摘要:

Our goal was to compare and contrast in the same normal twins the relative contribution of genetic and environmental factors to large interindividual variations in the metabolism of acetaminophen (APAP) and antipyrine. These drugs were selected because they are biotransformed by different mechanisms. A single oral dose of APAP (10 mg/kg) was given to six sets of monozygotic (MZ) and six sets of dizygotic (DZ) twins. All were normal, nonsmoking, nonmedicated, and male. Among these 24 subjects, there were 300% interindividual variations in rate constants for formation of the sulfate and glucuronide conjugates, as well as in the overall rate constant for APAP elimination. Intratwin variations for each measurement were as target within MZ as within DZ twinships, suggesting that predominantly environmental rather than genetic factors maintained interindividual variations. Two other observations support this conclusion: Intraindividual variations were frequently as large as interindividual variations, and regardless of zygosity for twins living together, intratwin correlation coefficients were almost twice those of twins living apart. Quite different results were obtained when these twins received antipyrine. After a single oral dose of antipyrine (18 mg/kg), 500% interindividual variations in rate constants for formation of the three main oxidative metabolites of antipyrine appeared to be mainly under genetic control. Also for antipyrine and its principal metabolites, intraindividual variations were much smaller than interindividual variations. In contrast to the results with APAP, regardless of zygosity, intratwin correlation coefficients for antipyrine were similar for twins living apart and twins living together. This comparison between APAP and antipyrine metabolism in the same carefully selected normal twins under apparently uniform environmental conditions reveals that interindividual variations in APAP metabolism arise from certain unidentified environmental factors, whereas genetic factors cause the large interindividual variations that occur in antipyrine disposition.Clinical Pharmacology and Therapeutics(1984)36,417–430; doi:10.1038/clpt.1984.1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.199

年代:1984

数据来源: WILEY

摘要:

To compare the effect of amiloride with that of oral potassium chloride (KCl) in hypokalemia, metabolic balance studies were carried out in hospitalized subjects with mild hypertension without edema who developed negative potassium balance after 4 days on hydrochlorothiazide (HCTZ). Subjects' diets contained measured amounts of sodium and potassium. While HCTZ treatment continued, oral preparations of either KCl solution or amiloride was added for 5 additional days. Potassium balance in the KCl‐treated group further decreased by −44.9 ± 32.3 mEq K+, while subjects on amiloride went into positive balance that averaged +51.7 ± 24.1 mEq K+. Hypokalemia after HCTZ did not respond to KCl, while K+levels rose from 3.32 ± 0.22 to 3.67 ± 0.26 mEq/l after amiloride.Clinical Pharmacology and Therapeutics(1984)36,431–435; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1984.200

年代:1984

数据来源: WILEY

摘要:

Amosulalol kinetic studies were conducted in seven subjects who received 0.16 mg/kg iv and in 18 subjects who received 12.5, 25, 50, 100, or 150 mg by mouth. Plasma levels of amosulalol after intravenous dosing declined biphasically and fitted a two‐compartment model. Kinetics were as follows: coefficients A = 0.85 ± 0.09 μg/ml and B = 0.22 ± 0.01 μg/ml; rate constants α = 2.78 ± 0.24 hr−1and β = 0.25 ± 0.01 hr−1; elimination rate constants, kl2= 1.36 ± 0.17 hr−1, k21= 0.78 ± 0.06 hr−1, and kel= 0.88 ± 0.06 hr−1; terminal phase volume of distribution = 0.75 ± 0.06 l/kg; clearance = 8.09 ± 0.54 l/hr; AUC = 1.22 ± 0.09 μg · hr/ml; and t½α = 0.26 ± 0.02 hr and t½β = 2.8 ± 0.1 hr. After single oral doses, amosulalol peak plasma levels were generally reached within 2 to 4 hr. Maximum plasma concentrations and AUC increased in a dose‐dependent manner, whereas t½s were about 5 hr (range 4.4 to 5.7 hr) at each dose. Systemic availability of amosulalol was about 100% as determined by the ratio of AUC after oral and intravenous dosing. These results suggest that amosulalol is well absorbed and is little affected by first‐pass metabolism.Clinical Pharmacology and Therapeutics(198

ISSN:0009-9236    

DOI:10.1038/clpt.1984.201

年代:1984

数据来源: WILEY

摘要:

