Biomedical subjects
M J Dalton
Publications and source records attributed to M J Dalton.
Kinetic effects of multiple oral doses of acetaminophen on a single oral dose of lamotrigine.
In this double-blind, randomized, crossover, placebo-controlled study, the effect of multiple oral doses of acetaminophen on lamotrigine disposition was examined in healthy volunteers. Eight volunteers received two single 300 mg oral doses of lamotrigine, administered 20 days apart. Acetaminophen (2.7 gm/day) or placebo was taken for 24 hours before and continued for 10 days after each lamotrigine dose. Area under the plasma concentration-time curve for lamotrigine [AUC(O-infinity)] and lamotrigine half-life were statistically decreased by 20% (229.0 +/- 62.5 micrograms.hr/ml versus 191.2 +/- 42.1 micrograms.hr/ml, p less than 0.01) and 15% (35.7 +/- 9.3 hours versus 30.2 +/- 7.3 hours, p less than 0.01), respectively, when concurrently administered with acetaminophen. There was no significant difference in the peak plasma concentration or the time to reach peak plasma concentration. The percentage of the dose of lamotrigine recovered in the urine (total) was significantly higher during the acetaminophen treatment (65.9% +/- 12.3% versus 72.5% +/- 5.7%, p = 0.048). Acetaminophen seems to facilitate lamotrigine removal through a yet to be determined mechanism(s).
Postperinatal mortality in a health district with a garrison town.
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Characteristics of pyridoxine overdose neuropathy syndrome.
A newly recognised neurotoxic syndrome due to pyridoxine (B6) overdose is described. It is the largest series of B6 intoxication hitherto reported. A raised serum B6 level was present in 172 women of whom 60% had neurological symptoms, which disappeared when B6 was withdrawn and reappeared in 4 cases when B6 was restarted. The mean dose of B6 in the 103 women with neurological symptoms was 117 +/- 92 mgs, compared with 116.2 +/- 66 mgs in the control group. There was a significant difference (P less than 0.01) in the average duration of ingestion of B6 in the neurotoxic group of 2.9 +/- 1.9 years compared with 1.6 +/- 2.1 years in controls. The symptoms were paraesthesia, hyperaesthesia, bone pains, muscle weakness, numbness and fasciculation, most marked on the extremities and predominantly bilateral unless there was a history of previous trauma to the limb. These women were taking a lower dose of B6 than previously described (1,2), which may account for the complete recovery within 6 months of stopping B6.
Ranitidine does not alter single-dose carbamazepine pharmacokinetics in healthy adults.
In our recent study, oral cimetidine increased carbamazepine plasma levels after a single oral dose by 26 percent and prolonged the elimination half-life by 18 percent. This effect of cimetidine on carbamazepine could have resulted from enhanced carbamazepine absorption and/or inhibited metabolism. To gain an insight into which mechanism was responsible, we repeated the study with ranitidine, which has nearly identical gastrointestinal effects as cimetidine, but does not inhibit oxidative metabolism. Eight healthy subjects received a single dose of carbamazepine 600 mg po on two occasions separated by one month. In a randomized sequence, they also received ranitidine 300 mg/d or matching placebo starting two days before and continuing until seven days after the carbamazepine dose. Ranitidine did not change the carbamazepine area under the plasma concentration-time curve (324.2 +/- 71.1 micrograms h/ml, placebo vs. 326.3 +/- 65.0 micrograms h/ml, ranitidine; p = 0.84) or the elimination half-life (32.2 +/- 6.4 h, placebo vs. 31.7 +/- 6.1 h, ranitidine; p = 0.62). Since ranitidine does not alter the pharmacokinetic profile of oral carbamazepine, it is unlikely that the changes observed with cimetidine were due to increased carbamazepine absorption. Therefore, the mechanism of the single-dose carbamazepine-cimetidine interaction is probably metabolic inhibition, although the exact pathway (or pathways) affected has not been identified.
Malnutition in infants receiving cult diets.
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The influence of cimetidine on single-dose carbamazepine pharmacokinetics.
The purpose of this study was to evaluate the influence of cimetidine on carbamazepine pharmacokinetics in healthy adults, since carbamazepine toxicity in a patient has been attributed to an interaction with cimetidine and in vitro and in vivo studies in rats have shown that cimetidine inhibits carbamazepine metabolism. Eight healthy volunteers received a single 600-mg oral dose of carbamazepine on two occasions, separated by 1 month. In a randomized crossover sequence, cimetidine 1,200 mg/day or placebo was taken for 48 h before and continuing for 7 days after each carbamazepine dose. Plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide and urine concentrations of carbamazepine, the 10,11-epoxide, and the transdiol metabolite were measured in samples collected for 154 h following each carbamazepine dose. Cimetidine treatment was associated with increases of 26 and 18% in carbamazepine area under the concentration-time curve (AUC) and elimination half-life, respectively. There was also an increase in carbamazepine-10,11-epoxide AUC (27%) and t 1/2 (12%) during cimetidine treatment. There was no difference in the ratio of the 10,11-epoxide to the carbamazepine AUC between treatments. The urinary excretion (expressed as molar percentage of the administered dose) of carbamazepine, 10,11-epoxide, and transdiol metabolite all increased with cimetidine. Although cimetidine appears to inhibit carbamazepine elimination based on the increased elimination half-life, the effect must be on carbamazepine metabolic pathways that we could not measure and that account for greater than 80% of the administered dose. The clinical significance of this interaction should be verified under steady-state conditions when carbamazepine autoinduction is present.
Cimetidine and carbamazepine: a complex drug interaction.
Cimetidine has been shown to inhibit the elimination of carbamazepine after a single oral dose. The mechanism of this interaction is thought to be inhibition of carbamazepine metabolism by the hepatic microsomal enzyme system. Because carbamazepine metabolism undergoes autoinduction with chronic administration, it is not known whether or not the clinical significance of this interaction can be predicted from the results of a single-dose study. The purpose of this study was to evaluate the presence of an interaction under steady-state enzyme-induced conditions. Using an open treatment design, carbamazepine, 300 mg b.i.d., was taken by eight healthy volunteers for 42 days (days 1-42). Cimetidine, 400 mg t.i.d., was taken for 7 days (days 29-35). Steady-state carbamazepine increased 17% after 2 days of cimetidine treatment (from 4.7 +/- 0.8 to 5.5 +/- 1.4 micrograms/ml; p less than 0.05). Six of the eight subjects noted side effects shortly after starting cimetidine treatment. Carbamazepine returned to the pre-cimetidine level and the side effects diminished by the 7th day of cimetidine administration. Therefore, the clinical significance of this interaction appears to be time dependent, and could not be predicted from the results of single-dose studies.