Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Jun 1991
Randomized Controlled Trial Comparative Study Clinical TrialEffect of caffeine on ibuprofen analgesia in postoperative oral surgery pain.
Recent studies have demonstrated that caffeine acts as an analgesic adjuvant when combined with acetaminophen, aspirin, or their mixture. Our objective was to determine whether similar enhancement of analgesia could be demonstrated when caffeine is combined with ibuprofen. On a double-blind basis, a single oral dose of ibuprofen (50, 100, or 200 mg), a combination of ibuprofen, 100 mg, with caffeine, 100 mg, a combination of ibuprofen, 200 mg, with caffeine, 100 mg, or placebo was randomly assigned to 298 outpatients with postoperative pain after the surgical removal of impacted third molars. ⋯ Relative potency estimates indicated that the combination was 2.4 to 2.8 times as potent as ibuprofen alone. The combination also had a more rapid onset and longer duration of analgesic action. The analgesic adjuvancy of caffeine clearly extends to combinations with nonsteroidal anti-inflammatory drugs other than acetaminophen or aspirin.
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Clin. Pharmacol. Ther. · Apr 1991
Comparative Study Clinical Trial Controlled Clinical TrialCentral analgesic effect of acetaminophen but not of aspirin.
The central nervous system effect of acetaminophen (paracetamol) and acetylsalicylic acid was investigated in healthy volunteers according to a crossover, double-blind, and placebo-controlled design. Ten subjects received, by intravenous route, a placebo, 1 gm acetaminophen, and 1 gm acetylsalicylic acid. Analgesia was assessed by measurement of the subjective pain threshold and the objective nociceptive flexion reflex threshold in response to selective transcutaneous electrical stimulations. ⋯ In contrast, acetylsalicylic acid had no noticeable effect on either threshold. These findings show that acetaminophen-induced analgesia is centrally mediated, in contrast to aspirin. The time delay between plasma concentration kinetics and acetaminophen analgesic effect is another argument in favor of its direct action on the central nervous system.
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Clin. Pharmacol. Ther. · Apr 1991
Monitoring cobalamin inactivation during nitrous oxide anesthesia by determination of homocysteine and folate in plasma and urine.
The effects of nitrous oxide-induced cobalamin inactivation on homocysteine and folate metabolism have been investigated. Plasma levels of cobalamin, folate, homocysteine, and methionine were determined in 40 patients before and after operation under nitrous oxide anesthesia (range of exposure time, 70 to 720 minutes). Twelve patients anesthetized with total intravenous anesthesia served as control subjects (range of exposure time, 115 to 600 minutes). ⋯ Urinary excretion of folate and homocysteine increased during and after nitrous oxide exposure (p less than 0.01 and p less than 0.002, respectively) and correlated with exposure time (p less than 0.01 and p less than 0.005, respectively). It can be concluded that disturbance of homocysteine and folate metabolism by nitrous oxide develops with little delay and return to normal levels requires several days. Elevation of plasma homocysteine levels may therefore be used for monitoring nitrous oxide-induced cobalamin inactivation.
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Clin. Pharmacol. Ther. · Sep 1990
Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid.
The incidence of valproic acid hepatotoxicity has been reported to increase in patients who are receiving polytherapy. A minor valproic acid metabolite, 2-propyl-4-pentenoic acid (4-ene-VPA), formed by a cytochrome P450-mediated reaction, has been shown to be a potent inducer of microvesicular steatosis in rats. This study tested the hypothesis that formation of 4-ene-VPA would be increased in patients taking valproic acid with carbamazepine or with phenytoin but decreased with coadministration of an inhibitor of cytochrome P450 (the antiepileptic drug stiripentol in 300 to 1200 mg daily doses) in healthy subjects. ⋯ Similar findings were obtained at 600 and 300 mg/day stiripentol. These findings provide evidence supporting a role for cytochrome P450 in the formation of the hepatotoxic metabolite, 4-ene-VPA, in humans. The increased formation of 4-ene-VPA associated with carbamazepine and phenytoin is striking in relation to the epidemiologic finding of increased incidence of valproic acid-related hepatotoxicity during polytherapy with P450 inducers.