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Biomedical subjects

J R Powell

Publications and source records attributed to J R Powell.

At least 109 records · Page 6Linked to original sources
PubMed1989

Fosinopril, a phosphinic acid inhibitor of angiotensin I converting enzyme: in vitro and preclinical in vivo pharmacology.

Fosinopril is the first member of a new chemical class of angiotensin I (AI) converting enzyme (ACE) inhibitors, the phosphinic acids. In vitro, SQ 27,519, the active moiety of the prodrug fosinopril, was a more potent inhibitor of purified rabbit lung ACE- (IC50 = 11 vs. 23 nM) and bradykinin-induced contractions of guinea pig ileum than captopril. In vivo, SQ 27,519 was equipotent to captopril as an inhibitor of an AI pressor response after intravenous (i.v.) administration to conscious rats and monkeys but appeared to be less potent in conscious dogs. After oral administration, fosinopril again was equipotent to captopril as an inhibitor of an AI pressor response in rats and monkeys and slightly less potent in dogs. However, both SQ 27,519 (i.v. studies) and fosinopril (oral studies) had a longer effect than captopril in all three species. When fosinopril was administered orally for 5 days, its effects on an AI pressor response were the same on days 1 and 5, suggesting lack of tolerance to the compound. The ACE inhibitory effect of captopril, but not fosinopril, was prolonged in conscious rats with glycerol-induced acute renal failure, suggesting that fosinopril is excreted by an extrarenal route. Finally, fosinopril had no effect on the pressor or chronotropic effects of norepinephrine (NE) or 1,1-dimethyl-4-phenylpiperinium (DMPP) or electrical stimulation of the sympathetic ganglia of pithed rats. Fosinopril attenuated the pressor, but not the chronotropic effects of tyramine. We conclude that fosinopril is a potent and long-lasting inhibitor of ACE in conscious animal models that does not impair adrenergic function or reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1989

Intraspecific and interspecific genetic variation in Drosophila.

Utilizing the technique of DNA-DNA hybridization, we have characterized the degree of genetic variability in single-copy DNA both within and between several species of Drosophila. The results of intraspecific variation studies indicate considerable variation both for levels of nucleotide heterozygosity (estimated to be over 2%) as well as for insertions-deletions. Interspecific studies confirm this great deal of variability and further establish an extreme heterogeneity within Drosophila genomes for rates of divergence. This heterogeneity is much more extreme than that seen between exons and introns. The degree of single-copy DNA divergence generally supports phylogenetic affinities deduced from more traditional methods. However, exceptions occur where single-copy DNA divergence is not correlated with other properties such as degree of chromosomal differentiation, morphology, or ability to form interspecific hybrids. We argue that single-copy DNA divergence as measured by DNA-DNA hybridization is an accurate indicator of phylogenetic relationships and therefore sheds light on the evolution of other biological properties. Many, if not most, evolutionary tests require an accurate phylogeny of the group being studied and DNA, because of the high information content inherent within the molecule, offers the best hope of deriving true phylogenies.

Animals↗
PubMed1989

Alcohol suppresses endothelium-dependent relaxation in rat mesenteric vascular beds.

The effects of prolonged infusions of ethanol on endothelium-dependent vasorelaxation induced by acetylcholine and adenosine triphosphate (ATP) and on endothelium-independent relaxation induced by papaverine were studied and compared in isolated perfused rat mesenteric artery preparations. Infusion of ethanol over 60 minutes at concentrations of 1.6, 4.7, 6.3, and 7.9 mg/ml caused concentration-related inhibition of norepinephrine-induced vasoconstriction. In preparations infused with 6.3 and 7.9 mg/ml, this effect reached a maximum after 10-20 minutes but had vanished by the end of the infusion; 1 hour after the end of the infusion, the effects of norepinephrine were potentiated by 71% and 108%, respectively. Acetylcholine-induced vasorelaxation (EC50 3.0 ng/ml in controls) was significantly reduced after 6.3 mg/ml ethanol infusion and totally abolished after 7.9 mg/ml ethanol infusion. ATP-induced vasorelaxation (EC50 180 ng/ml in controls) was also abolished after 7.9 mg/ml of ethanol infusion. By contrast, the vasorelaxant effects of papaverine were not affected by 7.9 mg/ml ethanol infusion. Light-microscopic examination revealed that the endothelial cells were present in ethanol-treated and in control mesenteric arterial beds. These observations indicate that ethanol suppresses endothelium-dependent vasorelaxation without apparent removal of the endothelial cells. The compromised relaxant capacity of the endothelium after ethanol and the resultant intensification of the vasoconstrictor response to norepinephrine may contribute to the development of vascular diseases such as hypertension and stroke.

