摘要:

Six healthy subjects were treated with 100 mg atenolol. After a therapy‐free interval of 4 wk the same subjects received the same dose of atenolol with furosemide, 40 mg, with calcium (as the lactate gluconate and carbonate), 500 mg, or with aluminum hydroxide, 5.6 gm. Atenolol alone and in combination was administered first as a single oral dose; a long‐term 6‐day treatment began 48 hr later. Addition of furosemide did not influence atenolol kinetics, but aluminum hydroxide led to an insignificant reduction (P>0.05) of mean peak plasma levels of about 20% and of the area under the plasma concentration‐time curve (AUC‐∞) from 5818 to 4353 ng ml−1hr (P>0.05). Calcium altered atenolol kinetics distinctly: mean peak plasma levels of atenolol fell 51% (P<0.001), AUC0‐∞fell from 5818 to 3935 ng ml−1hr (P<0.01) and elimination half‐life (t½) increased to a mean of 11.0 hr (compared to 6.2 hr with atenolol alone). The prolongation of t½ induced by calcium coadministration led to atenolol cumulation during the long‐term dosage. Twelve hours after atenolol, 100 mg, and calcium, 500 mg, exercise tachycardia was lower than with atenolol alone (P0.05).Clinical Pharmacology and Therapeutics(1981)30,429–

ISSN:0009-9236    

DOI:10.1038/clpt.1981.184

年代:1981

数据来源: WILEY

摘要:

The effect of short‐term caffeine withdrawal on lymphocyte beta‐adrenoceptor sensitivity was studied in seven men who had been drinking coffee daily for at least 3 mo before the study. The ratio of cyclic adenosine monophosphate production after in vitro incubation with isoproterenol and a blank was used to assess receptor sensitivity. There was a reduction in sensitivity to isoproterenol but not to prostaglandin E13 days after caffeine withdrawal. The mechanism of this effect is not clear, but may represent a biochemical correlate of caffeine‐withdrawal syndromeClinical Pharmacology and Therapeutics(1981)30,436–438; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1981.185

年代:1981

数据来源: WILEY

摘要:

Prazosin kinetics were studied after single doses (intravenous and oral, 0.5 mg) and after increasing multiple doses (0.5 to 5 mg three times daily) in eight patients with hypertension. After intravenous administration the kinetics could be described by a linear two‐compartment open model. Terminal half‐life (t½β) was about 3 hr and apparent volume of distribution (Vdβ) about 0.6 l/kg. After oral doses bioavailability ranged between 55% and 82%. Since total plasma clearance was low (0.14 l/kg x hr) incomplete bioavailability was the result of incomplete absorption rather than of first‐pass liver metabolism. The estimated extraction ratio was about 14%. Renal clearance was negligible; only 1% to 2% of the dose was recovered unchanged in urine. Binding to plasma proteins to both albumin and abatid glycoprotein was substantial (97%), with albumin being most important. Increasing multiple doses showed that prazosin followed first‐order kinetics with a linear correlation between dose and steady‐state plasma concentration (P<0.001). There were substantial variations in plasma concentrations between patients and there were also day‐to‐day variations in concentration within the same patient.Clinical Pharmacology and Therapeutics(1981)30,439–446; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1981.186

年代:1981

数据来源: WILEY

摘要:

The antihypertensive effects of prazosin in relation to its kinetics were studied after single doses (intravenous and oral, 0.5 mg) and during increasing multiple doses (0.5 to 5 mg three times a day). There was a fall in systolic and diastolic blood pressures of 10% to 14%, which was greater in the standing than in the sitting position. Prazosin plasma concentrations correlated with dose (P<0.001). After intravenous prazosin the fall in systolic and diastolic blood pressure and prazosin plasma concentration correlated (P<0.01) during the β‐elimination phase in all patients. In only five of eight patients, however, did mean plasma concentration and antihypertensive effect during continuous treatment with different doses correlate. The maximal fall in systolic blood pressure correlated (P<0.01) with that after the first oral steady‐state dose (0.5 mg three times daily), which indicates limited possibility of early identification of prazosin responders. There were no signs of overshoot of blood pressure when prazosin was withdrawn for a week. On rechallenge with a single oral dose of 2.5 mg prazosin there were no signs of enhanced hypotensive effect.Clinical Pharmacology and Therapeutics(1981)30,447–454; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1981.187

