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Biomedical subjects

J R Powell

Publications and source records attributed to J R Powell.

At least 181 records · Page 10Linked to original sources
PubMed1980

Evaluation of the absorption from some commercial enteric-release theophylline products.

In a single-dose bioavailability study, Wales, Robinson, Columbia, and Choledyl (Warner/Chilcott) enteric-coated tablets all allowed a bioavailability of theophylline (99% +/- 25%, 102% +/- 23%, 103% +/- 18%, and 98% +/- 15%; mean +/- SD, n = 12) statistically indistinguishable from that of the standard uncoated tablet (Searle 200 mg aminophylline). Only the Wales and Choledyl tablets (7.6, 4.2 hr) could be shown (p < 0.5) to generate a peak plasma theophylline concentration later than the standard (1.4 hr). All tablet brands demonstrated a significant lag time before appearance of theophylline in the plasma, and both Wales and Choledyl tablets also had a (tpeak-tlag) statistically different from that of the standard. Despite misleading indications from the mean plasma profile (plasma concentrations at each sampling time averaged over all subjects), plasma data from the individual participants and in vitro dissolution data show that, while release of theophylline from the Wales tablet might be inordinately slow, this is not a sustained-release preparation. Of the enteric-coated tablets only the Columbia product allowed significant levels in the first sample after dosage. Five of the 18 Columbia doses gave rise to 40-99% of the peak concentration in the 1-hr sample. In vitro, it takes 39 +/- 14 min for 40% of the theophylline content of Columbia tablets to dissolve in simulated intestinal fluid. Suprisingly rapid delivery of an enteric-coated tablet to the duodenum would appear to be required to allow a significant percentage of theophylline to be dissolved and absorbed before 1 hr. None of 12 Columbia tablets tested in vitro, however, allowed dissolution of more than 1.2% of their theophylline content during 1 hr immersion in simulated gastric fluid. Since once in intestinal fluid Columbia tablets appear to dissolve more rapidly than the other enteric products, it is not clear whether the five Columbia tablets in question had imperfections or wheter, in fact, this tablet brand more closely than the others represents the ideal of immediate release once in the duodenum. Plasma samples should be taken as early as 15 min after dosage when evaluating the bioavailability of enteric release products.

Adult↗
PubMed1980

Effect of quinine on digoxin kinetics.

Six subjects were evaluated for the effect of quinine, the l-isomer of quinidine, on digoxin pharmokinetics. A 1.0-mg intravenous digoxin dose was given before and during quinine administration, followed by the measurement of digoxin serum and urine concentrations for 96 hr after each dose. Quinine reduced digoxin total body clearance by 26% from 2.98 to 2.22 ml/min/kg (p < 0.03). Digoxin elimination half-life (t 1/2) was lengthened from 34.2 to 51.8 hr, reflecting a 32% decrease in digoxin elimination rate constant (p < 0.003). Quinine did not reduce digoxin renal clearance or any volumes of distribution. The amount of digoxin excreted into the urine increased from x = 628. 29 micrograms to x = 772.52 micrograms (p < 0.02). Digoxin nonrenal clearance decreased an average of 55% from 1.2 to 0.55 ml/min/kg (p < 0.05). These results suggest that quinine alters digoxin metabolism or biliary secretion, reducing digoxin total body clearance by a mechanism that is qualitatively similar, but quamtitatively different, from quinidine.

Adult↗
PubMed1980

Effect of dose on phenytoin absorption.

To determine the effect of dose on phenytoin bioavailability, a single intravenous 15-mg/kg dose, single oral doses of 400, 800, and 1,600 mg, and 1,600 mg in divided doses (400 mg every 3 hr) were given to six healthy male subjects. Values of Vmax (maximum elimination rate) and Km (serum concentration at which rate of elimination is one half the maximum rate) from the intravenous dose were used to determine the extent of absorption. Although no statistically significant difference in extent of phenytoin absorption was detected, the time to reach maximum phenytoin serum concentrations increased from 8.4 hr for the 400-mg dose and 13.2 hr for the 800-mg dose to 31.5 hr for the 1,600-mg dose. After the 400, 800, and 1,600-mg doses and 1,600-mg divided doses, the serum concentration peaks were 3,9, 5.7, 10.7, and 15.3 mg/l. It is suggested that the prolonged, but complete, absorption of large phenytoin doses is due to slow dissolution and continued absorption from the colon. Due to prolonged absorption of phenytoin, it may be necessary to use larger oral than intravenous loading doses to achieve the same maximum phenytoin serum concentrations.

Administration, Oral↗
PubMed1980

Digitoxin-quinidine interaction: pharmacokinetic evaluation.