Acetylcholine↗
PubMed1989

Influence of rifampin on tocainide pharmacokinetics in humans.

The effects of metabolic enzyme induction by rifampin on the pharmacokinetics of tocainide were studied in eight healthy volunteers. In an open, unrandomized fashion, volunteers received tocainide hydrochloride 600 mg orally. Blood samples were obtained immediately before and at various time intervals up to 48 hours after the dose. Urine samples were collected before and at various intervals up to 72 hours after the dose. Serum and urine samples were assayed for tocainide content by high-performance liquid chromatography. After a four-week washout period, volunteers ingested 300 mg of rifampin by mouth every 12 hours. After 10 doses, subjects received a second oral dose of tocainide hydrochloride 600 mg, and blood and urine samples were collected as before. During the sampling period, subjects continued to ingest rifampin 300 mg orally every 12 hours. Significant differences in elimination rate constant (average increase, 0.0545 to 0.0748 hr-1), elimination half-life (average reduction, 13.2 to 9.4 hours), oral clearance, and area under the concentration-time curve (average reduction, 76.8 to 55.0 mg.hr/L) between the control and rifampin treatment phases were observed. Volume of distribution and renal clearance of tocainide were not significantly different after rifampin treatment. Tocainide appears to be susceptible to significant drug-drug interactions mediated by metabolic enzyme induction.

Adult↗
PubMed1988

The effect of cimetidine dose timing on oral propranolol kinetics in adults.

Ten healthy male volunteers completed a study to determine the effect of cimetidine dose timing on the oral clearance of propranolol. Propranolol HCl 160 mg as tablets, was administered daily at 8 AM for 4 consecutive days on three occasions. In addition, cimetidine HCl 800 mg as tablets, was administered either simultaneously in the morning with propranolol (8 AM), at bedtime (10 PM), or not at all (control). Each treatment was separated by at least a 3-day washout. Propranolol and cimetidine serum samples were measured over the 24-hour dosing interval after the last propranolol dose. Cimetidine administration at 8 AM and 10 PM was associated with significant mean increases in the propranolol area under the serum concentration-time curve of 26% and 41%, respectively (P less than .002). The mean elimination half-life of propranolol was 6.3 hours during all three treatments. There was no significant difference in area under cimetidine serum concentration time curve between 8 AM and 10 PM dosing. Dosing cimetidine at bedtime 10 hours before propranolol does not diminish the magnitude of interaction.

Administration, Oral↗
PubMed1988

Calibration of the change in thermal stability of DNA duplexes and degree of base pair mismatch.

One method of determining the degree of base pair divergence between two sources of DNA (different strains, species, etc.) is to determine the decrease in thermal stability of hybrid duplex DNA due to mismatching of base pairs. Attempts to calibrate the change in median melting temperature (delta Tm) to base pair mismatch have led to conflicting results. We have studied the delta Tm between DNAs of known sequence over a range of from 0.55% to 7.2% base pair mismatch. The relationship of delta Tm and percent base pair mismatch is remarkably linear over this range with a correlation coefficient greater than 0.98. A delta Tm of 1 degree C corresponds to 1.7% base pair mismatch. This conversion is higher than that usually assumed and, therefore, rates of DNA evolution estimated by DNA-DNA hybridization studies are likely faster than previously thought.

Animals↗
PubMed1988

(Phosphinyloxy)acyl amino acid inhibitors of angiotensin converting enzyme (ACE). 1. Discovery of (S)-1-[6-amino-2-[[hydroxy(4-phenylbutyl)phosphinyl]oxy]-1-oxohexyl]-L -proline a novel orally active inhibitor of ACE.

