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Biomedical subjects

J R Powell

Publications and source records attributed to J R Powell.

At least 127 records · Page 7Linked to original sources
PubMed1987

Intraspecific DNA divergence in Drosophila: a study on parthenogenetic D. mercatorum.

Drosophila mercatorum is a species that can give rise to totally homozygous parthenogenetic strains. Using the technique of DNA-DNA hybridization, we have assessed the overall single-copy DNA differences among three independently derived strains that represent three independent genomes. Among strains, the average difference between homoduplex and heteroduplex median melting temperatures is 1.3 degrees C. This represents greater than or equal to 1.3% base-pair mismatch. Normalized percent of reassociation indicates further genetic differences, probably reflecting insertion/deletion differences and/or regions of the genome that are highly variable. This overall intraspecific genetic variation is higher than generally is thought to exist but is consistent with growing evidence of extensive DNA diversity within species of invertebrates. High intraspecific DNA variation may be correlated with rapid phyletic rates of evolution. Because of this high level of variation, the technique of DNA-DNA hybridization may be used to study intraspecific variation in invertebrates but is limited in its usefulness for higher systematic studies.

Animals↗
PubMed1987

SQ 27,786 and SQ 28,853: two angiotensin converting enzyme inhibitors with potent diuretic activity.

SQ 27,786 and SQ 28,853 were designed to possess both angiotensin converting enzyme (ACE) inhibitory and diuretic properties. Both compounds were given to conscious male Sprague-Dawley rats and mongrel female dogs to determine ACE inhibitory and diuretic activities. All animals had previously been equipped with indwelling arterial and venous catheters. Both compounds resulted in dose-related inhibition of an angiotensin I pressor response in rats after i.v. administration. The maximum response and duration of effect of both compounds were similar to that seen with equimolar doses of captopril. Oral doses of SQ 28,853 (50.0 mumol/kg) and SQ 27,786 (15.0 mumol/kg) resulted in 15 and 64% inhibition of ACE, respectively. In conscious normotensive dogs, both compounds (2.0 mg/kg, i.v.) resulted in complete inhibition of ACE. Urine volume was increased by 153 and 667% after SQ 27,786 and SQ 28,853, respectively. Similarly, sodium excretion was increased by 336% after SQ 27,786 and by 650% after SQ 28,853. SQ 27,786 and SQ 28,853 increased potassium excretion by 54 and 115%, respectively. No significant changes in blood pressure were observed with either compound in either species. These results demonstrate that both SQ 27,786 and SQ 28,853 are potent ACE inhibitors and diuretic agents in vivo.

Administration, Oral↗
PubMed1987

Academic-drug industry fellowships.

The UNC/BW fellowship, like other industry/academia collaborative fellowships, provides a unique training experience in clinical research. Both academia and the pharmaceutical industry have opened their doors and allowed clinical pharmacists to spend a year or more developing clinical research skills and an understanding of the drug development process. Is it worth it? Is this program a benefit to the individuals, to the sponsors, or to the profession of pharmacy? The survey of these fellows provides us with the individual's perspective on the benefit and quality of the fellowship. Most believed the fellowship provided them with training to meet their needs and interests. However, given this small number of individual opinions and comments, how do we determine whether the fellowship is meeting the original goal to train clinical pharmacists to be clinical researchers? By looking at the career paths of those who have completed the program, we may gain insight into whether the fellows are involved with research. Since the fellowship has been in existence for only six years, we really can look only at the initial placement of these clinical pharmacists. A majority have gained employment with clinical research responsibilities within the pharmaceutical industry. One measure of the research capabilities of these fellows is their contributions to the scientific literature; 10 papers and 3 abstracts have been generated by fellows since they completed their fellowships (Appendix I). As expected, the research contributions of the two-year fellows are greater than that of the one-year fellows. Seven one-year fellows did not have a publication.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Industry↗
PubMed1987

Mechanism of the vasodilatory effect of carvedilol in normal volunteers: a comparison with labetalol.

In a single blind parallel design, saline (n = 9), labetalol i.v. (40 mg n = 4, 80 mg n = 3), and carvedilol i.v. (15 mg n = 8) were given to volunteers with blood pressure (BP) recorded intraarterially. The effect of these treatments on the response to challenge doses of angiotensin II (to give a rise in mean BP of 20-25 mm Hg), isoproterenol (to give an increase in heart rate of 30-35 beats/min), and phenylephrine (to give a rise in mean BP of 20-25 mm Hg) were studied. The dose of i.v. carvedilol employed gave a greater fall in BP than the dose of labetalol used. Carvedilol appeared to be about four times more potent than labetalol in inhibiting the tachycardia to isoprenaline. Likewise, from inhibition of the pressor response to phenylephrine, it is concluded that carvedilol is four times more effective at the alpha receptor than labetalol. Neither drug was found to antagonize the pressor effects of angiotensin. Calculation of the half-life of carvedilol gave values of 2.2 to 9 h. The volume of distribution was found to be 1.54 l/kg and the total body clearance was 0.521 l/h/kg.

