluded that CPB does not induce major alterations in the time course of acebutolol and diacetolol plasma concentrations.