Biomedical subjects

B N Swanson

Publications and source records attributed to B N Swanson.

At least 19 recordsLinked to original sources

PubMed1993

Steady state serum concentrations of pravastatin and digoxin when given in combination.

Pravastatin is an HMG CoA reductase inhibitor used in the treatment of hypercholesterolaemia. The steady state pharmacokinetics of pravastatin (20 mg) and digoxin (0.2 mg) were evaluated in 18 healthy male subjects following the administration of each drug alone or in combination for 9 days. Serum and urine were collected for up to 48 h after the ninth dose in this open, randomized 3-way crossover study. Digoxin concentrations were measured by radioimmunoassay, and pravastatin and its metabolites. SQ 31,906 and SQ 31,945 were measured by GC-MS. Digoxin and pravastatin pharmacokinetics were unchanged following combined administration. Combination therapy with pravastatin and digoxin is unlikely to expose patients to additional risk compared with pravastatin alone.

Adult↗

PubMed1991

Dihydropyrimidine calcium channel blockers. 3. 3-Carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-pyrimidinecarboxylic acid esters as orally effective antihypertensive agents.

In order to explain the potent antihypertensive activity of the modestly active (IC50 = 3.2 microM) dihydropyrimidine calcium channel blocker 5, we carried out drug metabolism studies in the rat and found 5 is metabolized to compounds 6-10. Two of the metabolites, 6 (IC50 = 16 nM) and 7 (IC50 = 12 nM), were found to be responsible for the antihypertensive activity of compound 5. Potential metabolism of 6 into 7 in vivo precluded our interest in pursuing compounds related to 6. Structure-activity studies aimed at identifying additional aryl-substituted analogues of 7 led to 17g,j,p with comparable potential in vivo, though these compounds were less potent than 7 in vitro. To investigate the effects of absolute stereochemistry on potency, we resolved 7 via diastereomeric ureas 19a,b, prepared from 18 by treatment with (R)-alpha-methylbenzylamine. Our results demonstrate that the active R-(-)-enantiomer 20a of 7 is both more potent and longer acting than nifedipine (1) as an antihypertensive agent in the SHR. The in vivo potency and duration of 20a is comparable to the long-acting dihydropyridine amlodipine. The superior oral antihypertensive activity of 20a compared to that of previously described carbamates 2 (R2 = COOEt) could be explained by its improved oral bioavailability, possibly resulting from increased stability of the urea functionality.

Administration, Oral↗

PubMed1991

Pharmacokinetic interaction between propranolol and the HMG-CoA reductase inhibitors pravastatin and lovastatin.

1. Single oral 20 mg doses of the HMG-CoA reductase inhibitors pravastatin and lovastatin, with and without concomitant propranolol (40 mg twice daily), were administered to 16 healthy male subjects participating in a randomized, four-way crossover study. 2. Serum concentrations of total and active inhibitors were measured by bioassay and concentrations of pravastatin, two pravastatin metabolites and lovastatin acid were measured by gas chromatography/mass spectrometry. 3. Coadministration of propranolol with pravastatin reduced the mean area under the serum concentration-time curve (AUC) of total inhibitors by 23%, of active inhibitors by 20% and of pravastatin by 16%. 4. Coadministration of propranolol with lovastatin also resulted in decreases in the mean serum AUC of total inhibitors by 18%, of active inhibitors by 12% and of lovastatin acid by 13%. 5. These decreases in systemic drug concentrations may reflect enhanced drug first-pass hepatic clearance in the presence of propranolol. 6. The clinical significance of these changes is likely to be small.

Adult↗

PubMed1990

Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin.

