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Biomedical subjects

J R Haigh

Publications and source records attributed to J R Haigh.

31 records · Page 2Linked to original sources
PubMed1988

The effect of allopurinol on the steady-state pharmacokinetics of indomethacin.

The effect of 5 days treatment with allopurinol (300 mg) on the pharmacokinetics of indomethacin at steady-state was investigated in eight patients. Allopurinol produced no significant effect on the indomethacin serum concentration-time curve. Allopurinol did not alter significantly the amounts of indomethacin excreted in the urine within 8 h. However, the urinary ratio of N-deschlorobenzoylindomethacin to indomethacin was reduced significantly by allopurinol administration (P less than 0.05).

Adult↗
PubMed1988

Lipids and platelet function in runners.

The effect of distance running on the fatty acid composition of platelet and erythrocyte membranes has been investigated, together with platelet aggregation and levels of high density lipoprotein-cholesterol (HDLc), low density lipoprotein cholesterol (LDLc), total cholesterol and triglycerides in runners (n = 11) and healthy age-matched non-running controls (n = 12). Platelet aggregation and fatty acid composition of membrane lipids in both platelets and erythrocytes are similar in both groups with the following exceptions: in platelets docosahexaenoic acid (C22:6 omega 3) is significantly higher in runners; in erythrocytes the fatty acids C20:3 omega 6/C22:1 omega 9 and C22:5 omega 3 are significantly higher in runners. There were no significant differences between the levels of HDLc, LDLc and total cholesterol in runners and controls although triglycerides were significantly lower in runners. Possible beneficial effects of running are probably mediated through effects on serum lipid and lipoprotein concentrations, and probably not due to any antithrombotic effect of platelets.

Adult↗
PubMed1987

N-desmethylclobazam: a possible alternative to clobazam in the treatment of refractory epilepsy?

The development of anticonvulsant tolerance during 10 days treatment with either clobazam or its principal metabolite, N-desmethylclobazam (NDMC), was compared in mice using an i.v. infusion of pentylenetetrazole as the convulsive stimulus. Subsequently the anticonvulsant activity of NDMC was assessed in patients with refractory epilepsy. In mice, a highly significant tolerance (P less than 0.001) developed to clobazam (10 mg kg-1 twice daily). During the same period, there was no significant change (P greater than 0.05) in the protection afforded by NDMC (40 or 80 mg kg-1 twice daily) although some reduction in anticonvulsant activity was apparent. NDMC (30 mg once daily) was given to nine patients with frequent complex partial and/or grand mal seizures who had become tolerant to the anticonvulsant effect of clobazam. Seven of the patients had been free from benzodiazepine therapy for at least 2 weeks, while the other two patients were switched directly from clobazam. Eight of the nine patients showed a favourable response to NDMC. In the seven who had been given a holiday from clobazam the response to NDMC was similar to the initial response to clobazam and was achieved at plasma NDMC concentrations in the same range as those seen during clobazam administration (1000-3000 ng ml-1). It is concluded that NDMC is active as an anticonvulsant in man and there is evidence from the animal studies to suggest that it may be preferable to clobazam.

Adult↗
PubMed1987

The effect of cimetidine on the single dose pharmacokinetics of oral clobazam and N-desmethylclobazam.

The effect of cimetidine on the single dose pharmacokinetics of orally administered clobazam and N-desmethylclobazam (NDMC) was studied in volunteers. Cimetidine inhibited the elimination of both clobazam and NDMC and inhibited the rate of formation of NDMC from clobazam. The increase in the AUC for NDMC generated from clobazam was relatively greater than that for clobazam itself. This suggests that NDMC elimination is inhibited to a relatively greater extent than clobazam elimination. The increase in AUC for NDMC generated from clobazam was also relatively greater than that for NDMC administered orally. This would suggest that cimetidine either increases the bioavailability of clobazam or reduces that of NDMC. The increases in the AUC for NDMC and for clobazam in some individuals was of a magnitude which is likely to be clinically significant.

Adult↗
PubMed1987

Pharmacokinetics of N-desmethylclobazam in healthy volunteers and patients with epilepsy.