年代:1981

数据来源: WILEY

摘要:

The effect of a high‐protein meal on the hepatic clearance (ClH) of intravenous lidocaine, because of its conceptual importance in understanding first‐pass metabolic phenomena, was evaluated in nine healthy males. Our randomized crossover study demonstrated that mean ClHrose from 1245 to 1477 ml/min (P<0.03) as a result of the meal (i.e., mean area under the blood concentration‐time curve decreased 20%). The magnitude of the change in clearance correlated weakly with fasting ClH(r = 0.54; slope = ‐0.037% per ml/min; intercept = 67.2%; P<0.15). In a separate study, it was observed that the meal did not influence lidocaine serum protein binding; the free fraction of lidocaine in samples drawn from the subjects in the fasting state averaged 0.305 ± 0.027 while that from subjects who had eaten was 0.321 ± 0.042. These data suggest that the mean clearance of lidocaine is increased by stimulation of hepatic blood flow rate. Furthermore, the magnitude of this increase is consistent with expectations based on a simple physiologic model. Thus, these data provide experimental support for the hypothesis that transient increases in splanchnic blood flow rate observed after a high‐protein meal may explain apparent improvement of the oral bioavailability of model high intrinsic clearance drugs.Clinical Pharmacology and Therapeutics(1981)30,455–460; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1981.188

年代:1981

数据来源: WILEY

摘要:

Furosemide, 20 mg, was given intravenously as a bolus to seven patients with cirrhotic ascites and a 10‐mg intravenous bolus dose was given to three normal subjects. Furosemide concentrations were measured by a specific high‐performance liquid Chromatographie analytic method. The median plasma elimination half‐life (t½), volume of distribution at steady state (Vdss), and Vdareaof furosemide were 0.70 hr, 91 ml/kg, and 119 ml/kg in normal subjects. In the cirrhotic patients elimination t½ and Vd at steady state doubled and the Vdareaof furosemide was almost double that of the normal. There were no differences in plasma clearance or renal and nonrenal clearance between patients and controls, but five of the seven patients had lower renal clearances than controls. The water and sodium response to furosemide was directly related to the urinary furosemide excretion rate. We identified a subset of cirrhotic patients who responded poorly (125 ml/hr urinary output in the first 4 hr after furosemide compared to 300 ml/hr in the other patients and 400 ml/hr in the controls) to furosemide. These “poor responders” had the lowest renal clearance of furosemide and the lowest urinary furosemide excretion rates. Our data indicate that furosemide kinetics are altered in patients with cirrhotic ascites and lack of response in a subset of these patients is due to lack of delivery of furosemide to the renal site of its action.Clinical Pharmacology and Therapeutics(1981)30,461–467; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1981.189

年代:1981

数据来源: WILEY

摘要:

Ceforanide (500 mg) was infused intravenously over 30 min into six normal subjects, 10 nondialysis patients with renal insufficiency, and six hemodialysis patients. Dialysis patients received two ceforanide infusions, one immediately before dialysis and another during an interdialysis period. Sequential plasma samples over 24 to 72 hr were assayed for ceforanide. Peak ceforanide levels (mean = 69 ± 12 μg/ml) and volumes of distribution did not vary with creatinine clearance (Clcr, ml/min/1.73 m2) and both plasma clearance and renal clearance decreased linearly as Clcrdecreased. Mean nonrenal clearance (4.6 ± 1.8 ml/min/1.73 m2) did not vary with Clcr. Mean half‐life was 3 hr in the normal subjects, increasing to approximately 25 hr in patients with severe renal insufficiency. Hemodialysis resulted in removal of approximately 21% of the dose of ceforanide. Dosing recommendations for patients with renal insufficiency are provided.Clinical Pharmacology and Therapeutics(1981)30,468–474; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1981.190

年代:1981

数据来源: WILEY

摘要:

Twenty‐six healthy subjects from 19 to 85 yr old took single 15‐mg doses of flurazepam (FLZ). Concentrations of desalkylflurazepam (DAFLZ), its principal metabolite, were measured by gas‐liquid Chromatography in multiple samples drawn 7 or more days after the dose. For the first 6 to 8 hr after drug, several additional FLZ metabolites appeared in plasma, but only DAFLZ was detected from 12 hr onward. Its elimination half‐life (t½) (range, 37 to 289 hr) was longer in elderly than in young men (x̄ 74 and 160 hr, p<0.05), but t½ in young and elderly women was much the same (90 and 120 hr, P = NS). Eighteen of the 26 subjects then received FLZ, 15 mg, nightly for 15 consecutive nights. Blood samples were drawn during FLZ dosage and in the withdrawal period, and morning self‐ratings of mood and sleep patterns were obtained using visual analogue scales. DAFLZ cumulation was extensive, with a mean cumulation ratio of 7.5. Mean steady‐state plasma levels of DAFLZ were higher in elderly than in young men (81 and 53 ng/ml, P<0.05), but values were essentially the same in elderly and young women (85 and 86 ng/ml). Single‐dose t½ correlated with washout t½ after termination of FLZ treatment (r = 0.87, P<0.01). Clinical self‐ratings indicated increases over time in perception of morning sedation; changes slowly reverted to baseline in the week after dosage. Sleep patterns also improved on FLZ (shortened latency, longer duration, “deeper” sleep). After termination of treatment, sleep parameters returned to baseline with a suggestion of “overshoot” sleep disturbance at days 5 and 7 after drug. There was no evidence of increased sensitivity to FLZ in the elderly. Subjects did not perceive any impairment of intellectual function or motor performance, and no other adverse reactions were reported.Clinical Pharmacology and Therapeutics(1981)30,475

ISSN:0009-9236    

DOI:10.1038/clpt.1981.191

年代:1981

数据来源: WILEY

摘要:

In eight patients with end‐stage renal disease undergoing chronic hemodiaiysis moxalactam kinetics were examined. Volume of distribution (Vd), dialysance (Cd), and serum half‐life (t½) were determined during dialysis with a 1.3 or 1.6 m2dialyzer. The t½ was also determined during the interdialytic period. Vdwas 0.25 ± 0.04 l/kg and Cdwas 32.6 ± 11.7 ml/min and 67 ± 25.5 ml/min with the 1.3 and 1.6 m2dialyzers. The t½ was 4.8 ± 0.9 hr using the 1.3 m2dialyzer and 2.8 ± 0.6 hr using the 1.6 m2dialyzer. Moxalactam t½ during the interdialytic period was 23.4 ± 9.6 hr.Clinical Pharmacology and Therapeutics(1981)30,487–490; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1981.192

年代:1981

数据来源: WILEY

摘要:

Differences in plasma theophyiiine clearance (ClT) and metabolism between smoking and nonsmoking normal subjects were examined by analysis of plasma and urinary theophyiiine concentrations and of urinary metabolite concentrations under steady‐state oral dosing conditions. ClTin smokers (0.053 ± 0.006 l · hr−1· kg−1) was greater than in nonsmokers (0.032 ± 0.002 l · hr−1· kg−1, p<0.005). Analyses of urinary metabolites revealed that clearance to l‐methyiuric acid (Cl1MU) and clearance to 3‐methylxanthine (Cl3MX) were increased in smokers 1.99‐fold and 2.10‐fold over nonsmoking controls (P<0.005). Clearance to 1.3‐dimethyluric acid (ClDMU) was also enhanced in smokers 1.68‐fold compared to controls (P<0.01). The positive relationship between Cl1MUand Cl3MXin both smokers and nonsmokers (r = 0.98, P<0.001) supports the concept that the two 8‐demethylation pathways for theophyiiine metabolism are under common regulatory control and involve a form of cytochrome P450distinct from that mediating 8‐hydroxylation of theophyiiine to DMU. These results suggest that cigarette smoking induces both of the cytochrome P450‐mediated pathways of theophyiiine metabolism but that N‐demethylation may be increased to a greater extent than 8‐hydroxylation.Clinical Pharmacology and Therapeutics(1981

ISSN:0009-9236    

DOI:10.1038/clpt.1981.193

年代:1981

数据来源: WILEY