Adrenergic beta-Antagonists↗
PubMed1987

Inter-relationship between mucosal and systemic immunity determining the balance between damage and defense in the bovine gut in response to environmental antigens.

At weaning, the complex interactions of macromolecular components embracing maternally derived antibodies and antigens of microbial and dietary origin, grossly influence the immune response, directing it towards protective or damaging reactions in the intestinal mucosa. In young calves, passively acquired maternal antibody surprisingly enhances the systemic IgG1 mediated type III hypersensitivity reactions to dietary antigen. Furthermore, unresponsiveness to orally administered protein antigen in the young calf fails to develop. Additionally, antigens from gram negative bacteria can influence the development of IgE mediated hypersensitivity reactions. In the normal deleterious gut reactions to protein antigens from the lumen, IgE responses infrequently occur, and are transient. However, these can be reinforced by simultaneous challenge with protein and microbial antigen. These observations bring some new perspectives on health and nutrition of young farm animals at weaning.

Animals↗
PubMed1986

Liquid chromatographic assay and disposition of carvedilol in healthy volunteers.

Quantitative determination of serum concentrations of carvedilol [(+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl) amino]-2-propanol], a combined alpha- and beta-adrenergic receptor antagonist, was obtained using HPLC with spectrofluorometric detection. Carvedilol was extracted from alkalinized serum with ether and was subsequently back extracted with diluted phosphoric acid. This method proved to be sensitive and reproducible (mean coefficient of variation of 6.1% for 0.25 to 150 nanograms per milliliter of serum). A single dose of carvedilol (5, 10, or 15 mg) was given as an intravenous infusion to three healthy volunteers. Carvedilol serum concentration-time profiles were fitted best to a three-compartment model and the pharmacokinetic data revealed the following mean values: Vdss of 1.97 L/kg, mean residence time (MRT) of 4.66 h, and CL of 0.437 L X h-1 X kg-1.

Antihypertensive Agents↗
PubMed1986

Secondary structure predictions of human plasminogen and the bovine prothrombin kringle loops.

Secondary structural predictions, based upon the statistical methodology of Chou and Fasman, for the kringle loops of human plasminogen and bovine prothrombin suggest a "winding staircase" pattern of beta-turns, spaced by short regions of ordered and coil structures. Analysis of the predicted structures of the regions containing the two His (113 and 387) and Asp (136 and 410) residues in plasminogen kringles 1 and 4, which have been found to be important in binding the ligand, epsilon-aminocaproic acid, shows that all are localized at the same positions on beta-turns. In addition, both of the two Asp residues occur at the end of homologous nonapeptide regions common to all of the five human plasminogen and two bovine prothrombin kringles, indicating evolutionary conservation to preserve biologically critical conformations. Examination of the protein conformation in the region of Asn288, the residue which is glycosylated in one of the two circulating variants of human plasminogen, shows that it most likely exists in a position which may present topographical hindrance to post-translational attachment of carbohydrate, thus, possibly, explaining the incomplete glycosylation of human plasminogen with complex-type carbohydrate.

Amino Acid Sequence↗
PubMed1986

Examination of the secondary structure of the kringle 4 domain of human plasminogen.

The structure of a small region of human plasminogen (F4), consisting of amino acid residues Val354-Ala439 and containing its kringle 4 (K4) domain (residues Cys357-Cys434), has been predicted from Chou-Fasman calculations and hydropathy profiles, and compared to circular dichroism (CD) measurements on the isolated fragment. Calculations, by the Chou-Fasman method, of the probabilities of various types of secondary structures that exist in this region reveal that no helical structures are present. Of the total of 86 amino acid residues present in this K4-containing peptide region, 37% can adopt conformations of beta-pleated sheets, 48% of the amino acids can exist in beta-turns, and 15% of the residues can be present as coils. The structure of F4 in dilute aqueous solution has been experimentally evaluated by CD measurements. At pH = 7.4, in dilute salt solutions, a total of 64% beta-structures, 30% beta-turns, and 6% coiled structures is estimated to be present in this peptide region. Consideration of the marginal stability of many of the conformational regions of F4, as predicted by Chou-Fasman calculations, suggests that secondary structural flexibility is present in this fragment, which could result in ready adoption of new conformations. The hydropathy profile of F4 has been determined and suggests that this polypeptide is highly hydrophilic, especially in the regions of residues His387-Tyr396 and Cys406-Lys413. Thus, it appears as though a large portion of the surface of F4 can be exposed to solvent in its native conformation.

Chymotrypsin↗
PubMed1986

A single-dose pharmacokinetic study of the antisickling agent cetiedil.

