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T D Cowart

Publications and source records attributed to T D Cowart.

14 recordsLinked to original sources
PubMed1999

LC/MS/MS analysis of vesnarinone and its principal metabolites in plasma and urine.

An LC/MS/MS assay was developed and successfully used to quantitate vesnarinone and its principal metabolites (OPC-8230, OPC-18136, and OPC-18137) in human plasma and urine. Samples were pre-treated with liquid-solid extraction followed by simultaneous monitoring of primary and daughter ions which were used for the identification and quantitation of the analytes on LC/MS/MS. This assay offers advantages of specificity, speed and greater sensitivity over the previously developed HPLC-UV assay. The lower limit of quantitation is 500 ng x ml(-1) for vesnarinone and 20 ng x ml(-1) for OPC-8230, OPC-18137, and OPC-18136 in plasma. Methodology is similar for the estimation of these analytes in urine with the lower limit of quantitation being 500 ng x ml(-1) for vesnarinone and 100 ng x ml(-1) for each metabolite. Ascorbic acid was added to stabilize the analytes from degradation. This LC/MS/MS method was developed to overcome many practical problems associated with the HPLC method. The LC/MS/MS method offers the flexibility of analyzing additional metabolites and changing the linearity range to accommodate the differences in linear range (200-10000 ng x ml(-1) for vesnarinone and 20-1000 for metabolites) for the analytes.

Biotransformation↗
PubMed1999

Effect of disulfiram-mediated CYP2E1 inhibition on the disposition of vesnarinone.

Vesnarinone is an orally administered inotropic agent that is metabolized in vitro by the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1. The purpose of this study was to assess the contribution of CYP2E1 activity to the disposition of vesnarinone in humans by characterizing the pharmacokinetics before and after disulfiram-mediated CYP2E1 inhibition. The pharmacokinetics of vesnarinone 60 mg were determined in normal healthy volunteers (N = 7) before and after daily disulfiram administration (250 mg). Chlorzoxazone 250 mg was also administered before, during, and after disulfiram administration to serve as a positive control for CYP2E1 inhibition. Disulfiram treatment decreased 6-hydroxychlorzoxazone formation clearance by nearly 95% but effected only a modest decrease in vesnarinone apparent oral clearance (5.7 +/- 1.0 vs. 5.0 +/- 0.5 ml/min; p = 0.022). In contrast to the modest effect on the parent drug, disulfiram treatment substantially increased plasma concentrations of the primary metabolite OPC-18692. The Cmax of OPC-18692 was increased approximately 7-fold, and the area under the plasma concentration-time curve was increased 18-fold (2.9 +/- 0.9 vs. 53.7 +/- 33.2 micrograms.h/ml; p = 0.006). The results indicate that CYP2E1 inhibition has only a modest, clinically insignificant effect on vesnarinone disposition but markedly increases plasma concentrations of the OPC-18692 metabolite. The pharmacological properties of this metabolite have not been fully defined; thus, the clinical importance of this observation depends on whether this metabolite contributes to any of the toxicity associated with vesnarinone administration.

Adult↗
PubMed1998

Direct myocardial effects of OPC-18790 in human heart failure: beneficial effects on contractile and diastolic function demonstrated by intracoronary infusion with pressure-volume analysis.

OBJECTIVES: We sought to determine the precise myocardial effects of OPC-18790 as demonstrated by intracoronary administration. BACKGROUND: Although previous studies have determined the cardiovascular effects of a novel intravenous inotrope, OPC-18790, the observed benefits on contractile and diastolic function may have been confounded by the marked changes in peripheral loading associated with this drug when given intravenously. METHODS: Eight heart failure patients received intracoronary OPC-18790 at 31.25 microg/min for 20 min, and then at 62.5 microg/min for another 20 min. Hemodynamic variables and pressure-volume indexes using the conductance catheter method were determined at baseline and then after the two doses. RESULTS: There were no significant effects on heart rate, cardiac output or loading conditions, including afterload as determined by systemic vascular resistance and arterial elastance (Ea) and preload as determined by end-diastolic volume (EDV). There were significant increases in end-systolic elastance (Ees) from 0.74+/-0.11 to 0.90+/-0.16 mm Hg/ml at 31.25 microg/min and to 137+/-0.33 mm Hg/ml at 62.5 microg/min (p < 0.05 by analysis of variance [ANOVA]). Diastolic function improved, as determined by the time constant for isovolumetric relaxation tau, which decreased significantly from baseline to 31.25 microg/min (94+/-9 to 79+/-9 ms, p < 0.05), and did not shorten further at 62.5 microg/min (78+/-8 ms, p=NS). There were significant decreases in right atrial pressure (9+/-1 to 7+/-1 mm Hg, p < 0.01 by ANOVA) and mean pulmonary artery wedge pressure (21+/-3 to 16+/-2 mm Hg, p < 0.05 by ANOVA). This fall in filling pressures was not accompanied by any change in EDV. Inspection of the diastolic portion of the pressure-volume curve confirmed a downward shift consistent with pericardial release in five of the eight patients. CONCLUSIONS: Intracoronary administration of OPC-18790 demonstrates that the direct myocardial effects of this agent include a modest increase in inotropy and improvement in diastolic function, both of which occur without increases in heart rate, indicating that this agent may be beneficial for the intravenous treatment of congestive heart failure.