The synthesis of a series of orally active, phosphinyloxyacyl proline inhibitors of angiotensin converting enzyme (ACE) is described. The in vitro and in vivo ACE inhibitory activities are reported for each compound. The structure-activity relationship for this series of compounds in relation to the carboxyalkyl dipeptide ACE inhibitors as well as other types of hydroxyphosphinyl-containing ACE inhibitors (e.g., the corresponding nitrogen and carbon isosteres) is discussed. Within an isosteric series of phosphorus-containing inhibitors based on the lysylproline terminal dipeptide sequence, only the phosphonates (oxygen isosteres) show a high level of oral activity. Optimum potency and oral activity in the phosphonate series occurs with the (phenylbutyl)- and n-hexylphosphonate side chains. An aminobutyl side chain in the P1' residue is an absolute requirement for full expression of oral activity. The most potent of these compounds, 8b (SQ 29,852), has intravenous and oral activities superior in potency to those of captopril in the normotensive rat.

Administration, Oral↗
PubMed1988

Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines.

Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Rates and patterns of scnDNA and mtDNA divergence within the Drosophila melanogaster subgroup.

Levels of DNA divergence among the eight species of the Drosophila melanogaster subgroup and D. takahashii have been determined using the technique of DNA-DNA hybridization. Two types of DNA were used: single-copy nuclear DNA (scnDNA) and mitochondrial DNA (mtDNA). The major findings are: (1) A phylogeny has been derived for the group based on scnDNA which is congruent with chromosomal data, morphology, and behavior. The three homosequential species, simulans, sechellia, and mauritiana, are very closely related; the scnDNA divergence indicate the two island species are a monophyletic group. (2) The rates of change of scnDNA and mtDNA are not greatly different; if anything scnDNA evolves faster than mtDNA. (3) The rates of scnDNA evolution are not closely correlated to chromosomal (inversion) evolution. (4) The Drosophila genome appears to consist of two distinct classes of scnDNA with respect to rate of evolutionary change, a very rapidly evolving fraction and a relatively conservative fraction. (5) The absolute rate of change was estimated to be at least 1.7% nucleotide substitution per one million years. (6) DNA distance estimates based on restriction site variation are correlated with distances based on DNA-DNA hybridization, although the correlation is not very strong.

Animals↗
PubMed1988

Pressor responses induced by Bay K 8644 involve both release of adrenal catecholamines and calcium channel activation.

1. The dihydropyridine calcium channel activator, Bay K 8644, is believed to increase mean arterial blood pressure in several animal models, as a result of direct activation of vascular smooth muscle cells by increasing calcium influx through the voltage-dependent calcium channels. The purpose of the current study was to elucidate further the mechanism of action of Bay K 8644, by examining the possibility that the pressor response to Bay K 8644 may also be the result of indirect activation of the vascular smooth muscle cells by release of adrenal catecholamines. 2. Intravenous administration of Bay K 8644 increased mean arterial pressure in a dose-dependent manner in conscious, normotensive rats. This pressor response was blocked by calcium channel blockers (nifedipine, verapamil, and diltiazem) at doses lower than were necessary to decrease resting mean arterial pressure. 3. alpha-Adrenoceptor antagonists (phentolamine, yohimbine, and prazosin) completely blocked the Bay K 8644-induced pressor responses and converted them to depressor responses. Adrenalectomy did not alter the inhibitory effect of phentolamine on the pressor response to Bay K 8644. However, adrenalectomy or adrenal demedullectomy prevented the phentolamine-induced reversal of the Bay K 8644 pressor response to a depressor response. In addition, adrenalectomy did not affect the ability of phentolamine to reverse the pressor response to exogenous adrenaline administration to a depressor response. 4. These data suggest that the pressor response to Bay K 8644 may involve both direct activation of vascular smooth muscle cells and indirect activation of the muscle cells by release of adrenal catecholamines.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

Accuracy of tobramycin delivery by four i.v. infusion methods.

