[Trapezius muscle paralysis after plastic surgery. 2 cases].
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Biomedical subjects
Publications and source records attributed to B Cenraud.
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The kinetics of clobazam taken 3 h before, during, and 3 h after a standard hospital meal were studied in six healthy volunteers. Peak plasma levels were significantly lower when the drug was taken with or after meals suggesting that the rate of absorption was reduced by food. The mean area under the concentration vs time curve was not affected by the time of drug administration indicating that the meal had no effect upon the extent of absorption.
The effect of meals on valproic acid (VPA) absorption from an enteric coated (EC) formulation was investigated. In study I, six adult normal volunteers received a single 500 mg dose of sodium valproate in randomized treatments: fasting (A), with a meal (B) or 3 hours after a meal (C). There were significant differences between treatments in the latency period (Lp) defined as the time during which measured concentrations of VPA were less than 1 microgram/ml. Lp values for treatments A, B and C were: 1.67 +/- 1.25 hr, 6.75 +/- 3.98 hr and 7.63 +/- 3.15 hr respectively. In study II, six subjects (five from study I) received in a randomized fashion a 400 mg intravenous bolus dose of VPA and a 500 mg EC VPA tablet, 3 hours after a meal. The mean Lp value was 8.1 +/- 1.6 hr and the mean bioavailability was 100%. Clearance, volume of distribution and half-life values obtained after intravenous dosing were comparable to literature values. These results indicate that food intake delays but does not decrease the extent of absorption of VPA from an enteric coated formulation.
In 17 epileptics receiving carbamazepine (CBZ) alone or in combination with other anticonvulsant drugs, administration of triacetyloleandomycin (Tri A) led to an acute and unexpected intoxication (drowsiness, nausea, vomiting, and dizziness). Similar symptoms occurred again in 3 patients after Tri A was administered a second time. The same toxic manifestations were observed in two patients receiving CBZ and erythromycin. A rapid increase in plasma levels of CBZ occurred after institution of Tri A therapy in 6 patients, the CBZ levels quickly returning to normal after withdrawal of Tri A. Thus, it is suggested that the observed intoxication is due to the simultaneous administration of CBZ and Tri A (or erythromycin). The possible role of hepatic dysfunction in this syndrome of intoxication is discussed. Furthermore, the intoxication may be at least partially related to serum electrolyte disturbances, as suggested by one case in which obvious signs of water intoxication were detected. The severity and frequency of intoxication should lead to proscribing Tri A or other macrolide antibiotics in patients receiving CBZ.
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Severe vigilance disturbances are rarely observed during sodium valproate treatment. Two such cases are reported, with rapid appearance of mental confusion after starting treatment, associated with an overall slowing of the E.E.G. the plasma levels of the different anti-epileptic agents were normal or only slightly raised and could not have caused the phenomenon. Clinical and electrical signs regressed as rapidly after stopping valproate administration as they had appeared after starting treatment.
Patients on long term valproate treatment exhibit unusual fluctuations in steady-state plasma levels of valproic acid. In order to delineate the underlying mechanisms of these fluctuations, 2 studies were undertaken. In the oral study, 6 epileptic patients received enteric-coated sodium valproate tablets (on a bid regimen for at least 1 month) and plasma levels were monitored on an hourly basis during 24 hours. In the intravenous study, 5 patients received first an intravenous bolus dose (800mg) of sodium valproate followed a week later by a combination intravenous loading dose/constant rate infusion for 36 hours. Plasma valproic acid concentrations were monitored hourly during the infusion study. In the oral study, valproic acid concentrations in all subjects continued to decay for 5 to 6 hours following the 8pm dose. The mean fluctuation in concentrations during 24 hours was 112.8 +/- 31.6%. Consecutive fasting levels were not reproducible. In the intravenous study, small but significant oscillations were present at steady-state; fluctuations ranged from 22 to 34%. However, no circadian rhythm was apparent. On the basis of these findings, it appears that the value of a single fasting sample during therapeutic monitoring of valproic acid is questionable. For an accurate evaluation of valproic acid plasma levels, an average concentration based upon several daily determinations should be performed.
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An increase in drug metabolic clearance results in a decrease in concentration of parent drug but the effect on concentration of metabolite has been unclear. The effect of increases in the clearance of parent drug and/or metabolite upon the metabolite concentration, metabolite-to-parent drug concentration ratio, and fraction metabolized is described theoretically. It is shown that several combinations of increases in specific clearances can lead to qualitatively similar effects on steady state concentration of metabolite. The effect of increases in metabolic clearances of the clobazam-norclobazam system caused by carbamazepine treatment was studied in normal volunteers. The steady state concentration of metabolite (norclobazam) increased 1.4-fold and the ratio of metabolite to parent drug increased 4-fold. These effects of carbamazepine on clobazam-norclobazam pharmacokinetics could be a result of five theoretical cases. It is concluded that at least the formation clearance of norclobazam was increased. Carbamazepine treatment caused at least a 4-fold increase in the N-demethylation clearance of clobazam. It was also deduced that, in the baseline state, no more than 70% of the clobazam dose was metabolized to norclobazam, even though the norclobazam concentration was more than twice the clobazam concentration.