Aged↗
PubMed1996

Acute cardiovascular effects of OPC-18790 in patients with congestive heart failure. Time- and dose-dependence analysis based on pressure-volume relations.

BACKGROUND: OPC-18790 is a water-soluble quinolinone derivative that shares the pharmacological properties of vesnarinone and that may be useful for treating heart failure. We studied the contribution and relative dose sensitivities of the inotropic, lusitropic, and vascular effects of OPC-18790 in patients with dilated cardiomyopathy. METHODS AND RESULTS: Pressure-volume (PV) analysis was performed in 17 patients who received either 5 micrograms.kg-1.min-1 (low dose, n = 10) or 10 micrograms.kg-1.min-1 (high dose, n = 7) OPC-18790 by 1-hour IV infusion. Right heart pressures and flow and left heart PV relations (conductance catheter) were measured at baseline and every 15 minutes during infusion. Transient inferior vena caval obstruction was used to determine PV relations. Both doses produced venodilation reflected by a 10% decline in left ventricular end-diastolic volume and a 30% fall in atrial and pulmonary artery pressures. Arterial dilation was four times greater at the high dose, with an approximately 40% fall in effective arterial elastance and systemic resistance. Contractility rose by 25% to 100% (depending on PV index) with both doses. Ventricular-arterial coupling (ratio of ventricular end-systolic to arterial elastances) was approximately 0.25 at baseline and doubled (or tripled) at low (or high) dose, correlating with improved efficiency. Isovolumetric relaxation shortened, whereas the diastolic PV relation was generally unchanged. Heart rate was unaltered. CONCLUSIONS: OPC-18790 has potent venous and arterial vasodilator effects and moderate inotropic and lusitropic effects without a change in heart rate. These combined actions suggest a unique potential of OPC-18790 for heart failure treatment.

Blood Pressure↗
PubMed1990

Pharmacokinetics and metabolism of oral doses of a 4'-methylthio derivative of propranolol in man.

1. The objective of this study was to determine the oral dose pharmacokinetics and metabolism of 4'-methylthiopropranolol (MTP) in man and compare the results with observations for propranolol in previous studies. 2. Three women and five men received single oral doses of MTP, dose range 5-320 mg. Plasma concentration of MTP over time were measured by gas chromatography-mass spectrometry. MTP metabolites in urine were identified by comparative high-performance liquid chromatographic (HPLC) retention times and mass spectrometry with previously characterized reference compounds and quantified by HPLC. 3. The oral clearance of MTP of 1.2-1.4 l/min for the 80, 160 and 320 mg doses was about one third of the value previously reported for propranolol. The half-life for MTP (3.3-4.1 h) was, however, similar to that of propranolol. In contrast to propranolol, the peak (2.5 h) plasma concentrations of MTP increased linearly with dose (5-320 mg). 4. The oral clearance for MTP was about 2-fold higher in the men than in the women (P less than 0.01). In addition, the clearance of the (S)-enantiomer was about 30% higher than that of the (R)-enantiomer (P less than 0.05), which was a reversal of that seen with propranolol. 5. The metabolism of MTP resulted mainly in sulphur oxidation to sulphoxide and sulphone metabolites. These two metabolites accounted for 75% of the MTP dose. This switching from aromatic carbon oxidation for propranolol to sulphur oxidation for MTP is proposed as the basis of the lower oral clearance of MTP. 6. This study also demonstrated higher plasma binding of MTP (unbound fraction 3.7%) than of propranolol (10.5%; P less than 0.01), a factor probably contributing to decreased tissue distribution of MTP.