The oral bioavailability of two HMG-CoA reductase inhibitors, pravastatin and lovastatin, was investigated in this randomized, two-way crossover study. Twenty healthy men were randomly assigned to treatment with a 40-mg dose of pravastatin or lovastatin once daily for 1 week; steady state kinetics were assessed after the last dose. After 1 week of washout, each subject received the alternate treatment. Serum specimens were assayed by gas chromatography/mass spectrometry (GC/MS) for intact pravastatin or lovastatin acid and by bioassay for active inhibitor concentration and, after hydrolysis of lactones, for total inhibitor concentration. The systemic bioavailabilities of total (active plus potentially active) inhibitors for the two drugs were different, with the mean AUC value for lovastatin being 50% higher than that of pravastatin (mean +/- SEM AUC0-24 values of 285 +/- 25 and 189 +/- 13 ng-equiv x hr/mL, respectively, P less than .0001). Pravastatin, which is administered as the monosodium salt, is present in the systemic circulation as the open acid; lovastatin, which is administered as the lactone, is present as both open-acid active metabolites (62%) and closed-ring lactone metabolites (38%), which are potentially active. Based on mean AUC values, pravastatin accounted for 75% of the active inhibitors from a pravastatin dose. Lovastatin acid accounted for just 25% of the active inhibitors from a lovastatin dose, with the remainder due to other active metabolites. Significant decreases from baseline in total and low-density lipoprotein (LDL) cholesterol were observed during the first treatment leg for both pravastatin and lovastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1990

Dihydropyrimidine calcium channel blockers. 2. 3-substituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines.

To enhance the intrinsic potency of dihydropyrimidine calcium channel blockers, we have modified the structure of previously described 2-heteroalkyl-1,4-dihydropyrimidines 2 to 3-substituted 1,4-dihydropyrimidines 3. Structure-activity studies using potassium-depolarized rabbit aorta show that ortho, meta-disubstituted aryl derivatives are more potent than either ortho- or meta-monosubstituted compounds. While vasorelaxant activity was critically dependent on the size of the C5 ester group, isopropyl ester being the best, a variety of substituents (carbamate, acyl, sulfonyl, alkyl) were tolerated at N3. Our results show dihydropyrimidines 3 are significantly more potent than corresponding 2-heteroalkyl-1,4-dihydropyrimidines 2 and only slightly less potent than similarly substituted 2-heteroalkyl-1,4-dihydropyridines 4 and 5. Whereas dihydropyridine enantiomers usually show 10-15-fold difference in activity, the enantiomers of dihydropyrimidine 3j show more than a 1000-fold difference in activity. These results strengthen the requirement of an enamino ester for binding to the dihydropyridine receptor and indicate a nonspecific role for the N3-substituent.

Animals↗

PubMed1989

Effect of repeated doses of L-5-hydroxytryptophan and carbidopa on prolactin and aldosterone secretion in man.

To evaluate changes in serum prolactin and plasma and urine aldosterone after a serotonergic challenge, 8 healthy men (19 to 42 yr), taking dexamethasone (0.75 mg qid), received the serotonin precursor L-5-hydroxytryptophan (L5HTP; 100 mg qid) with the peripheral decarboxylase inhibitor carbidopa (C; 50 mq qid) or matching placebos in a randomized, crossover manner. Serum prolactin concentration increased in all subjects after L5HTP/C in comparison to placebo, mean (SD) prolactin (ng/ml) at 8 h after dosing was 19.8 +/- 6.3 after L5HTP/C and 12.0 +/- 3.1 after placebo (p less than 0.05). In contrast, in comparison to values on placebo, L5HTP/C had no apparent effect on mean plasma concentration at all observation times; mean (SD) aldosterone (ng/dl) at 8 h after dosing was 12.0 +/- 5.1 and 12.0 +/- 3.8 after placebo (NS). Mean (SD) urinary aldosterone (micrograms/24 h), Na+(mEq/24 h) and K+(mEq/24 h) excretion were 7.0 +/- 4.4, 49.3 +/- 30.6, 30.1 +/- 11.2, after L5HTP/C and 7.4 +/- 5.8, 59.7 +/- 23.9, 33.3 +/- 7.4 after placebo (NS). Under these study conditions, subacute serotonergic stimulation with oral L5HTP/C resulted in prolactin but not aldosterone release.

5-Hydroxytryptophan↗

PubMed1986

Effect of renal failure or biliary stasis on the pharmacokinetics of amiodarone in the rat.

