Biomedical subjects

D J Silberstein

Publications and source records attributed to D J Silberstein.

10 recordsLinked to original sources

PubMed1990

The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone.

Propranolol and the sodium-channel-blocking antiarrhythmic agent propafenone share structural features. Although propafenone's beta-blocking actions are readily demonstrable in vitro, clinically significant beta-blockade occurs inconsistently in vivo. In this study, we tested the hypothesis that genetically determined variations in the biotransformation of propafenone to its 5-hydroxy metabolite account for variations in the drug's beta-blocking action. We assessed beta-blockade by measuring the reduction in tachycardia produced by boluses of isoproterenol and treadmill exercise in 14 normal subjects during treatment with placebo and with 150, 225, and 300 mg of propafenone every eight hours for five days each. Nine subjects (with the extensive-metabolizer phenotype) metabolized most of the propafenone to 5-hydroxy propafenone, and five (with the poor-metabolizer phenotype) did not produce this metabolite. At the lower dosages, beta-blockade was present in both groups but was significantly greater in the subjects with poor metabolism, in whom deficient 5-hydroxylation was associated with higher plasma propafenone levels. At the highest dose, a similar degree of beta-blockade was observed in the two groups. Propafenone also had a higher affinity for beta 2 receptors in vitro than either of its major metabolites. We conclude that the degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which is necessary for beta-blockade, and that this action of propafenone is considerably enhanced in patients with deficient 5-hydroxylation of propafenone.

Adrenergic beta-Antagonists↗

PubMed1990

Low sodium intake corrects abnormality in beta-receptor-mediated arterial vasodilation in patients with hypertension: correlation with beta-receptor function in vitro.

To determine the contribution of altered beta-receptor function in the vasculature to the increased peripheral vascular resistance seen in hypertension, the effects of intra-arterial infusions of isoproterenol and epinephrine on forearm blood flow were determined in 11 male normotensive subjects and 11 male hypertensive subjects during 10 and 250 mmol/day sodium diets. Increased sodium intake from 10 to 250 mmol produced contrasting effects in the hypertensive and normotensive subjects. In the hypertensive subjects, sensitivity to isoproterenol decreased when sodium intake increased (median effective dose increased from 39 [95% confidence limits, 30 to 50] to 70 [95% confidence limits, 42 to 116] ng/min, p less than 0.05). On the other hand, in the normotensive subjects increased sodium intake resulted in an increased sensitivity to isoproterenol induced vasodilation (median effective dose decreased from 52 [38 to 71] to 29 [22 to 38] ng/min, p less than 0.01). No change occurred in sensitivity to epinephrine or in the maximum vasodilatory response to ischemia during dietary changes. Changes in beta-receptors on lymphocyte membranes paralleled the changes seen in vascular sensitivity so that the proportion of receptors exhibiting high affinity for agonists, a reflection of receptor adenylate cyclase coupling, decreased in the hypertensive subjects from 38.0% +/- 3.8% when they were receiving 10 mmol/day sodium to 29.6% +/- 2.7% when they were receiving 250 mmol/day sodium (p less than 0.01). However, the proportion increased from 32.4% +/- 3.7% for normotensive subjects receiving 10 mmol/day sodium to 47.1% +/- 7.8% for normotensive subjects receiving 250 mmol/day sodium (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

A mechanism of D-(+)-sotalol effects on heart rate not related to beta-adrenoceptor antagonism.

1. In order to determine whether the effects of d- or (+)-sotalol on heart rate are mediated by beta-adrenoceptor antagonism or might be due to other actions, we administered (+)-sotalol (400 mg every 12 h), atenolol (50 mg every 12 h) and placebo to eight healthy volunteers in a randomized, double-blind, crossover study. We also studied the affinity of human lymphocyte beta 2-adrenoceptor for (+)-sotalol, (-)-sotalol, and (+/-)-propranolol. 2. Compared with placebo, atenolol significantly reduced resting, standing and peak exercise heart rate whereas (+)-sotalol significantly reduced standing and peak exercise heart rate, but not resting heart rate. Atenolol significantly reduced resting, standing and peak exercise blood pressure while (+)-sotalol had no effect. 3. (+)-sotalol and atenolol both shifted the relationship between isoprenaline dose and heart rate to the right by similar degrees at the dosages tested. 4. (+)-sotalol but not atenolol significantly prolonged QTc interval. The degree of QTc prolongation due to (+)-sotalol, which has been shown to parallel action potential prolongation in the sinus node, correlated significantly with the reduction in peak exercise. heart rate it produced (r = 0.71, n = 8, P less than 0.05). 5. The affinity of the human lymphocyte beta 2-adrenoceptor was approximately 60-fold greater for (-)-sotalol (Ki, 108 +/- 12 nM) than for (+)-sotalol (Ki, 6,410 +/- 1,020 nM), and approximately 20,000-fold greater for (+/-)-propranolol (Ki, 0.33 +/- 0.08 nM) than for (+)-sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Racial differences in drug response. Altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American whites.