The effect of quinidine on digitoxin single-dose pharmacokinetics was evaluated in five healthy adults. Blood was collected for 3 weeks, and a complete urine collection was obtained for 4 days, after a single intravenous dose of digitoxin. The protocol was conducted once while each subject was taking oral quinidine, for 3 weeks, and then repeated 10 days after discontinuing quinidine treatment. Quinidine induced the following changes in digitoxin pharmacokinetics: Elimination half-life was prolonged from 174 +/- 25 to 261 +/- 58 hours (p less than 0.02); total body clearance decreased from 1.54 +/- 0.40 to 1.09 +/- 0.31 mL/h . kg (p less than 0.05); renal clearance decreased from 0.65 +/- 0.07 to 0.46 +/- 0.17 mL/h . kg (p less than 0.05). Digitoxin volume of distribution and protein binding were unaltered by quinidine. Quinidine caused a rise in serum digitoxin levels. Digitoxin total body clearance was decreased by quinidine to an extent comparable to that reported for digoxin; however, the mechanism of the interaction with the two digitalis glycosides may, in part, be different.

Adult↗
PubMed1980

Increased total and regional vascular resistance produced by propranolol.

Propranolol when administered acutely causes little change in blood pressure and a decrease in cardiac output. Blood pressure is maintained due to increased vascular resistance. The purpose of this investigation was to determine if increased vascular resistance after propranolol occurs uniformly among various tissues and if increased resistance is due to reflex vasoconstriction. Total and regional vascular resistance were determined with the radioactive microsphere technique in dogs anesthetized with chloralose. Intravenous propranolol, 1 mg/kg, caused little change in blood pressure, cardiac rate, cardiac output and total and regional vascular resistance 30 min after administration. These changes were not different than changes after saline injection. In dogs pretreated with the alpha adrenergic receptor antagonist, dibozane, i.v. propranolol did not affect cardiac rate or blood pressure but reduced cardiac output and increased total peripheral resistance. Vascular resistance in brain, heart, lung, duodenum and skin was increased whereas kidney, spleen and muscle vascular resistance was not significantly changed. It is concluded that increased vascular resistance produced by propranolol does not occur uniformly among tissues. Increased vascular resistance after propranolol is not due to reflex activation of alpha adrenergic receptors but may involve alterations in unidentified vasoconstrictor or vasodilator influences in certain vascular beds.

Animals↗
PubMed1979

Evidence for selection by male mating success in natural populations of Drosophila pseudoobscura.

Gene arrangement frequencies were determined at two stages in the life history of Drosophila pseudoobscura taken from nature. Three populations in the central highlands of Mexico were each sampled twice during 1976. Gene arrangement frequencies were measured in adult males and in larvae that were the offspring of females collected at the same time. The adult males were in all likelihood a representative sample of those who fathered the larvae produced by the wild females. Differences in gene arrangement frequency between these two life stages should indicate the operation of natural selection. One-third of our comparisons of common gene arrangement frequencies in males and in larvae from the next generation were statistically significant, as were one-third of our comparisons of total frequency arrays in the two life stages. We consider the components of selection that could produce such frequency changes and reason that male mating success must be the major one. Gene arrangement frequencies in the Mexican populations fluctuate within wide bounds. Selection must act to retain the polymorphism in the face of this flux in gene arrangement frequencies, and we suggest that male mating success plays an important role.

Animals↗
PubMed1979

Population genetics of Drosophila amylase. I. Genetic control of tissue-specific expression in D. pseudoobscura.

Drosophila pseudoobscura is polymorphic for tissue-specific expression of alpha-amylase in adult midguts. This enzyme is encoded by a single locus, Amy, on the third chromosome. In this paper we show: (1) Up to about 12 days post-eclosion, the midgut activity patterns remain stable; after 12 days areas not showing activity previously begin to show activity. Thus, the genes controlling the expression of Amy are temporally acting. (2) Diet affects the quantitative, but not the qualitative, expression of Amy. (3) The expression of Amy in adult midguts is under genetic control. Selection for different frequencies of patterns is possible; realized heritabilities are 0.20 to 0.50. Partial linkage with third chromosome inversions has been demonstrated; the genes or elements controlling Amy expression are not, however, confined to the third chromosome. (4) The genetic elements controlling tissue-specific expression of amylase do not coordinately control the expression of five other "digestive-type" enzymes that were studied.--This polymorphism appears to be analogous to that studied by Abraham and Doane (1978) in D. melanogaster, wherein they have mapped regulatory genes.

Amylases↗
PubMed1979

Population genetics of Drosophila amylase. II. Geographic patterns in D. pseudoobscura.

Morph frequencies of three related polymorphisms were determined in ten natural populations of Drosophila pseudoobscura. They are the well-known inversion polymorphism of the third chromosome and the polymorphism for alpha-amylase produced by the structural gene Amy (which resides on the third chromosome). The third polymorphism was for tissue-specific expression of Amy in adult midguts; a total of 13 different patterns of activity have been observed. The preceding paper (Powell and Lichtenfels 1979) reports evidence that the variation in Amy expression is under polygenic control. Here we show that the polymorphism for midgut patterns occurs in natural populations and is not an artifact of laboratory rearing.--From population to population, Amy allele frequencies and frequencies of inversions belonging to different phylads vary coordinately. The geographic variation in alpha-amylase midgut activity patterns is uncorrelated with that for the other two types of polymorphisms. Furthermore, no correlation was detected between activity pattern(s) and Amy genotype(s) when both were assayed in the same individual.--These results imply that whatever the evolutionary-ecological forces are that control frequencies of the structural gene variants, they are not the same factors that control the frequencies of polymorphic genetic factors responsible for the tissue-specific expression of the enzyme.