Administration, Oral↗
PubMed1989

Pathway-selective sex differences in the metabolic clearance of propranolol in human subjects.

This study determined the total clearance of propranolol and the partial clearances through each of its three primary metabolic pathways after administration of an 80 mg single oral dose in 28 young, white subjects (13 women; 15 men). The oral clearance of propranolol was significantly higher (63%, p less than 0.02) in the men (65.7 +/- 7.7 ml/min/kg; mean +/- SE) than in the women (40.2 +/- 6.2 ml/min/kg). This sex difference was mainly attributable to a 137% higher clearance through the P-450-mediated side-chain oxidation in the men (p less than 0.001). There was also a 52% higher clearance through glucuronidation in the men (p less than 0.02). In contrast, the clearance through the P-450-mediated ring oxidation was not different between men and women. After administration of simultaneous intravenous doses of hexadeuterium-labeled drug (0.1 mg/kg) to 11 of the subjects, there were no differences between men and women in volume of distribution or half-life. Moreover, there were no sex differences in plasma and blood binding of propranolol. This study thus demonstrates that higher plasma levels of propranolol occur in women than in men after oral doses and suggests that some drug metabolizing enzymes, but not others, are regulated by sex hormones in human beings.

Administration, Oral↗
PubMed1988

Verapamil-induced natriuretic and diuretic effects: dependency on sodium intake.

The influence of dietary sodium on the antihypertensive effects of verapamil and on components of sodium, water, and calcium metabolism was studied in nine white patients 50 to 65 years old with normal renin hypertension. Diets consisting of 109 and 259 mEq Na were given for 5 days each before the study drug was given. On days 4 and 9, intravenous verapamil (0.075 mg/kg) and oral verapamil (80 mg) were given, followed by 80 mg at 8-hour intervals for three doses. On days 1, 4, 5, 9, and 10, serum and urine electrolytes, osmolality (urine [Uosm], serum [Sosm], and osmolar clearance [Cosm]), calcium plasma renin activity (PRA), and levels of serum aldosterone, 1,25-hydroxyvitamin D, serum ionized calcium, parathyroid hormone, atrial natriuretic hormone (atriopeptin), and erythrocyte calcium and electrolytes were measured. On days 5 and 10, serial plasma samples for measurement of verapamil and norverapamil levels were drawn immediately after the last oral dose of verapamil. After verapamil, Uosm and Cosm decreased during both 109 and 259 mEq sodium diets (Uosm, p less than 0.025; Cosm, p less than 0.01 and p less than 0.025, respectively), but free water clearance increased during each diet (p less than 0.01). Urine volume and sodium excretion increased with the 259 mEq sodium diet (p less than 0.025 and p less than 0.01, respectively). There were no significant changes in measured values of components of calcium metabolism with either diet or after verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Selective induction of propranolol metabolism by smoking: additional effects on renal clearance of metabolites.

The objective of this study was to examine the effect of cigarette smoking on the activities of the three primary pathways governing propranolol metabolism in human subjects, i.e., glucuronidation, side-chain oxidation and ring oxidation. A single 80-mg dose of propranolol p.o. together with 40 muCi of 4-[3H]propranolol was given to six smoking and seven nonsmoking, young, white, male subjects and the oral clearance of propranolol and the partial clearances through these pathways were determined. The oral clearance of propranolol was increased by 77% (P less than .02) in smokers compared with nonsmokers. This apparent induction of propranolol metabolism was due to a 122% increase in side-chain oxidation (P less than .001) and a 55% increase in glucuronidation (P less than .01). There was no significant effect of smoking on aromatic ring oxidation. Smokers had a 30% greater renal clearance of total metabolites (P less than .05), due mainly to a 53% greater renal clearance of the acidic propranolol metabolite naphthoxylactic acid (P less than .001). These data show a selective effect of smoking on propranolol metabolism and suggest that side-chain oxidation and glucuronidation are mediated by isoenzymes inducible by aromatic hydrocarbons. The selective effect of smoking on the renal clearance of the major propranolol metabolite naphthoxylactic acid may be due to induction of a renal transport protein.