The accuracy of tobramycin delivery by four methods of intermittent intravenous infusion was studied in 11 healthy male volunteers. Subjects received intravenous tobramycin (as the sulfate salt) 1.5 mg/kg by each of four infusion methods in a nonblinded, randomized, four-way crossover design. The methods used for intravenous infusion were (1) minibag via gravity flow (MG), (2) minibag with the secondary infusion tubing inserted below a volumetric infusion pump (MP), (3) metered chamber via volumetric infusion pump (MC), and (4) syringe pump (SP). Doses were diluted to a volume of 50 mL, except for the two minibag methods, for which the dilution was necessarily greater because of manufacturer overfill. Intravenous flow rates for both primary fluid and drug administration were set at 100 mL/hr, and the duration of drug infusion was documented by observation for each administered dose. The fluid volume of 12 minibags was measured to assess manufacturer overfill. Fluid remaining in the secondary i.v. tubing for the minibag methods was collected after the infusion. Seventeen blood samples were obtained before and at various time intervals after each dose and analyzed in duplicate for tobramycin content by fluorescence polarization immunoassay. A mean of 10% of each dose remained in the secondary i.v. tubing at the completion of the infusion for the minibag methods, whereas less than 1% of each dose remained in the secondary tubing for the SP method.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Effect of four intravenous infusion methods on tobramycin pharmacokinetics.

The influence of four intermittent intravenous infusion methods on the determination of tobramycin pharmacokinetic values and predicted doses was evaluated in 11 healthy adult volunteers. Each subject received tobramycin (as the sulfate salt) 1.5 mg/kg by each of four i.v. infusion methods: (1) minibag via gravity flow (MG), (2) minibag with the secondary infusion tubing inserted below a volumetric pump (MP), (3) metered chamber via volumetric pump (MC), and (4) syringe pump (SP). Infusion rates were initially set to administer each dose over a 30-minute period. Sixteen blood samples were obtained over an eight-hour period before and at various time intervals after each dose and were analyzed for tobramycin content by fluorescence polarization immunoassay. Area under the serum concentration-time curve from time zero to infinity (AUC0-infinity) was calculated by the trapezoidal rule. Serum tobramycin concentration data for each subject were fitted to a biexponential decay model with zero-order input. beta and V beta were calculated from fitted data. One-compartment pharmacokinetic values, elimination rate constant (kappa), apparent volume of distribution (V), and predicted doses to achieve steady-state peak concentrations of 6 micrograms/mL were calculated by the method of Sawchuk and Zaske. There were no significant differences in either beta or kappa among the infusion methods. V beta values (mean +/- S.D.) for the methods were 0.240 +/- 0.025 (MG), 0.257 +/- 0.025 (MP), 0.221 +/- 0.027 (MC), and 0.231 +/- 0.032 (SP) L/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1987

Bovine monoclonal antibodies to the F5 (K99) pilus antigen of E. coli, produced by murine/bovine hybridomas.

Lymph node cells from calves immunized with purified pilus antigen of K99+ enterotoxigenic E. coli (ETEC) were fused with mouse myeloma (NSO) cells, and with non-Ig producing mouse/calf hybridomas or with a bovine Ig-producing mouse/calf/calf secondary hybridoma. Lines secreting bovine monoclonal IgG1 specific for K99 pilus antigen in an ELISA were obtained in each case. The two lines derived from xenohybridoma fusion partners have been secreting anti-K99 bovine monoclonal antibody for over one year in continual passage. None of the antibodies cross-reacted with other pilus types including K88, CFAI, CFAII, 987P or CP; they all inhibited agglutination of horse RBC (which have a K99 receptor) in the presence of K99 antigen; they showed positive fluorescence in an indirect binding assay on K99+ ETEC and inhibited K99+ ETEC adhesion to piglet enterocytes. These antibodies have potential prophylactic and therapeutic use in control and treatment of diarrhoea.

Animals↗
PubMed1987

The effect of oral cimetidine on total and unbound serum lidocaine concentrations in patients with suspected myocardial infarction.

