The effects of three beta blockers on liver blood flow and hepatic enzyme activity were investigated. Eight healthy subjects received placebo, 100 mg metoprolol, 40 mg nadolol, and 60 mg propranolol orally three times a day for four days in a randomized block design. On the fourth day of each treatment, beta blockade was measured by inhibition of exercise-induced tachycardia and apparent liver blood flow was measured by indocyanine green clearance. Plasma concentrations of the beta blockers were measured 2 hours after the early morning dose. Metoprolol produced the greatest inhibition of exercise tachycardia. All three drugs appeared to reduce liver blood flow, but this was only statistically significant in the case of propranolol. Enzyme inhibition occurred but to a varying extent. Propranolol produced a 36 per cent fall in antipyrine clearance (P less than 0.1) while metoprolol and nadolol both caused a 12 per cent reduction (P less than 0.05 and P = 0.06, respectively). Wide interindividual variation in the plasma concentrations of the drugs limit interpretation, but the results suggest that at the doses used, metoprolol and nadolol may be less likely to cause significant drug interaction by enzyme inhibition than propranolol.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

The effect of velnacrine on the mixed function oxidase system.

Velnacrine is a centrally acting anticholinesterase which has been considered for use in the treatment of Alzheimer's disease. If proven to be of value, it will be used concurrently with other medications. Its potential to cause interaction is, therefore, important to study. The aim of this work was to investigate velnacrine as an inhibitor of hepatic oxidative enzymes. The effects of velnacrine on antipyrine metabolism in isolated rat hepatic microsomes were compared to those of cimetidine. Aliquots of 200, 250 and 300 micrograms/ml antipyrine were incubated alone, with 20 micrograms/ml cimetidine and with each of 20, 50 and 100 micrograms/ml velnacrine. The concentrations of antipyrine and of its metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine were assayed by reverse phase high performance liquid chromatography. Cimetidine inhibited production of all three metabolites. Velnacrine did not affect 3-hydroxymethylantipyrine production. Mean inhibition of 4-hydroxyantipyrine production of 15%, 30% and 25% (P < 0.01), and of 14%, 25% and 12% of norantipyrine production (P < 0.01) occurred. These results indicate that velnacrine may inhibit the enzymes responsible for the metabolism of antipyrine to norantipyrine and 4-hydroxyantipyrine. The clearance rate of drugs that are metabolised through the hepatic oxidase system may, therefore, be reduced in the presence of concurrent treatment with velnacrine.

Animals↗

PubMedDate not supplied

Effect of tacrine hydrochloride on hepatic drug metabolism.

The aim was to assess tacrine hydrochloride (THA) as an inhibitor of rat hepatic oxidative enzymes. A model of hepatic microsome oxidative metabolism was established using antipyrine (AP) incubated with NADPH. AP and its metabolites, 3-hydroxymethyl antipyrine (HMA). 4-hydroxy antipyrine (OHA) and norantipyrine (NORA) were measured by high performance liquid chromatography (HPLC). Aliquots of 200, 400 and 600 microg/ml antipyrine were incubated with the microsomal preparation alone, with 20 microg/ml cimetidine or with 40, 80 or 200 microg/ml THA. Cimetidine inhibited HMA production by 35-38% (P<0.001) and OHA production by 49-52% (P<0.001). Incubation with the 3 concentrations of THA inhibited HMA production by 17%, 24% and 41% (P<0.001) and OHA production by 52%, 55% and 79%, respectively (P<0.001). NORA was identifiable when antipyrine was incubated with NADPH alone, but could not be identified after incubation with either cimetidine or THA. This study has shown that THA causes the inhibition of AP metabolism to HMA, OHA and possibly NORA. We suggest THA is an inhibitor of three different hepatic microsomal cytochrome P-450 enzyme sub-families.

Animals↗

PubMedDate not supplied

Assessment of the value of therapeutic monitoring of tacrine in Alzheimer's disease.

OBJECTIVES: The purpose of this study was to validate the lower end of the putative therapeutic range of serum tacrine concentrations of 7-20 ng ml(-1) in the treatment of Alzheimer's disease. METHODS: The relationship between dose, steady-state serum tacrine concentrations and change in MMSE score (a measure of cognitive function) was examined in 106 Alzheimer's disease patients who had been treated with the drug for 12 weeks. RESULTS: In all, 72% of patients showed some response, but there was no relationship between dose and the chance of a favourable outcome. The proportion of patients with serum concentrations above 7 ng x ml(-1) who improved (79%) was significantly greater than that of those with serum concentrations below this level (47%) (P < 0.02). Also, a significantly greater proportion of patients with serum concentrations above both 5 ng x ml(-1) and 9 ng x ml(-1) showed improvement in comparison to those with concentrations below these levels. CONCLUSIONS: This study indicates that therapeutic monitoring of serum tacrine concentrations might increase the possibility of responding to tacrine by some 68%. This represents an important contribution to the management of Alzheimer's disease patients with this drug, and may also be relevant to the use of the newer generation of cholinesterase inhibitors.

Aged↗

PubMedDate not supplied

Association between nonadministration of subconjunctival cefuroxime and postoperative endophthalmitis.

PURPOSE: To determine whether not administering subconjunctival cefuroxime during cataract surgery is associated with postoperative endophthalmitis. SETTING: Southampton Eye Unit, Southampton General Hospital, England. METHODS: This retrospective, case-control study comprised nine patients who developed endophthalmitis after cataract surgery in a single ophthalmic unit over a 21 month period. Ten control patients for each case were randomly chosen from patients having cataract surgery within 1 week of the endophthalmitis case. RESULTS: None of the nine endophthalmitis patients received peroperative subconjunctival cefuroxime compared with 43 of 90 control patients (47.8%) (P = 0.008). No other variables were found to be associated with development of endophthalmitis in this study. CONCLUSION: Nonadministration of subconjunctival cefuroxime was associated with subsequent endophthalmitis. A further study to determine whether the observed association is causal is therefore warranted.

Adult↗