To determine whether the pharmacokinetics and pharmacodynamics of beta-blockade differ among racial groups, we gave 10 men of Chinese descent and 10 American white men 10, 20, 40, and 80 mg of propranolol every eight hours; the dosages were given in random order, and each dose was given for one day. The degree of beta-blockade was measured as the reduction in the heart rate and blood pressure in the supine and upright positions and during treadmill exercise testing. The Chinese subjects had at least a twofold greater sensitivity to the beta-blocking effects of propranolol than the white subjects, as indicated by the mean (+/- SEM) plasma concentrations producing a 20 percent reduction in the heart rate in both the supine position (197 +/- 31 vs. 536 +/- 58 nmol per liter; P less than 0.05) and the upright position (131 +/- 27 vs. 343 +/- 39 nmol per liter; P less than 0.05) and after exercise testing (96 +/- 12 vs. 185 +/- 23 nmol per liter; P less than 0.05). In addition, the Chinese subjects had much greater sensitivity to the hypotensive effects of propranolol, as shown by the concentrations that reduced blood pressure by 10 percent in the supine position (73 +/- 5 vs. 748 +/- 7 nmol per liter; P less than 0.01) and in the upright position (89 +/- 5 vs. 401 +/- 6 nmol per liter; P less than 0.01). No difference in beta-receptor density or affinity of lymphocytes was found between the groups. The Chinese group had a 45 percent higher free fraction of propranolol in plasma, which may have contributed to the increased drug effect but cannot explain it entirely. This group metabolized propranolol more rapidly than the white group, which resulted in a 76 percent higher clearance of an oral dose (3740 +/- 737 vs. 2125 +/- 214 ml per minute; P less than 0.05) because of increased metabolism through multiple metabolic pathways. We conclude that Chinese men have greater sensitivity than white men to the effects of propranolol on heart rate and blood pressure. Decreased protein binding may be responsible in part, but most of the effect remains to be explained.

Adult↗

PubMed1989

Interindividual differences in beta-receptor density contribute to variability in response to beta-adrenoceptor antagonists.

To determine the role of changes in receptor density and the considerable interindividual variability in the response to beta-adrenergic antagonists, we determined the relationship between the beta-blockade produced by propranolol and the beta-adrenergic receptor density (Bmax) in 16 healthy subjects who received 10, 20, 40, and 80 mg propranolol every 8 hours for 1 day at each dosage level. The extent of beta-blockade produced was assessed as the reduction in exercise tachycardia. The extent of beta-blockade correlated with pretreatment lymphocyte Bmax (30 mg/day: r = 0.6290, p less than 0.05; 60 mg/day: r = 0.5279, p less than 0.05; 120 mg/day: r = 0.5888, p less than 0.01; 240 mg/day: r = 0.6783, p less than 0.005). When the extent of beta-blockade was corrected for plasma propranolol concentrations, the correlation was further improved (30 mg/day: r = 0.7636, p less than 0.001; 60 mg/day: r = 0.7218, p less than 0.002; 120 mg/day: r = 0.7814, p less than 0.001; 240 mg/day: r = 0.6899, p less than 0.005). We conclude that the density of beta-adrenergic receptors is one of the principal factors that control beta-receptor response to antagonists in human beings.

Adult↗

PubMed1989

Stereoselective disposition and pharmacologic activity of propafenone enantiomers.

Propafenone is an antiarrhythmic drug that produces a variable degree of beta-blockade in humans and is administered as a racemate. To examine the relative contribution of the individual enantiomers to pharmacologic effects seen during treatment with propafenone, we assessed the steady-state plasma concentrations of (+)-S-propafenone and (-)-R-propafenone in seven patients who were on long-term oral therapy, and we evaluated the electrophysiologic and beta-blocking properties of both enantiomers in vitro. The metabolism of propafenone is known to be polymorphic and to cosegregate with that of debrisoquine-4-hydroxylation. Among five patients with the extensive metabolizer phenotype (EM), the ratio of the area under the plasma concentration-time curve of (+)-S-propafenone to (-)-R-propafenone was 1.73 +/- 0.15 (mean +/- SD). In the other two patients, who had the poor metabolizer phenotype (PM), the concentrations of both enantiomers were elevated but the S/R ratios were similar to those seen in patients with EM. In canine cardiac Purkinje fibers, both enantiomers produced similar frequency-dependent depression of maximum upstroke of phase 0. In contrast, the affinity of the human lymphocyte beta 2-adrenoceptor was approximately 100-fold greater for (+)-S-propafenone (Ki, 7.2 +/- 2.9 nM) than for the (-)-R-enantiomer (Ki, 571 +/- 141 nM). We conclude that during long-term oral therapy, propafenone undergoes stereoselective disposition in patients with either EM or PM. beta-Blockade during propafenone therapy is likely related to accumulation of (+)-S-propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Altered beta-adrenoceptor internalization does not explain reduced beta-adrenergic responsiveness in the elderly.

