Influence of a continuous cimetidine infusion on lidocaine plasma concentrations in patients.
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Adult↗
Biomedical subjects
J R Powell
Publications and source records attributed to J R Powell.
Inhibition of tolbutamide elimination by cimetidine but not ranitidine.
This study was designed to compare the effects of equivalent therapeutic doses of two H2 antagonists, cimetidine and ranitidine, on tolbutamide pharmacokinetics. Twelve healthy men were given a 1-g oral dose of tolbutamide on three occasions. Subjects were randomly assigned to three treatments in a crossover fashion: cimetidine 1,200 mg/d, ranitidine 300 mg/d, and placebo. Cimetidine significantly increased the tolbutamide area under the plasma concentration-time curve by 20% (range, -5% to 42%), increased the elimination half-life by 17%, and decreased the carboxytolbutamide:tolbutamide plasma ratio from 0.042 to 0.036. Ranitidine did not significantly alter tolbutamide pharmacokinetics.
Adult↗
The effects of antacid and propantheline on the absorption of oral ranitidine.
The effects of propantheline bromide and an aluminum hydroxide/magnesium hydroxide suspension on absorption of ranitidine were evaluated in 12 healthy volunteers according to a Latin square design. Ranitidine 150 mg was administered alone, with 30 ml antacid or preceded by 15 mg propantheline. Ten serum samples were obtained over 12 hours during each treatment period for measurement of ranitidine concentration. The antacid had no significant effect on ranitidine absorption, but propantheline increased the relative bioavailability of ranitidine by 22%. In addition, there was a trend, although not statistically significant, for propantheline to increase the maximum ranitidine serum concentration and the time to maximum serum concentration. Ranitidine can be administered concomitantly with the evaluated doses of antacid and propantheline without a clinically significant alteration in its absorption.
Administration, Oral↗
Venous irritation related to intravenous administration of phenytoin versus fosphenytoin.
STUDY OBJECTIVE: To compare the frequency, severity, and time course of venous irritation after administration of a single intravenous dose of phenytoin with an equimolar dose of fosphenytoin, a water-soluble phenytoin prodrug. DESIGN: Randomized, double-blind, two-period, crossover study. SETTING: University hospital clinical research unit. PATIENTS: Twelve healthy volunteers within 15% of ideal body weight and with no clinically significant abnormalities on physical examination, medical history, or laboratory assessment. INTERVENTIONS: Volunteers randomly received a 30-minute infusion of phenytoin sodium 250 mg (250 mg/5 ml) or an equimolar dose of fosphenytoin 375 mg (375 mg/5 ml). Subjects returned for the crossover treatment 14-21 days later. MEASUREMENTS AND MAIN RESULTS: Subjects assessed venous irritation (pain, burning, itching), and investigators evaluated phlebitis (erythema, swelling, tenderness), induration, exudation, and cording. Phenytoin was associated with a significantly higher degree of pain at the infusion site in all subjects and a significant degree of phlebitis in eight subjects (p < 0.05); cording occurred in six subjects. The time course of phenytoin-induced phlebitis was bimodal. Erythema and tenderness were prominent at the end of the infusion and again at 24 hours. Cording was first noted between 24 hours and 1 week after infusion. In contrast, fosphenytoin was associated with mild pain in two subjects, one incident of phlebitis, and no erythema or cording. CONCLUSIONS: Fosphenytoin administration resulted in significantly less venous irritation and phlebitis compared with an equimolar dose of phenytoin. The clinical use of this water-soluble phenytoin prodrug should minimize the frequency and severity of infusion-site reactions and should allow convenient, rapid, intravenous administration of drug, undiluted or admixed with intravenous solutions.
Adolescent↗
Temperature related genetic divergence in Drosophila body size.
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Adaptation, Biological↗
Population genetics of Mexican Drosophila. I. Chromosomal variation in natural populations of Drosophila pseudoobscura from Central Mexico.
Drosophila pseudoobscura populations of Central Mexico are chromosomally highly polymorphic. Five gene arangements in the third chromosome are endemic, including the two newly described in the present article. The phylogenetic tree of the gene arrangements known in the species is shown in Figure 1. The ones found in Central Mexico all belong to the Santa Cruz "phylad", while in the northern part of the species area both Santa Cruz and Standard phylads are widespread. Some inferences concerning the evolutionary history of the species are presented.
Animals↗
Interaction of imidazoline alpha-adrenergic receptor antagonists with histamine receptors.
