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 (CLCR < 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 (CLCR > 30 ml.min-1) should not be changed. In patients with moderate renal impairment (CLCR 10-30 ml.min-1) it should be reduced by 50%. In patients with severe renal impairment (CLCR < 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.
Thirty-two pregnant hypertensive patients were treated with oxprenolol administered in combination with dihydralazine as Trasipressolg tablets. Before delivery, oxprenolol was demonstrable in the maternal plasma and the amniotic fluid. The free fraction of oxprenolol in the maternal serum (15% + 7.8; mean + s.d.; n = 25) was similar to that in normal serum. At the end of delivery, oxprenolol was found in both the maternal and umbilical plasma in most cases. Measurable, but low oxprenolol concentrations were present in the newborn plasma. After delivery, oxprenolol was demonstrable in the maternal plasma and breast milk. An infant weighing 3 kg and consuming 500 ml of breast milk per day would receive a maximum dose 60 times less than the normal daily dose for a hypertensive adult (4 mg/kg).
Impaired vascular reactivity during combined ultrafiltration-hemodialysis (UF+HD) compared with hemofiltration (HF) remains a rather enigmatic problem, the causes of which are still not well understood. Although a number of factors have been claimed to be responsible, most recent studies point to a major role of the extracorporeal blood temperature, which is usually lower during HF compared with UF + HD. However, previous studies in which hemodynamics were studied during UF + HD and HF in relation to the extracorporeal blood temperature are limited by the use of acetate in UF + HD, and measurements were often confined to BP and heart rate. Therefore, arterial BP, as well as forearm vascular resistance (FVR) and venous tone (strain-gauge plethysmography), was measured in 11 hemodialysis patients during 3 h UF + HD (37.5 degrees C) and predilution HF (39.0 degrees C = warm HF), resulting in equivalent extracorporeal blood temperatures. Patients were also studied during cold HF at an infusate temperature of 36.0 degrees C. UF + HD and HF were matched with respect to the dialysate and infusate composition (bicarbonate), bio-compatibility factors, and small molecule clearance. At equivalent temperatures, UF + HD and HF were associated with a comparable vascular and BP response. Only cold HF was associated with a significant increase in FVR. In addition, FVR and venous tone, as well as arterial BP, were all significantly higher during cold HF compared with both UF + HD and warm HF. These results indicate that the disparity in vascular reactivity between UF + HD and HF is primarily related to differences in the extracorporeal blood temperature.
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