The single dose intravenous pharmacokinetics of amiodarone (50 mg/kg) were examined in rats with 72 h of biliary stasis secondary to bile duct ligation compared with paired control animals; and in rats with uranyl nitrate induced acute renal failure compared with paired control animals. Plasma and tissue levels (liver, kidney, heart, and lung) of amiodarone (1) and its N-deethyl metabolite 2 were obtained at 4 and 24 h following drug administration. Pharmacokinetic parameters were derived from plasma samples obtained over a 24-h period. Compared with controls, biliary stasis caused a decrease in the total clearance of 1 (1.74 versus 0.35 L/h/kg) and in the volume of distribution at steady state (21.1 versus 5.0 L/kg); renal failure caused a decrease in total clearance (1.67 versus 0.9 L/h/kg) and an increase in apparent elimination half-life (13.7 versus 10.1 h). Both disease processes produced significantly higher plasma levels of 1 when compared with control animals at 4 and 24 h. However, only the cholestatic animals had consistently higher tissue levels of 1 in the face of elevated plasma levels. In normal rats, no 1 or 2 was detected in the urine after a 50 mg/kg intravenous dose of 1, and less than 0.5% of the total dose of amiodarone (1) was excreted into bile by 12 h.

Amiodarone↗

PubMed1985

Radioenzymatic assay of angiotensin-converting enzyme inhibitors in plasma and urine.

A rapid, sensitive assay for angiotensin-converting enzyme (ACE) inhibitors is described. Biological samples were diluted with methanol to precipitate endogenous ACE and centrifuged. Supernatants were further diluted with 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer, pH 8. Diluted samples were incubated at 37 degrees C with the substrate [3H]hippurylglycylglycine and rabbit lung ACE for 45 min. Acid (1.0 N HCl) was then added, and the product, [3H]hippuric acid, was extracted into a water-immiscible scintillation cocktail. Drug standards were prepared in the biological matrix to correct for drug recovery. A computer program was used to convert radioactivity (dpm) to units of enzyme activity and then correlate enzyme activity with drug concentration. The ester prodrugs fosenopril and enalapril could be assayed down to 4 ng/ml in plasma after ester hydrolysis with NaOH. Drug disposition studies in rats, dogs, and monkeys have demonstrated that the method can be readily adapted to any ACE inhibitor and is suitable for determining drug bioavailability and pharmacokinetics.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1985

Effect of captopril and hydrochlorothiazide on the response to pressor agents in hypertensives.

The effect on arterial pressure of incremental doses of norepinephrine (2 to 10 micrograms/min) and angiotensin II (50 to 800 ng/min) administered over 10 min periods was studied in sodium-replete hypertensive patients after crossover oral treatments with placebo, captopril 50 mg in a single dose, captopril 50 mg three times daily for one week and hydrochlorothiazide 50 mg daily for a week. Neither captopril nor hydrochlorothiazide affected the dose response to infusions of angiotensin II. In comparison to placebo responses, however, both single and multiple-dose captopril therapy, and hydrochlorothiazide attenuated the pressor responses to infusions of norepinephrine. Captopril significantly depressed angiotensin converting enzyme activity from pre-dose levels and angiotensin II infusions significantly elevated plasma aldosterone concentrations. These results confirm findings reported for single dose captopril in normotensive volunteers and indicate that attenuation of the vascular responsiveness to sympathetic stimulation may contribute to the antihypertensive effects of captopril and hydrochlorothiazide therapy.

Adult↗

PubMed1985

Effect of phenobarbitone on the pharmacokinetics and tissue levels of amiodarone in the rat.

Phenobarbitone pretreatment has been shown to increase amiodarone total clearance and decrease amiodarone elimination half-life after a single intravenous amiodarone dose in the rat. Coadministration of phenobarbitone with amiodarone for 7 days resulted in decreased tissue amiodarone levels compared to controls. These results may have implications for patients undergoing therapy with amiodarone and concomitant potent enzyme inducing drugs.

Amiodarone↗

PubMed1985

Sulindac and ibuprofen inhibit furosemide-stimulated renin release but not natriuresis in men on a normal sodium diet.