Adult↗
PubMed1986

Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis.

The influence of a high-protein meal as compared to fasting on the disposition of simultaneous intravenous and oral doses of propranolol, as well as on indocyanine green clearance, was examined in six normal subjects. The intravenous dose (0.1 mg/kg) was unlabeled propranolol and the oral dose (80 mg) was a stereospecifically deuterium-labeled pseudoracemate of propranolol. Systemic clearance of propranolol increased 38%, from 1005 +/- 57 to 1384 +/- 115 ml/min (mean +/- SE; P less than 0.05) as a result of the meal, with no change in t1/2 or apparent volume of distribution. A 12% decrease in oral clearance occurred with the meal but was not statistically significant (3717 +/- 185 ml/min, fasting; 3245 +/- 498 after meal), whereas bioavailability increased 67% (27.2% +/- 1.7% fasting; 45.5% +/- 4.3% after meal; P less than 0.01). Estimated hepatic blood flow, as measured by indocyanine green clearance, rose 34% 60 minutes after the meal (1719 +/- 155 ml/min fasting; 2304 +/- 218 ml/min after meal; P less than 0.02). A difference was observed in the oral clearance of the propranolol enantiomers in the fasting state, but this difference was unaffected by the meal. These alterations in propranolol disposition, as the result of a high-protein meal, are consistent with a transient increase in hepatic blood flow.

Administration, Oral↗
PubMed1984

Stereoselective clearance and distribution of intravenous propranolol.

Our objective was to determine the kinetics of (+)- and (-)-propranolol after intravenous doses of racemic drug. Five normal subjects received 0.1 mg/kg of a pseudoracemate of propranolol that consisted of deuterium-labeled (+)-propranolol and unlabeled (-)-propranolol. Plasma concentrations of (+)- and (-)-propranolol as measured by gas chromatography-mass spectrometry demonstrated enantiomeric differences in systemic clearance (Cls) [(+)-propranolol, 1.21 +/- 0.15 l/min; (-)-propranolol, 1.03 +/- 0.12 l/min; P less than 0.01] and apparent volume of distribution (Vd) [(+)-propranolol, 4.82 +/- 0.34 l/kg; (-)-propranolol, 4.08 +/- 0.33 l/kg; P less than 0.001], but no difference in distribution or elimination t1/2s (t1/2 beta 3.5 hr). The higher Cls of (+)-propranolol suggests stereoselective hepatic elimination. The higher apparent Vd of (+)-propranolol is mainly related to its lower plasma binding [(+)-propranolol, 20.3 +/- 0.8% unbound; (-)-propranolol, 17.6 +/- 0.7% unbound; P less than 0.001]. There was no stereoselective uptake by red blood cells. These findings demonstrate that multiple stereoselective mechanisms are involved in the disposition of propranolol and determine the access of the drug to active sites.

Adult↗
PubMed1984

Use of nifedipine as an adjunct to current antihypertensive therapy.

Ten hypertensive patients with poor responses to standard antihypertensive therapy were treated with the calcium channel antagonist nifedipine in an attempt to obtain better BP control. The drug was highly effective in significantly lowering BP immediately (average decrease, 58/29 mm Hg) and after three to eight weeks of maintenance therapy (average decrease, 49/27 mm Hg), with no significant change in heart rate observed at either time. No adverse interactions between nifedipine and other concurrent medications, including digoxin and beta-adrenergic blockers, were noted. Drug-related side effects of tachycardia or flushing necessitated the withdrawal of nifedipine therapy in two patients. We conclude that nifedipine may be safely employed in an outpatient setting as a useful adjunct to current antihypertensive drug regimens.

Adrenergic beta-Antagonists↗
PubMed1982

Antihypertensive effects of lofexidine in patients with essential hypertension.

1 Single oral doses of lofexidine, 0.1, 0.3, and 0.6 mg produced dose related decreases in supine and standing arterial pressure and heart rate in nineteen patients with essential hypertension. 2 A mean oral antihypertensive threshold dose of less than 0.1 mg was estimated. 3 Lofexidine decreased mean urinary noradrenaline excretion 28% and caused significant retention of sodium and water. 4 The most prominent side effects were sedation and orthostatic dizziness. 5 Lofexidine is pharmacologically similar to, but apparently less potent than clonidine as an antihypertensive agent.

Adolescent↗