In this study, we prospectively evaluated the effect of oral cimetidine on serum lidocaine concentrations in 6 patients with suspected myocardial infarction. Compared to baseline lidocaine levels, total lidocaine concentrations increased by 8.2 +/- 7.8% at 6 hours, 16.4 +/- 9.0% at 12 hours and 27.9 +/- 9.4% at 24 hours after two doses of oral cimetidine. Unbound lidocaine concentrations increased by 14.3 +/- 4.1% at 6 hours, and 18.3 +/- 10.3% at 24 hours after cimetidine. In patients with myocardial infarction (3), total lidocaine concentrations increased by 24.2 +/- 10.4%, whereas unbound lidocaine increased by 8.9 +/- 10.2% at 24 hours. Therefore, increases in total lidocaine concentrations after cimetidine administration were considerably less than those previously reported and empiric dosage reductions of lidocaine in patients receiving cimetidine may not be appropriate.

Administration, Oral↗
PubMed1987

Simultaneous objective and subjective evaluation of meclofenamate sodium in the treatment of primary dysmenorrhea.

Eighteen patients participated in a double-blind, placebo-controlled, single-dose, crossover study of meclofenamate sodium in women with primary dysmenorrhea. Simultaneous evaluations of pain intensity and pain relief, sampling of continuous intrauterine pressure recording, and monitoring of blood meclofenamate levels were carried out. Improvements in pain intensity and pain relief were observed at 45 minutes and reached statistical significance at and beyond 1 hour 45 minutes after meclofenamate therapy. Ten of 14 uterine pressure parameters showed statistically significant responses after drug therapy and 12 of the 14 parameters showed statistically significant differences in time-response patterns. Statistically significant changes were noted as early as 45 minutes after meclofenamate therapy. Statistically significant correlations were found between and among the parameters of blood drug level and the subjective and objective measures. No drug-related adverse effects were found.

Adult↗
PubMed1987

Substituted 1,2,3,4-tetrahydroaminonaphthols: antihypertensive agents, calcium channel blockers, and adrenergic receptor blockers with catecholamine-depleting effects.

Substituted 1,2,3,4-tetrahydroaminonaphthols were found to be calcium channel blockers with antihypertensive properties. These compounds also possessed adrenergic beta-receptor blocking activity. From the structure-activity studies, no clear correlation emerged between the in vitro calcium channel blocking activity and the acute anti-hypertensive activity in cannulated spontaneously hypertensive rats. Extensive pharmacological testing of selected compounds indicated that aminonaphthols are antihypertensive agents with many pharmacological properties. The relative contribution of various pharmacological actions toward the observed antihypertensive activity is unclear. Since the clinically useful calcium channel blocker verapamil is structurally related to these compounds, one of the aminonaphthols, trans-3-[(3,3-diphenylpropyl)amino]-1,2,3,4-tetrahydro-6,7 -dimethoxy-2-naphthalenol (12), was compared with verapamil for calcium channel blocking activity, adrenergic blocking activity, and catecholamine-depleting activity. Both compounds were found to be equipotent in these test systems.

Action Potentials↗
PubMed1987

Clinical pharmacology of carvedilol in normal volunteers.

The mechanism of the vasodilatory action of carvedilol (BM 14190), a new antihypertensive agent, was investigated in normal volunteers. Intra-arterial blood pressure and ECG were monitored continuously. Carvedilol (1 mg/min for 15 minutes) produced a rapid reduction in blood pressure and a transient increase in heart rate. At the end of infusion, systolic and diastolic blood pressure were reduced by 23% (-32.3 mm Hg) and 18% (-13.6 mm Hg), respectively, whereas heart rate was not different from baseline. At the doses used, the hypotensive effect of carvedilol was greater than that of labetalol (36 and 72 mg in 15 minutes). Carvedilol and labetalol antagonized isoproterenol-induced hypotension and tachycardia, at serum levels greater than or equal to 8 and 20 mg/ml, respectively. Both drugs antagonized phenylephrine pressor effects. A similar degree of inhibition (25% of control) of pressor effects was observed for carvedilol and labetalol when their respective serum concentrations were 23 ng/ml and 80 ng/ml. Neither carvedilol nor labetalol had any effect on AII pressor responses. Carvedilol serum levels as high as 150 ng/ml failed to inhibit AII-induced pressor responses. Our results suggest that at the doses used in this study, carvedilol has both alpha 1-and nonselective beta-receptor blocking properties. Moreover, carvedilol is approximately three to five times more potent than labetalol in blocking alpha 1-and beta-receptors and in reducing blood pressure.

Adult↗