We compared the effect of two commonly prescribed nonsteroidal anti-inflammatory drugs, ibuprofen and sulindac, and placebo on intravenous furosemide-induced natriuresis and renin stimulation in 11 healthy male volunteers, consuming a 100 mEq sodium, 80 mEq potassium diet. Chronic (6-day) therapy with each agent was followed by a 1-week washout period. There were no significant treatment-related differences in either urine volume or sodium excretion for any of the designated collection periods or for the cumulative value for the 4 h after furosemide administration. Similarly, differences among groups were not observed for creatinine clearance, urinary potassium and urinary chloride excretion. Mean basal plasma renin activity levels prior to furosemide administration on day 6 were significantly lower in the presence of ibuprofen (1.5 +/- 2.0 ng/ml/h;p less than 0.01) and sulindac (2,3 +/- 0.9 ng/ml/h; p less than 0.05), compared with placebo (3.3 +/- 1.1 ng/ml/h); the difference between the two NSAIDs was also significant (p less than 0.05). Mean plasma renin activity levels in the 4 h after furosemide increased significantly at all time points in comparison to basal values, but were significantly less for ibuprofen and sulindac groups in the first hour. Our data suggest that the natriuresis following intravenous furosemide in men consuming a normal sodium intake is not prostaglandin-dependent. Furthermore, the observation that sulindac suppressed basal and stimulated plasma renin activity levels, albeit to a lesser extent than ibuprofen, questions the claim that sulindac "spares' the kidney and compels further evaluation of this issue.

Adult↗

PubMed1984

Bucindolol, a beta-adrenoceptor blocker with vasodilatory action: its effect in systemic hypertension.

Bucindolol is a newly developed, nonselective beta-adrenergic blocking agent with intrinsic sympathomimetic activity and direct vasodilator properties. In 14 patients with mild to moderate essential hypertension, the effects of bucindolol, hydrochlorothiazide and their combination on blood pressure (BP), heart rate (HR) and parameters of the renin-aldosterone system were compared with those after placebo. Bucindolol's antihypertensive effect was evident within the first hour after drug administration, maximal at 2 to 3 hours, and lasted for as long as 12 hours. Compared with placebo values (108 +/- 5 mm Hg), both bucindolol (97 +/- 9 mm Hg) and hydrochlorothiazide (99 +/- 10 mm Hg) alone significantly and comparably reduced the 12-hour averaged standing diastolic BP, with the combination resulting in approximately additive effects (91 +/- 9 mm Hg). Although bucindolol alone did not affect HR, it attenuated the hydrochlorothiazide-induced increase in HR. There was a tendency for bucindolol to decrease plasma renin activity. Except for transient postural hypotension in 2 patients, bucindolol was well tolerated.

Adrenergic beta-Antagonists↗

PubMed1984

Enalapril, a new nonsulfhydryl angiotensin converting enzyme inhibitor, does not potentiate morphine analgesia.

Sprague-Dawley rats received oral doses of enalapril maleate (5 mg/kg), a potent, nonsulfhydryl, angiotensin converting enzyme inhibitor, or saline. Sixty min later, morphine sulfate, 5 mg/kg, or saline was injected subcutaneously. Response to a thermal stimulus was monitored before and up to 5 h ter morphine injection using the rat tail flick test. Serum ACE activity was greater than 90% inhibited by enalapril throughout the experiment. Enalapril did not exhibit analgesic activity nor did it potentiate morphine analgesia.

Analgesia↗

PubMed1984

Antihypertensive efficacy of once daily MK-521, a new nonsulfhydryl angiotensin-converting enzyme inhibitor.

The effects of the new nonsulfhydryl-containing oral converting-enzyme inhibitor MK-521 on blood pressure, heart rate, angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration were assessed in 10 hypertensive patients. After a 2-week no-treatment period, patients received placebo and then 14 days each: MK-521 20 mg once daily, hydrochlorothiazide 50 mg once daily and the latter 2 in combination. During the last day of each treatment, the mean (+/- standard deviation) time-averaged (1- to 12-hour) standing diastolic blood pressure decreased from 106 +/- 8 (placebo) to 95 +/- 10 mm Hg with MK-521, 95 +/- 13 mm Hg with hydrochlorothiazide (p less than 0.05 vs placebo) and 88 +/- 11 mm Hg with the combination (p less than 0.05 vs all other treatments). The antihypertensive effect of MK-521 was maintained 24 hours after dosing. Heart rate did not change significantly after MK-521 treatment. MK-521 caused a marked suppression of converting enzyme activity for over 24 hours; plasma renin activity increased significantly after each active treatment and MK-521 significantly decreased the hydrochlorothiazide-induced elevation of plasma aldosterone concentration. In this short-term trial, MK-521 was well tolerated.

Adult↗

PubMed1984

Relationship of morphine-induced miosis to plasma concentration in normal subjects.