We compared the efficacy and safety of nitrendipine with that of hydralazine in 21 subjects with essential hypertension. Nitrendipine or hydralazine was given in a double‐blind manner after a placebo period. Dose was titrated to diastolic blood pressure (BP) ≤90 mm Hg and the dose established during titration was continued for 5 to 7 wk. Both supine and erect BP were decreased by both drugs, but heart rate was affected only minimally. Myocardial oxygen demand decreased only with nitrendipine (P<0.05), although the change may have been the result of somewhat higher systolic BP while on placebo. Hydralazine induced minimal changes in levels of plasma catecholamines, but plasma norepinephrine levels rose in subjects on nitrendipine. Side effects encountered with both drugs were much the same, although nitrendipine was more often associated with mild fatigue. There were mild elevations in liver function parameters in two subjects on nitrendipine. There was little difference between the effects of nitrendipine and hydralazine in hypertension.Clinical Pharmacology and Therapeutics(1984)36,444–450; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1984.202

年代:1984

数据来源: WILEY

摘要:

Healthy subjects received single doses of diazepam (5 to 10 mg iv), lorazepam (2 mg iv), or alprazolam (1 mg orally) on two occasions, once in the control state and once with propranolol, 80 mg three times a day. Compliance with the propranolol regimen was verified by measurement of serum propranolol levels (overall X̄: 100 ng/ml) and by reduction in sensitivity to intravenous metaproterenol to one‐thirtieth that of the control value. Propranolol prolonged diazepam elimination t½ (58 and 49 hr), reduced its clearance (0.20 and 0.24 ml/min/kg), and increased the 168‐hr AUC for desmethyldiazepam, the major metabolite of diazepam (5.63 and 4.81 µg/ml · hr). Propranolol had no significant effect on lorazepam t½ (13.2 and 12.7 hr) or clearance (1.33 and 1.36 ml/min/kg), nor on alprazolam t½ (15.9 and 18.5 hr) or clearance (1.1 and 0.8 ml/min/kg). Thus propranolol induces a small but significant reduction in clearance of diazepam, biotransformed mainly by the oxidative reaction ofN‐demethylation. Propranolol does not impair lorazepam clearance by glucuronide conjugation nor that of alprazolam by aliphatic hydroxylation.Clinical Pharmacology and Therapeutics(1984)36,451–455; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1984.203

年代:1984

数据来源: WILEY

摘要:

The effects of captopril in several humoral factors were studied to elucidate the role of the renin‐angiotensin (RA) system in arterial and venous pressures and renal function in patients with severe chronic congestive heart failure. A single oral dose of captopril in 20 subjects reduced mean arterial blood pressure from 77 to 67 mm Hg; this decrease correlated with baseline plasma renin activity (PRA). The increase in PRA and the decrease in plasma aldosterone levels after captopril were much greater in subjects with higher PRA. Plasma norepinephrine (NE) levels decreased, while those of epinephrine did not change. Peripheral venous pressure declined from 107 to 77 mm H2O; this decrease correlated with the change in NE levels. During 7‐day captopril therapy, urine volume and sodium excretion increased (1145 to 1136 ml/day and 76 to 94 mEq/day) in 11 subjects in whom renal function was followed. Renal plasma flow (RPF) rose from 237 to 364 ml/min, while glomerular filtration rate did not change; the filtration fraction decreased from 32% to 23%. Simultaneous infusion of aprotinin in six of the subjects did not affect the captopril‐induced increase in RPF, despite the suppression of plasma bradykinin levels. These results suggest that captopril reduces arterial blood pressure in patients with high PRA through inhibition of the RA system and dilates veins by attenuation of sympathetic nervous activity. Increased RPF and urinary sodium excretion induced by captopril might result from inhibition of the RA system; the kallikrein‐kinin system or bradykinin‐mediated prostaglandins do not appear to play a major role.Clinical Pharmacology and Therapeutics(1984)36,456–463; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1984.204

年代:1984

数据来源: WILEY

摘要:

Iloprost is a chemically stable derivative of carbaprostacyclin. We studied its hemodynamic effects in 10 patients in an intensive care unit. Iloprost was infused intravenously for 3 days for the treatment of advanced obliterative arterial disease of the lower extremities. Clinically significant hemodynamic responses were obtained with an infusion rate of 0.5 ng/kg/min. All subjects tolerated the dose of 4 ng/kg/min, which increased heart rate an average of 11% and cardiac index an average of 26%. This infusion rate decreased mean arterial pressure by 15%, total peripheral resistance by 31%, and pulmonary vascular resistance by 34%. Mean pulmonary arterial pressure, pulmonary capillary wedge pressure, left and right ventricular stroke work indices, and rate pressure product did not change. At higher doses of up to 8 ng/kg/min, responses were augmented only slightly, but side effects such as headache, nausea, and abdominal colics became more prominent. The data show iloprost to be a potent vasodilator that reduces both pre‐ and afterload and presumably induces a compensatory increase in cardiac output and heart rate, but does not increase the work load or oxygen demand of the heart.Clinical Pharmacology and Therapeutics(1984)36,464–469; doi:10.1038/clpt.1984