To determine whether altered beta-adrenoceptor internalization contributes to the reduced adrenergic responsiveness of the elderly, the ability to internalize beta-adrenoceptors in young and elderly men was studied by in vitro exposure of whole lymphocytes to a range of isoproterenol concentrations. The total numbers of receptors per cell were similar in the two groups [young, 1645 +/- 206 +/- SE); elderly, 1707 +/- 120], as were the basal levels of beta-adrenoceptor internalization (young, 8.85 +/- 1.09%; elderly, 8.73 +/- 1.35%). Incubation in the presence of isoproterenol resulted in dose-dependent internalization of receptors. The EC50 values for isoproterenol-induced internalization were similar in the young (20.7 +/- 3.5 nmol/L) and elderly groups (26.9 +/- 4.4 nmol/L). These results suggest that altered receptor internalization does not contribute to impaired beta-adrenoceptor function in the elderly.

Adolescent↗

PubMed1988

Dibromosulphophthalein: its pharmacokinetics and binding to hepatic cytosol proteins in rats with acute renal failure.

1. The pharmacokinetics, biliary excretion and binding of dibromosulphophthalein (DBSP) to plasma proteins and hepatic cytosol proteins have been studied in male rats with glycerol-induced acute renal failure (ARF). 2. The rate constants for hepatic uptake, efflux from liver to plasma and excretion into bile were all significantly decreased in rats with ARF. Furthermore, the plasma clearance of DBSP was also reduced. 3. The initial (0-10 min) and maximum biliary excretion rates of DBSP were both diminished in animals with ARF. The maximum excretion rate occurred between 5-10 min in control rats and 10-15 min in rats with ARF. However, there was no statistically significant change in the percentage dose recovered from bile after 30 min. 4. The plasma-protein binding of DBSP was decreased in rats with ARF and this change was due to a significant reduction in the association constant for the primary binding sites. 5. The binding of DBSP to ligandin (Y protein) was reduced by about 38% in rats with ARF but no change was noted in binding to Z protein. Reduced binding to ligandin was accompanied by decreased total liver glutathione S-transferase (GST) activity and a 36% reduction in the GST activity of ligandin. 6. The results support the contention that altered hepatic handling of cholephilic dyes in rats with ARF may be due to reduced binding to ligandin.

Acute Kidney Injury↗

PubMed1987

Pharmacokinetics and biliary excretion of rose bengal in rats with acute and chronic renal failure.

The effects of glycerol-induced acute renal failure (ARF) and surgically induced chronic renal failure (CRF) on the pharmacokinetics and biliary excretion of rose bengal have been examined in the rat. Both the pharmacokinetics and biliary excretion of rose bengal were unaltered in either ARF or CRF. The latter results in CRF contrast with those of Tse et al (1976, Int. J. Nucl. Med. Biol. 3: 134-137) who reported decreased removal of the dye from blood and reduced biliary excretion. In addition, rose bengal behaves differently from bromosulphophthalein and indocyanine green whose hepatic uptake and initial biliary excretion are known to be decreased in ARF. The results suggest that rose bengal may have a hepato-biliary transport route which differs from that of bromosulphophthalein and indocyanine green, and the findings also emphasize the selective nature of altered organic anion uptake by the liver in ARF.

Acute Kidney Injury↗

PubMed1986

Effect of acute renal failure on the disposition and elimination of [3H]N-acetyl procainamide ethobromide in the rat.

The effect of glycerol-induced acute renal failure (ARF) on the disposition and elimination of the organic cation [3H]N-acetyl procainamide ethobromide (APAEB) was investigated in the rat. In rats with ARF the plasma clearance, rate constant for the terminal portion of the plasma concentration-time curve and apparent volume of distribution were all decreased (P less than 0.01). Furthermore, the renal clearance of APAEB and the percentage dose excreted in urine were reduced by 85 and 74%, respectively. Decreased renal excretion probably accounted for the altered kinetics of APAEB in ARF because ligation of the renal pedicles of control rats produced changes in the kinetics of APAEB that were similar to those seen in animals with ARF. No change in either the hepatic content of APAEB or its biliary excretion were detected in rats with ARF. Similarly, the hepatic handling of ouabain and taurocholic acid was previously found to be unaltered in ARF; but by contrast, the hepatic uptake and initial biliary excretion of bromosulphophthalein and indocyanine green were decreased (Bowmer & Yates 1984, Br. J. Pharmacol. 83: 773-782). Together these studies indicate that there is a selective impairment of hepato-biliary transport in ARF.

Acecainide↗