The relationship between morphine plasma concentration and pupil diameter was evaluated 2-10 h following intravenous administration of morphine sulfate (10 mg). Seven healthy male volunteers received 10 mg of morphine intravenously following pretreatment for 4 d with either cimetidine (300 mg po four times a day) or placebo in a single blind, balanced crossover study. Pupil diameters were measured directly from contact prints using calipers and a photographed millimeter scale. Cimetidine pretreatment had no significant effect on pupil size either before or after morphine administration or on morphine pharmacokinetics. The relationship between morphine plasma concentration (2-10 h postdose) and pupil diameter was evaluated from the pooled data from both morphine treatment periods by perpendicular least-square regression. In each individual, a strong relationship existed between morphine plasma concentrations and pupil diameter (r = -0.76 to -0.91; p less than 0.05). Weaker correlations for both pupil diameter (r = -0.65; p less than 0.0001) and the absolute change in pupil diameter from baseline (r = 0.72; p less than 0.0001) for the grouped data probably reflect intersubject variation in morphine sensitivity. Thus, the miotic response to an intravenous dose of morphine varies in proportion to morphine plasma concentration.

Adult↗

PubMed1984

Influence of food on the bioavailability of enalapril.

In a randomized, two-period crossover study in 12 normal volunteers, serum and urine concentrations of the angiotensin-converting enzyme inhibitor enalapril and its active metabolite enalaprilat were determined following administration of a single 40-mg tablet of enalapril maleate administered both in the fasting state and with a standard breakfast. A 7-d interval separated the two treatment periods. Area under the serum concentration-time curves for enalaprilat and urinary recoveries for enalaprilat and total drug did not differ significantly between the fed and fasted conditions. The mean observed maximum serum concentration of enalaprilat was slightly higher for the fasting treatment, but the time to peak concentration was almost identical for the two treatments. Enalapril maleate is unlike the prototype angiotensin-converting enzyme inhibitor captopril in that a standard meal does not appear to influence absorption of this new drug.

Adult↗

PubMed1984

Hemodynamic and humoral responses to enalapril and nifedipine in the rat.

The hemodynamic and humoral effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor, and nifedipine, a calcium-entry blocker, were evaluated in conscious spontaneously hypertensive rats (SHR). Rats received enalapril (5 mg/kg, po) or vehicle, followed in one hour by nifedipine (2.5 mg/kg, ip) or its vehicle. After treatment with enalapril alone, systolic blood pressure (BP) declined over a 3 hour period from 204 +/- 4 (mean +/- SE) to 168 +/- 6 mm Hg and remained suppressed for an additional 4 hours. Heart rate (HR) did not change. Plasma renin activity (PRA) increased approximately 9-fold and serum ACE was maximally inhibited. BP response to nifedipine was more rapid, greater in magnitude (-59 +/- 6 mm Hg) and shorter in duration; heart rate increased and remained elevated for 2.5 hours. PRA only rose two-fold. After the drugs in combination, BP declined as rapidly and to the same degree as after nifedipine and remained reduced for a longer duration. Treatment with enalapril attenuated the reflex tachycardia observed after nifedipine. These data suggest that coadministration of an ACE inhibitor and calcium-entry blocker may provide better blood pressure control than either drug class alone and at the same time prevent the reflex tachycardia frequently observed after nifedipine.

Animals↗

PubMed1984

Steady-state serum amiodarone concentrations: relationships with antiarrhythmic efficacy and toxicity.

The relationship of apparent steady-state serum concentrations of amiodarone and its metabolite, desethylamiodarone, to therapeutic and toxic effects was assessed in 127 patients who had treatment-resistant ventricular or supraventricular arrhythmias or were intolerant to other agents. After at least 2 months (mean, 9.8) of treatment with daily maintenance doses of 200 to 600 mg, arrhythmias were effectively suppressed in 78% of patients. Arrhythmias recurred in 47% of patients with serum amiodarone concentrations of less than 1.0 mg/L, whereas only 14% of patients with higher concentrations had recurrences (p less than 0.005). Side effects, most of them mild, occurred in 57%; only 9 patients required discontinuation of drug therapy. The risk of developing adverse reactions was related to serum amiodarone concentrations (p less than 0.0001). Adverse reactions were common in patients with serum values exceeding 2.5 mg/L, although pulmonary complications did occur at lower concentrations. Monitoring serum amiodarone concentrations may differentiate failure of drug therapy from suboptimal dosing and reduce the incidence of concentration-related side effects.

Adult↗