ISSN:0009-9236    

DOI:10.1038/clpt.1984.205

年代:1984

数据来源: WILEY

摘要:

Hemodynamic and humoral events after intraoperative discontinuation of nitroprusside were studied in subjects without and with pretreatment with intravenous propranolol, 0.1 mg · kg−1Nitroprusside‐induced hypotension was associated with increases in heart rate, cardiac output, plasma renin activity (PRA), and catecholamine levels; these changes were prevented by propranolol. In subjects pretreated with propranolol, dose requirements of nitroprusside for hypotension of comparable degree and duration decreased 40%. On discontinuation of nitroprusside, mean systemic pressure rose to 100.2 mm Hg—a level higher than prehypotension and awake values—because of increased systemic vascular resistance. Hemodynamic events were associated with persistent elevations of PRA and catecholamine levels. These rebound changes were maximal 15 min after nitroprusside withdrawal and returned to control levels 30 to 60 min later. Pretreatment with propranolol completely prevented rebound hemodynamic events after nitroprusside. Persistent elevations of PRA and catecholamine levels after nitroprusside action subsided were responsible for the effects of withdrawal.Clinical Pharmacology and Therapeutics(1984)36,470–477; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1984.206

年代:1984

数据来源: WILEY

摘要:

The effect of acute alterations of serum digoxin concentration (SDIG) on the renal clearance of digoxin (CDIG) was studied in six normal subjects undergoing water diuresis. Digoxin in a 5% dextrose and water solution was infused at a rate of 0.01 µg/kg/min (low dose). One hour after the infusion began, three 20‐min urine samples for clearance determination were taken. The digoxin infusion rate was then increased to 0.05 µg/kg/min (high dose) and three additional urine samples were taken an hour later. With low doses of digoxin, the SDIGwas (X̄ ± SD) 0.63 ± 0.08 ng/ml, CDIGwas 252.3 ± 65.1 ml/min, inulin clearance (CIN) was 96.8 ± 15.7 ml/min, the ratio CDIG/CINwas 2.59 ± 0.38, and renal blood flow (CPAH) was 516 ± 90 ml/min. With the high‐dose infusion, SDIGrose to 3.23 ± 0.44 ng/ml; CIN, CDIG, CDIG/CIN, and CPAHremained stable. CDIGcorrelated strongly with both CINand CPAH. We conclude that in normal subjects undergoing water diuresis, CDIG/CINis not altered by acutely increasing SDIG, digoxin is extensively secreted by the nephron, and CDIGis linearly related to renal plasma flow.Clinical Pharmacology and Therapeutics(1984)36,478–484; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1984.207

年代:1984

数据来源: WILEY

摘要:

Isosorbide 5‐mononitrate (IS‐5‐MN) and isosorbide 2‐mononitrate (IS‐2‐MN) kinetics were studied in two groups of young healthy subjects after intravenous injection of 5 mg of both and after oral doses of 20 mg of IS‐2‐MN and 10, 15, and 20 mg of IS‐5‐MN. Mononitrate plasma levels were measured by GLC with capillary columns. After intravenous injection, IS‐5‐MN and IS‐2‐MN plasma levels declined biexponentially and could be described by an open two‐compartment body model. Distribution t½ was rapid; 8.6 min for IS‐5‐MN and 12.5 min for IS‐2‐MN. Substances were distributed throughout body water; volume of distribution at steady state (Vdss) was 48 l for IS‐5‐MN and 55 l for IS‐2‐MN and elimination t½ was 4.15 hr for IS‐5‐MN and 1.9 hr for IS‐2‐MN. Total plasma clearance was 8.5 l/hr for IS‐5‐MN and 23.2 l/hr for IS‐2‐MN. After oral doses the mononitrates were rapidly and completely absorbed (absorption t½ ranged from 2.5 to 5 min) from the gastrointestinal tract without first‐pass metabolism, i.e., absolute systemic availability was 100%. In the dose range studied, kinetics of the two mononitrates were linear. Compared with isosorbide dinitrate, mononitrate kinetics are different because of greater systemic availability, slower clearance, and smaller Vdss.Clinical Pharm

ISSN:0009-9236    

DOI:10.1038/clpt.1984.208

年代:1984

数据来源: WILEY