Alleles↗
PubMed1979

Characterization of vascular histamine receptors in the rat.

1 In the rat the decrease in blood pressure caused by histamine involves activation of both H1- and H2-receptors. Since arterial pressure measurements alone do not permit the separation of responses into cardiac and vascular components, the following experiments were undertaken to study vascular histamine receptors. 2 Vascular responses were studied in the autoperfused hindquarters of anaesthetized rats. Intra-arterial histamine caused vasodilatation which was only partially attenuated by treatment with mepyramine, an H1-receptor antagonist. Treatment with metiamide, the H2-receptor antagonist, did not affect vasodilatation caused by histamine but did attenuate vasodilatation which persisted after mepyramine. 3 Intra-arterial 4-methylhistamine, an H2-receptor agonist, caused vasodilatation which was reduced by metiamide. The H1-receptor agonist, 2-(2-pyridyl)ethylamine also caused vasodilatation which was blocked by mepyramine. 4 It is concluded that in the rat, histamine causes vasodilatation mediated by both H1- and H2-receptors.

Animals↗
PubMed1979

Carotid sinus reflex coronary vasoconstriction during controlled myocardial oxygen metabolism in the dog.

We studied carotid baroreceptor reflex coronary vasoconstriction in closed-chest dogs with controlled aortic blood pressure and myocardial oxygen metabloism. The dogs were anesthetized with morphine and chloralose. Left coronary blood flow was measured by a cannula-tip flowmeter, and myocardial oxygen metabolism was calculated by measuring the arterial-coronary sinus oxygen difference. A bilateral vagotomy was performed in all animals and they were treated with propranolol. Reduction of carotid sinus pressure to 40 mm Hg caused an increase in aortic pressure that was limited to 15 mm Hg by means of a pressure-control reservoir. During carotid hypotension, heart rate and myocardial oxygen metabolism were unchanged but diastolic conronary vascular resistance increased by 21%. Intracoronary artery infusion of norepinephrine had similar effects. After interruption of the reflex are with the alpha-adrenergic receptor antagonist, dibozane, carotid sinus hypotension and the same increase in aortic pressure (15 mm Hg) resulted in only a 5% increase in diastolic coronary resistance. Dibozane also reduced the coronary responses to norepinephrine. It is concluded that carotid sinus hypotension results in reflex sympathetic alpha-receptor coronary vasoconstriction and that this reflex vasoconstriction is independent of changes in myocardial oxygen metabolism or changes in aortic pressure.

Animals↗
PubMed1978

Changes in theophylline clearance during acute illness.

Three patients demonstrated twofold to threefold changes in total-body theophylline clearance during the course of a single hospitalization for an acute illness. These changes paralleled the changes in the patients' clinical status. Theophylline clearance decreased in one patient with worsening airway obstruction, whereas clearance increased in one patient with resolving pneumonia and in one patient with improving congestive heart failure. Total-body theophylline clearance may be unstable in acute, severe illness. Close monitoring of plasma theophylline concentration in such situations will allow appropriate dose adjustments to be made and is, therefore, indicated.

Acute Disease↗
PubMed1978

Theophylline disposition in acutely ill hospitalized patients. The effect of smoking, heart failure, severe airway obstruction, and pneumonia.

Theophylline disposition (clearance, volume of distribution, and half-life) was measured in 31 normal volunteers and 26 acutely ill patients with airway obstruction within 24 hours of hospital admission and again when intravenous aminophylline was discontinued 2 to 10 days later. Sex, age, race, the diagnosis of asthma, and the diagnosis of chronic bronchitis were not significantly correlated with clearance. Clearance was significantly increased in smokers and significantly decreased in patients with congestive heart failure, pneumonia, and severe bronchial obstruction. The volume of distribution was not correlated with these variables. Within 24 hours of admission, the mean clearance in our patients without congestive heart failure or pneumonia was 44.5 ml per hour per kg of body weight, 40 per cent less than the value on which the widely used 0.9 mg per kg per hour dosage is based. The unexplained interindividual variability of clearance was significantly higher amont patients than control subjects, but intraindividual variability in clearance was not different in these 2 groups after correction for the effects of smoking, congestive heart failure, and so on. Large variability in clearance among patients makes the plasma theophylline concentration resulting from any dosage relatively uncertain. Based on the the results of this study, recommendations are made concerning theophylline dosage computation, and the clinical circumstances calling for determination of plasma theophylline concentrations.

Acute Disease↗