In vivo recovery (IVR) is traditionally used as a parameter to characterize the pharmacokinetic properties of coagulation factors. It has also been suggested that dosing of factor VIII (FVIII) and factor IX (FIX) can be adjusted according to the need of the individual patient, based on an individually determined IVR value. This approach, however, requires that the individual IVR value is more reliably representative for the patient than the mean value in the population, i.e. that there is less variance within than between the individuals. The aim of this investigation was to compare intra- and interindividual variance in IVR (as U dL1 per U kg1) for FVIII and plasma-derived FIX in a cohort of non-bleeding patients with haemophilia. The data were collected retrospectively from six clinical studies, yielding 297 IVR determinations in 50 patients with haemophilia A and 93 determinations in 13 patients with haemophilia B. For FVIII, the mean variance within patients exceeded the between-patient variance. Thus, an individually determined IVR value is apparently no more informative than an average, or population, value for the dosing of FVIII. There was no apparent relationship between IVR and age of the patient (1.5-67 years). For FIX, the mean variance within patients was lower than the between-patient variance, and there was a significant positive relationship between IVR and age (13-69 years). From these data, it seems probable that using an individual IVR confers little advantage in comparison to using an age-specific population mean value. Dose tailoring of coagulation factor treatment has been applied successfully after determination of the entire single-dose curve of FVIII:C or FIX:C in the patient and calculation of the relevant pharmacokinetic parameters. However, the findings presented here do not support the assumption that dosing of FVIII or FIX can be individualized on the basis of a clinically determined IVR value.
dose requirements of factor VIII over the age range 3-74 years.
The use of cholinergic drugs, either alone or in combination with other drugs, has been suggested as an approach to improve treatment outcome for patients suffering from neuropathic pain. The present study was undertaken in the rat spared nerve injury model of neuropathic pain to evaluate the effect of the cholinesterase inhibitor donepezil when administered (1) alone and (2) as low-dose in combination with the first-line recommendation gabapentin. The co-administration studies were performed following single and multiple dosing. Single, parenteral dosing of donepezil (1, 1.5 and 3 mg/kg s.c.) produced a dose-dependent reversal of the neuropathic pain behaviour. Co-administration of a sub-effective dose of donepezil (0.5 mg/kg s.c.) and low doses of gabapentin (10 and 30 mg/kg s.c.) resulted in a three- to fourfold increase of the analgesic effect, in comparison with gabapentin administered alone. Following multiple, oral dosing, gabapentin (25 mg/kg p.o.) was administered once daily over 20 days. Addition of donepezil (1.5 mg/kg p.o.) from day 11 to day 20 resulted in improved analgesia during the period of combination therapy, in comparison with the gabapentin monotherapy period. Furthermore, the treatment effects were stable in both the mono- and the combination therapy period, indicating that tolerance development does not occur within the studied time frame. In conclusion, the results from this preclinical study support the use of donepezil as adjunctive to gabapentin to improve the therapeutic outcome in the management of neuropathic pain.
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