摘要:

Clinical Pharmacology and Therapeutics(1984)35,431–437; doi:10.1038/clpt.1984.

ISSN:0009-9236    

DOI:10.1038/clpt.1984.56

年代:1984

数据来源: WILEY

摘要:

To evaluate the effect of puberty on the net renal tubular secretion of digoxin, we measured the ratio of digoxin clearance to creatinine clearance in 23 patients aged 4 to 2] yr and correlated this ratio with both sexual maturity (Tanner31stage) and chronologic age. All subjects were at steady‐state levels for digoxin treatment; all had normal serum creatinine values for age as well as normal serum potassium levels. Mean ratio for immature children (n = 14, Tanner 1 through 3.5) was 1.45 ± 0.66. Mean ratio for mature adolescents (n = 9, Tanner 4 through 5) was 0.95 ± 0.28. The difference between the two groups was significant (P<0.05). When patients were regrouped by age using either 13 or 15 yr as a cutoff, the difference in ratios was no longer statistically significant. Based on 45 subjects (new and from our previous study21) aged 2 mo to 80 yr, there was a significant decrease in the clearance ratio with increasing age, but when the 23 subjects aged 4 to 21 yr were analyzed separately, the correlation between ratio and age was not significant. It appears that the decrease in net renal tubular secretion of digoxin from childhood to adulthood correlates better with full sexual maturation at puberty (Tanner 4 through 5) than with chronologic age. This observation may represent a developmental change in pharmacokinetics with broader significance than for digoxin disposition alone.Clinical Pharmacology and Therapeutics(1984)35,438–446; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.57

年代:1984

数据来源: WILEY

摘要:

Five healthy subjects were given oral14C‐propranolol (10 µCi, 40 mg) alone and in combination with hydralazine, 25 and 50 mg. Hydralazine increased propranolol peak concentrations from 25 ±7 ng/ml to 61 ± 10 and 85 ± 11 ng/ml, reduced time to peak concentrations from 2.2 ± 0.2 hr to 0.7 ±0.1 and 0.8 ±0.1 hr, and increased area under the propranolol concentration : time curves from 153 ±38 ng · ml−1· hr to 246 ± 64 and 324 ng · ml−1· hr (in all cases P<0.05). Hydralazine did not change the fraction of the14C‐propranolol dose recovered in the urine as basic, acidic, and polar metabolites: 0.28 ± 0.02, 0.27 ± 0.03, and 0.44 ± 0.03. The urinary excretion rate of radioactive metabolites of propranolol in acid, basic, and residue fractions increased in the 0 = to = 2‐hr time interval after hydralazine but there was no change in the relative proportion of each metabolite fraction at any time. Similar results were obtained by HPLC. Studies with radioactive propranolol indicate that a major acid and basic metabolite remains to be defined in addition to unextracted polar metabolites. Our data indicate that hydralazine increases propranolol bioavailability by its hemodynamic actions rather than by inhibition of its metabolism.Clinical Pharmacology and Therapeutics(1984)35,447–4

ISSN:0009-9236    

DOI:10.1038/clpt.1984.58

年代:1984

数据来源: WILEY

摘要:

Cardiac electrophysiologic effects of a single oral dose of labetalol were determined in seven patients 4 to 9 days after a coronary artery bypass graft. Surface ECG and bipolar electrograms recorded from temporary pacing wires affixed to the normal right ventricle and abnormal left ventricle at the time of surgery were used to determine conduction intervals. Electrophysiologic parameters were recorded during fixed‐rate atrial pacing. Sinus heart rate and blood pressure were monitored. Three patients received 100 mg and four patients received 200 mg labetalol. The drug had no significant effect on intraventricular conduction intervals or QRS duration. It did not significantly influence sinus heart rate or AV conduction time, but in two patients there was prolongation in AV conduction that may have been drug‐induced. Labetalol induced a modest but significant decrease in systolic and diastolic blood pressure. In another study propranolol, unlike labetalol, had prolonged AV and intraventricular conduction in the abnormal left ventricle, but not in the normal right ventricle. The absence of these effects with labetalol may reflect lesser local anesthetic effect on intraventricular conduction and an α‐adrenergic blocking effect that interferes with β‐blockade–induced prolongation of AV conduction.Clinical Pharmacology and Therapeutics(1984)35,454–460; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1984.59

年代:1984

数据来源: WILEY

摘要:

Nonselective β‐blockers increase peripheral vascular resistance and, sometimes, blood pressure (BP); increased responsiveness to circulating pressor agents could be one of the underlying mechanisms. Heart rate (HR) and BP responses to graded intravenous infusions of epinephrine, norepinephrine, and angiotensin II were recorded after placebo and then after 4 wk of β‐blocker treatment (nadolol or propranolol, 240 mg/day) in 10 healthy young men. Adequacy of β‐blockade was demonstrated by a mean 31% decrease in HR response to bicycle exercise, with no differences between the two β‐blockers. Under placebo conditions epinephrine lowered diastolic BP and raised HR; these effects were reversed during treatment with β‐blockers. β‐Blockade potentiated BP responses to norepinephrine and angiotensin II: Thirty‐five percent less norepinephrine and 52% less angiotensin II were required to increase mean BP by 15 mm Hg. A final study 2 wk after β‐blocker cessation revealed the absence of lasting effect. These results confirm the concept of unopposed α‐constriction for epinephrine and also demonstrate increased BP responses to norepinephrine and angiotensin II during chronic β‐blockade.Clinical Pharmacology and Therapeutics(1984)35,461

