Epidemiologic investigation of the relative clearance of haloperidol by mixed-effect modeling using routine clinical pharmacokinetic data in Japanese patients.

The steady-state trough concentrations of haloperidol were studied to clarify the role of the characteristics of Japanese patients in estimating haloperidol dosing regimens by using routine therapeutic drug-monitoring data. Nonlinear mixed-effects modeling (NONMEM) was used to estimate the effect of a variety of developmental and demographic factors on haloperidol clearance values using 270 serum level measurements obtained from 191 patients during their clinical course. The final model describing haloperidol's relative clearance was CL = 0.74 x TBW(0.594) x DOSE(0.326) x 1.32CO1 x 0.867AGE, where CL is clearance (measured in liters per hour), TBW is the total body weight (in kilograms), DOSE is the daily dose of haloperidol (in grams per kilogram per day), CO1 = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin, or carbamazepine) and CO1 = 0 otherwise, and AGE = 1 for patients aged 55 years or older and AGE = 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or older showed a 13.3% reduction in clearance values compared with the younger population.

Pharmacokinetic interactions among phenobarbital, carbamazepine, and valproic acid in pediatric Japanese patients: clinical considerations on steady-state serum concentration-dose ratios.

With antiepileptic drugs, the marked inter- and intrapatient variability of the concentration-dose ratio makes it difficult to predict serum concentrations from the dose administered per kilogram. The effects of comedication on steady-state serum concentration/dose ratios of antiepileptic drugs were evaluated retrospectively in 669 pediatric patients. To avoid complex pharmacokinetic interactions among multiple antiepileptic drugs, the data on serum concentrations in the current study were collected from patients who were co-administered only one additional antiepileptic drug (phenobarbital-carbamazepine, phenobarbital-valproic acid, or carbamazepine-valproic acid) or who received monotherapy. The concentration/dose ratio for the antiepileptic drugs increased significantly with body weight in children up to 15 years old. Associated therapy with antiepileptic drugs affected the concentration/dose ratio. Therefore, routine monitoring of serum concentrations of the antiepileptic drugs is extremely useful, particularly in children and in patients who require associated antiepileptic medication.

[Modification of noxious spinal stimulation on trigemino-trigeminal reflex--analysis in an in vitro brainstem-spinal cord preparation from newborn rats].

Whether reflex responses of the trigeminal motoneurons induced by the stimulation of the trigeminal sensory root (Vs) are inhibited by heterotopic noxious conditioning stimulation applied to the tail was investigated, using a novel in vitro brainstem-spinal cord preparation isolated together with the hindlimbs and tail of newborn rats. The neural activity evoked by electrical stimulation of Vs with a suction electrode was monitored from the trigeminal motor root (Vm) with a suction electrode in a recording chamber. The tail was pinched with forceps as the heterotopic noxious conditioning stimulation (tail pinch). In some experiments, a plastic septum sealed with Vaseline was used to partition the pool for the brainstem from that for the other part of the preparation. The results were as follows: (1) electrical stimulation of Vs induced a long lasting (duration: over 300 ms) positive potential with a peak-latency of about 80 ms in Vm; (2) the response was suppressed in amplitude by the tail pinch; (3) the suppressive effect of the tail pinch was blocked by bath application of naloxone (50 microM) to the brainstem chamber; and (4) removal of the mesencephalon from the preparation did not affect the suppressive effects of the tail pinch. It was concluded that the trigeminal reflex response is suppressed by noxious conditioning stimulation on the remote region, and that in this suppression opioid receptors located in the lower brainstem are involved. This in vitro preparation will be useful for investigations of the neural mechanisms underlying nociceptive modification of neural activity.