Cetiedil citrate is an antisickling agent shown to be effective in reducing the severity and duration of acute sickle cell crisis. With the use of a sensitive GC/MS assay, the pharmacokinetic profile of cetiedil was studied in normal men and in men with sickle cell anemia who were not in crisis at the time of study. A peak cetiedil concentration of 70 to 200 ng/ml was found immediately after a 30-minute drug infusion. The plasma level then gradually declined to approximately 10 ng/ml during a 3-hour distributive phase. Computer analysis of the data was most consistent with a three-compartment model. No pharmacokinetic differences were found between the normal men and the subjects with sickle cell. Because the cetiedil plasma levels achieved during this in vivo study are well below concentrations that exhibit antisickling activity in vitro, additional clinical studies will be necessary before an optimal dosing regimen can be established.

Adult↗
PubMed1986

Ranitidine at very large doses does not inhibit theophylline elimination.

While most controlled studies in humans indicate that ranitidine does not alter drug metabolism, there is some evidence that ranitidine may have this property. If ranitidine does inhibit drug metabolism in a predictable manner, such an effect might be expressed at higher ranitidine doses. Our study was designed to contrast the effects of large doses of ranitidine (1200 and 4200 mg/day) and cimetidine (1200 mg/day) on theophylline elimination. Whereas cimetidine decreased theophylline clearance in 11 of 12 subjects by a mean of 19.4%, neither ranitidine dose affected theophylline disposition. While case reports indicate ranitidine may inhibit theophylline metabolism specifically and drug metabolism in general, we were not able in our controlled study to detect any effect of ranitidine on theophylline elimination even at ranitidine doses up to fourteenfold greater than are generally prescribed.

Administration, Oral↗
PubMed1986

Rates of nucleotide substitution in Drosophila mitochondrial DNA and nuclear DNA are similar.

While the majority of DNA in eukaryotes is in the nucleus, a small but functionally significant amount is found in organelles such as chloroplasts and mitochondria. A recent, rather remarkable, finding has been that in vertebrates the DNA in the mitochondria (mtDNA) is evolving 5-10 times faster than the DNA in the nucleus. No similar studies have been done with invertebrates. Using the technique of DNA X DNA hybridization, we have measured the degree of nucleotide substitution between Drosophila melanogaster and Drosophila yakuba for both single-copy nuclear DNA (scnDNA) and mtDNA. The change in melting temperature is the same in both types of DNA hybrids. Thus we conclude that mtDNA and scnDNA are evolving at similar rates in these Drosophila. Considerable DNA sequence data are available for the mtDNAs studied, allowing us to estimate that a 1 degree C change in melting temperature corresponds to a 1.5-2% base-pair mismatch.

Animals↗
PubMed1986

Effect of duration of lidocaine infusion and route of cimetidine administration on lidocaine pharmacokinetics.

The effects of the duration of lidocaine infusion and the route of cimetidine administration on lidocaine pharmacokinetics were evaluated in a randomized, three-phase crossover study of six healthy men. Lidocaine hydrochloride 100 mg was administered intravenously over two minutes, and plasma lidocaine concentrations were determined before treatment and at various intervals for three hours. Immediately after the three-hour sample was obtained, a second 100-mg dose of lidocaine hydrochloride was given, followed by a 21-hour constant infusion at a rate of 2 mg/min. Plasma lidocaine concentrations were determined at various intervals during the infusion and for eight hours afterward. Urine was collected during the last five hours of the infusion and assayed for lidocaine, monoethylglycinexylidide (MEGX), and glycinexylidide (GX). The following treatments were administered to each subject in a crossover manner: a placebo tablet every six hours, beginning two days before lidocaine administration; cimetidine 300 mg orally every six hours, beginning two days before lidocaine administration; and cimetidine hydrochloride 300 mg i.v. every six hours, beginning one hour before lidocaine administration. Each medication was given until the lidocaine infusion was discontinued. Subjects fasted and remained supine throughout each treatment period. Oral cimetidine increased the area under the concentration-time curve for lidocaine by 14.7% and increased the elimination half-life of lidocaine; i.v. cimetidine did not have a significant effect on lidocaine disposition. Lidocaine clearance was 34% lower under steady-state than single-dose conditions, but the effects of cimetidine on lidocaine disposition were similar under both conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

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.

Adult↗
PubMed1985

Oral infection of Aedes aegypti with yellow fever virus: geographic variation and genetic considerations.

Twenty-eight populations representing a worldwide distribution of Aedes aegypti were tested for their ability to become orally infected with yellow fever virus (YFV). Populations had been analyzed for genetic variations at 11 isozyme loci and assigned to one of 8 genetic geographic groups of Ae. aegypti. Infection rates suggest that populations showing isozyme genetic relatedness also demonstrate similarity to oral infection rates with YFV. The findings support the hypothesis that genetic variation exists for oral susceptibility to YFV in Ae. aegypti.

Aedes↗