The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites

We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated.The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2–2.5-times higher in patients with severe renal impairment (CL_CR<10 ml·min^–1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects.The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance.The maximum target dose in patients with slight renal impairment (CL_CR>30 ml·min^–1) should not be changed. In patients with moderate renal impairment (CL_CR10–30 ml·min^–1) it should be reduced by 50%. In patients with severe renal impairment (CL_CR<10 ml·min^–1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.     

Pharmacokinetics of oxiracetam in elderly patients after 800 mg oral doses, comparison with non-geriatric healthy subjects

The pharmacokinetics of oxiracetam have been studied in eighteen elderly patients and in six healthy non-geriatric adults. A 800 mg single oral dose was administered in the morning of the first day and repeatedly, every 12 h, from day 2 evening to day 10 morning, to the elderly patients. The healthy non-geriatric adults were given a 800 mg single oral dose of oxiracetam. In healthy non-geriatric subjects after a single oral administration of 800 mg, the normalized plasma levels of oxiracetam for 1 mg/kg dose were similar to those already recorded after a 2000 mg single dose of oxiracetam. Therefore, there was no tendency towards non-linear pharmacokinetics of oxiracetam between 800 and 2000 mg single doses in healthy subjects. After the single oral dose, the mean area under the plasma concentration-time curve of oxiracetam in elderly patients was increased by a factor of two as compared to that observed in non-geriatric healthy subjects whereas the maximum concentration (Cmax) was almost not modified and slightly delayed. This can be explained by a slower absorption and elimination in the elderly patients. The highest oxiracetam levels were predominantly recorded in the oldest patients. The slower elimination (mean T1/2 = 12.3 h in elderly and 7.7 h in healthy subjects) could be attributed to a physiological decrease of the renal function. The volume of distribution was not significantly modified in the elderly patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention of myocardial ischemia during exercise 8 hours after use of transdermal nitrate derivatives

A controlled (placebo) double blind trial of a 20 cm2 transdermal system delivering 10 mg of Trinitrin per 24 hours, was carried out in 18 patients with stable angina and significant coronary artery disease. The exercise stress tests were performed at the same time of day using Bruce's protocol and computerised analysis (Case Marquette) after a 48 hour wash out period. All patients had two basal positive and reproducible exercise tests interrupted because of induced anginal pain and/or greater than or equal to 3.5 mm ST depression. There was no significant difference between the basal exercise stress tests and those performed after placebo. With the active drug the onset of ischaemia was delayed (ST less than -1 mm = 217 +/- 122 sec vs 150 +/- 70 sec with placebo, p less than 0.01); the duration of exercise was prolonged (419 +/- 119 sec vs 328 +/- 94 sec with placebo, p less than 0.01); for the same theoretical maximal heart rate, the ST depression was less (-1.6 +/- 0.9 mm vs -2.1 +/- 0.7 mm with placebo, p less than 0.01). On the other hand, the double rate pressure product was unchanged at rest and on effort. These results obtained after a 48 hour therapeutic window show statistically significant benefits with an increase in exercise tolerance and a decrease in myocardial ischaemia 8 hours after the application of transdermal Trinitrin system.     

Pharmacokinetics of oxiracetam in patients with renal impairment after a 800 mg single oral dose

The pharmacokinetics of oxiracetam in patients with renal impairment were investigated after administration of a 800 mg single oral dose of oxiracetam. The renal insufficiency was estimated on the basis of the creatinine clearance (CLcr) which ranged from 9 to 95 ml/min among the 20 patients. In plasma, the terminal elimination half-life (T1/2) ranged from 10.6 to 68.1 h, the highest T1/2 corresponding to the patients with a high degree of renal impairment. In urine, the amounts of oxiracetam excreted during the 48 h postdosing represented 8.3 to 82.6% of the dose. They were lower in patients with a high degree of renal impairment. The correlations between the total clearance of oxiracetam, the renal clearance, the terminal apparent elimination rate constant in plasma, and CLcr were estimated by linear regression analysis. The correlation coefficients were 0.916, 0.985 and 0.803 respectively. The apparent volume of distribution of the central compartment V(1) and the total volume of distribution at the steady-state V(SS) were not dependent on the degree of renal impairment. The mean values +/- SD were 25.9 +/- 13.0 litres and 48.3 +/- 21.5 litres respectively. Oxiracetam concentrations in plasma of patients were estimated for repeated administration of 800 mg of oxiracetam.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperkinetic shock in viral and pneumococcal pneumonias

Summary Ten patients, suffering from severe viral or bacterial pneumonia had circulatory shock, characterised haemodynamically by normal or high cardiac output (CI=4.1±1.2 1/min/m²) and low systemic resistance (SVR=14±3.7 mm Hg/1/min/m²). Existence of such a hyperkinetic state greatly complicates the management of patients. Plasma volume expansion, performed in five cases of initial hypovolaemia, and Dopamine infusion (five patients) increased markedly the intra-pulmonary shunting. High level PEEP ventilation was not tolerated, despite the improvement of blood gases it produced. Extra-corporeal membrane lung oxygenation (three cases), whilst giving an initial decrease of shunting and restoring SVR, produced no long term survivors. All the ten patients died from intractable shock and severe hypoxaemia. Spontaneous ventilation with positive expiratory pressure (CPAP) is believed to be an attractive alternative, due to its absence of deleterious haemodynamic effects.Abbreviations D(a-v) O ₂ arteriovenous oxygen difference - CI cardiac index - PaO ₂ arterial oxygen tension - PEEP positive end expiratory pressure - PVE plasma volume expansion - PVR pulmonary vascular resitance - PWP pulmonary wedge pressure - intra pulmonary shunting - SAP mean systemic arterial pressure - SVR systemic vascular resistance - VO ₂ oxygen consumption - VA veno arterial This work was supported by grants from CNATMS-INSERM (No. 17-03-1976) INSERM (75-1-84.5) and Université Paris Val-de-Marne (900-659-017)