1. The single dose pharmacokinetics of N-desmethylclobazam (NDMC) and clobazam were studied in eight healthy male volunteers. 2. Steady-state pharmacokinetic data are described from four healthy male volunteers and eight epileptic patients taking NDMC. 3. A single 30 mg dose of NDMC produced a greater Cmax (P less than 0.001) and AUC0-infinity (P less than 0.005) and a shorter tmax (P less than 0.05) and t1/2 (P less than 0.01) for NDMC than did 30 mg clobazam. 4. Mean steady-state NDMC concentrations were greater in male patients than in female patients and also in male patients compared with male volunteers. The differences between patients and volunteers might be explained by concomitant antiepileptic medication.

Adult↗
PubMed1986

Benzodiazepine cross-tolerance in mice extends to sodium valproate.

Slow intravenous infusion of pentylenetetrazol was used to measure the convulsive threshold in mice. The anticonvulsant effects of clobazam, clonazepam, diazepam, lorazepam, sodium phenobarbitone and sodium valproate were assessed in naive animals and compared with the effects of the same compounds in animals which had been pretreated (twice daily for 3 days) with one of the benzodiazepines or sodium valproate. Cross-tolerance was observed between all the benzodiazepines but not between benzodiazepines and sodium phenobarbitone. Animals pretreated with the benzodiazepines were cross-tolerant to valproate, but the converse was not true; nor did sodium valproate induce tolerance to itself.

Animals↗
PubMed1986

Tolerance to the anticonvulsant effect of clonazepam in mice: no concurrent change in plasma concentration.

Clonazepam was administered for 10 or more days on three different dose regimens (0.5, 0.25 and 0.08 mg kg-1 twice daily) to mice given pentetrazol by slow intravenous infusion. Plasma concentrations of clonazepam were assayed by high performance liquid chromatography. Tolerance developed to the anticonvulsant effect of clonazepam at all doses but was incomplete and could be overcome by increasing the dose. With the 0.5 and 0.25 mg kg-1 regimens there was no significant change in the drug plasma concentrations during development of tolerance; on the lowest dose, levels were below the limits of accurate detection. Anticonvulsant tolerance does not seem to be the result of a disturbance in clonazepam metabolism.

Animals↗
PubMed1985

Differences between the tolerance characteristics of two anticonvulsant benzodiazepines.

Clobazam (10 mg/kg) and clonazepam (0.25 mg/kg) were administered to mice twice daily by the intraperitoneal route. The development of tolerance to their anticonvulsant effect was compared using a slow intravenous infusion of pentylenetetrazole as the convulsant stimulus. Tolerance to clonazepam developed gradually throughout a 72 h study and did not become significant until the fifth dose. In contrast, tolerance to clobazam occurred extremely rapidly, after only one dose; it was manifested as a single step and no further significant change in protection was observed. Recovery from benzodiazepine tolerance was also studied and seen to occur rapidly with both these compounds; following cessation of dosing, protection was restored to initial levels within 36-48 h.

Animals↗
PubMed1984

Plasma concentrations of clobazam and its N-desmethyl metabolite; protection against pentetrazol-induced convulsions in mice.

The anticonvulsant effects of acute administration of clobazam and its principal metabolite N-desmethylclobazam were studied in mice. Pentetrazol, given by slow intravenous infusion 1 or 2 h after the anticonvulsant dose, was used as the convulsant stimulus. Log dose response relationships for both clobazam and N-desmethylclobazam appeared linear, but there was no correlation between plasma concentrations of clobazam and protection. However, correlation between plasma concentrations of N-desmethylclobazam and protection was significant in both cases.

Animals↗
PubMed1983

Development of tolerance to the anticonvulsant effects of clobazam.

The anticonvulsant properties of the 1,5-benzodiazepine clobazam were studied in mice during and after chronic treatment at two different dose levels. Pentylenetetrazol given by slow intravenous infusion was used as the convulsant stimulus. Tolerance to the anticonvulsant effects was observed; this was rapid in onset and could be overcome by increasing the dose of clobazam.

Animals↗