Because the alpha-adrenergic receptor antagonists phentolamine and tolazoline are similar in structure to histamine, it is possible that the vasodilatation caused by these drugs may be due in part to stimulation of histamine receptors. The vascular effects of these agents were studied in the hindquarters of rats and the gracilis muscle of dogs. To eliminate interruption of sympathetic vasoconstrictor tone as a mechanism of vasodilatation, all animals were treated with the alpha-adrenergic receptor antagonist, dibozane. After dibozane, histamine caused vasodilatation in the rat, whereas both tolazoline and phentolamine caused vasoconstriction. It is concluded that phentolamine and tolazoline do not stimulate vascular histamine receptors in the rat. In the dog, after alpha-receptor blockade, phentolamine and tolazoline caused vasodilatation, as did histamine. Responses to histamine were partially attenuated by mepyramine and greatly attenuated by the combination of mepyramine and metiamide, indicating the participation of both H1- and H2-histamine receptors. Vasodilatation caused by phentolamine was not reduced by antihistamines and does not appear to involve histamine receptors. Vasodilatation following tolazoline was blocked by metiamide but not mepyramine. It is concluded that in addition to blockade of alpha-adrenergic receptors, tolazoline can cause vasodilatation by stimulation of histamine H2-receptors.
Adrenergic alpha-Antagonists↗
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.
Adult↗
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.
Adult↗
Absolute bioavailability of phenytoin after 3-phosphoryloxymethyl phenytoin disodium (ACC-9653) administration to humans.
3-Phosphoryloxymethyl phenytoin disodium (ACC-9653) is a water-soluble investigational phenytoin (PHT) prodrug for parenteral administration. The objectives of this investigation were to determine the absolute bioavailability and free fraction of PHT after intravenous (i.v.) administration of ACC-9653. Twelve healthy male volunteers received PHT sodium (250 mg/5 ml; 229.95 mg free acid) and ACC-9653 (375 mg/5 ml; 232.87 mg free acid) i.v. in 30 min in a randomized, double-blind cross-over fashion. The conversion half-life (t 1/2) of ACC-9653 to PHT was 9.3 +/- 2.7 min. ACC-9653 was not detected in urine and greater than 99% of ACC-9653 was converted to PHT. The PHT area under the curve (AUC) was not statistically different between treatments; the bioavailability of PHT after ACC-9653 was 99 +/- 11%. The fraction of unbound converted PHT at the end of the prodrug infusion, in the presence of 44 micrograms/ml ACC-9653, was significantly higher than at 180 min, when the concentration of ACC-9653 was 0.1 microgram/ml. ACC-9653 was shown to be a bioequivalent PHT prodrug exhibiting less irritation at the injection site than the current marketed PHT.
Biological Availability↗
Multiskilled health practitioners. Applications to group practice.
Multiskilled health practitioners (MSHPs) may be used to reduce costs and increase the availability of services for group practices. There are a variety of possible competency combinations for MSHPs, many of which are unique to the needs of specific health care facilities. Examples of MSHPs as well as employer and employee perceptions of multiskilled needs relevant to health care delivery and applications to the group practice setting are presented.
Allied Health Personnel↗
Geographic genetic differentiation and arbovirus competency: Aedes aegypti and yellow fever.
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Aedes↗
Comparison of quantitative methods to assess hepatic function: Pugh's classification, indocyanine green, antipyrine, and dextromethorphan.
STUDY OBJECTIVES: To compare three quantitative metabolic markers used to assess hepatic function, indocyanine green (ICG), a high-extraction marker; antipyrine, a low-extraction marker; and dextromethorphan, a P-450IID6 marker, with the clinically used Pugh's classification. DESIGN: Comparison of 12 healthy controls with 12 age- and sex-matched patients with different degrees of liver disease. SETTING: Research center in a university-affiliated teaching hospital. PATIENTS: The 12 patients had different degrees of liver disease: 4 mild (Pugh's score 6 or 7); 4 moderate (Pugh's score 8 or 9); and 4 severe (Pugh's score > or = 10). Each level had an equal number of men and women subjects. MEASUREMENTS AND MAIN RESULTS: Clearance of ICG detected mild alterations in hepatic function as efficiently as it did for moderate and severe impairment, but it lacked the specificity to distinguish among the classification groups. In contrast, antipyrine was effective in identifying moderate and severe hepatic impairment; however, its clearance was not reduced in mild liver disease. Pugh's classification appears to be a clinically useful method of assessing the global degree of hepatic impairment in patients with chronic disease, and there was a significant correlation between it and antipyrine clearance (r = 0.67, p = 0.0003) and ICG clearance (r = 0.86, p = 0.0001). Four of eight patients with a Pugh's score greater than 8 had a dextromethorphan metabolic ratio expression reflective of a poor metabolizer phenotype based on 0- to 4-hour urine collection, but only two of those eight patients were classified as poor metabolizers based on 4- to 12-hour urine collection. These percentages of poor metabolizers are substantially higher than for historical controls (8.5-10.4%) and most likely reflect a decrease in the P-450IID6 functional ability with progression of liver disease. However, due to small sample size and lack of knowledge of the patients' genotypes, these data are only suggestive. CONCLUSION: Pugh's classification appears to be a reliable indicator of the degree of chronic liver disease and could be employed as a drug development research classification tool; however, it does not replace quantitative metabolic markers, especially isozyme-specific markers.
Adult↗