ISSN:0009-9236    

DOI:10.1038/clpt.1984.60

年代:1984

数据来源: WILEY

摘要:

The relationship between amitriptyline (AT) metabolism and clinical response was studied in 14 outpatients treated with a daily dose of 150 mg AT. Riboflavin was added to the medication to check compliance. On days 0, 2, and 7 and at 3, 6, 9, and 13 wk after onset of therapy, blood samples were drawn from the patients 3 (±0.5) hr after the first morning dose and a sample of the first morning urine was taken to check riboflavin. Serum levels of AT and its metabolites, nortriptyline (NT), E‐ and 7,‐10‐hydroxynortriptyline (E‐ and Z‐10‐OH‐NT), total (E + Z) 10‐hydroxyamitriptyline (tot‐10‐OH‐AT), and desmethylnortriptyline (DNT), were measured by means of HPLC while minimizing adsorption onto glass. On day 0 and after 6 and 13 wk the severity of the depressive disorder was scored by means of the self‐rating depression scale of Zung.28Mean steady‐state concentrations of AT, NT, and E‐10‐OH‐NT were in the order of 100 µg/l and tot‐10‐OH‐AT and Z‐10‐OH‐NT approximated 20 µg/l. DNT concentrations were under 15 µg/l. There was great variation in metabolic pattern between patients. After 6 wk concentrations of all compounds were approximately 15% lower than at 3 wk, indicating a weak autoinducible effect of AT or its metabolites. Steady‐state concentrations of AT correlated well with that of NT (r = 0.64; P<0.05) but not with that of E‐10‐OH‐NT. The means of the Zung score at 6 and 13 wk were lower than the mean of the baseline score (P<0.0001). Correlation coefficients between the mean percentage improvement in Zung score and the steady‐state concentrations of AT, NT, E‐10‐OH‐NT, and age were −0.06, 0.10, −0.46, and −0.64.Clinical P

ISSN:0009-9236    

DOI:10.1038/clpt.1984.61

年代:1984

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1984)35,473; doi:10.1038/clpt.1984.62

ISSN:0009-9236    

DOI:10.1038/clpt.1984.62

年代:1984

数据来源: WILEY

摘要:

Diphenhydramine (DPHM) disposition was examined in nine patients with chronic alcohol‐related liver disease and in eight normal subjects. Sleep of 1 to 2 hr duration was induced in all subjects by a 0.8 mg/kg iv dose without an apparent increase in cerebral sensitivity in the patients with cirrhosis. Protein binding as determined by equilibrium dialysis (3H‐DPHM) revealed a 15% decrease in the cirrhotic patients, while recovery of unchanged DPHM in urine (2%) was of the same order in the two groups. Computerized biexponential curve analysis was used to compare the plasma profiles for five of the patients and six of the normal subjects. Monoexponential curve analysis of the terminal β‐phase, including all subjects, was also used to compare the two groups. The means of plasma clearance and apparent volume of distribution in cirrhotic patients were respectively less and greater than in normal subjects, but these differences were not significant. The t½ for the β‐phase (t½β), which reflects this reciprocal trend, was increased in the patients (15.2 ±7.5 and 9.3 ± 0.9 hr). This correlated in part with severity of disease, with r = 0.723 between t½β and the serum bilirubin levels. In conclusion, a single intravenous dose of DPHM provided safe and effective sedation in patients with cirrhosis.Clinical Pharmacology and Therapeutics(1984)35,474–479; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.63

年代:1984

数据来源: WILEY

摘要:

Acetaminophen metabolism and clearance after a single 1 gm oral dose of the drug was investigated in 12 healthy men, six of whom were cigarette smokers, and in six men who were receiving anticonvulsant drugs for epilepsy. The 12 healthy subjects were studied before and after 1 wk of pretreatment with cimetidine (1 gm/day) or sulfinpyrazone (800 mg/day). There was no significant difference in acetaminophen clearance (ClAP) between nonsmokers and smokers; cimetidine pretreatment had no effect on ClAP. Neither cigarette smoking nor cimetidine pretreatment had a significant effect on any of the metabolic pathways of acetaminophen. In contrast, sulfinpyrazone pretreatment increased ClAPby 23% (from 5.70 ± 0.21 to 7.00 ± 0.39 ml/min/kg) and ClAPwas 46% greater in the epileptic subjects who received anticonvulsant drugs than in the control group (8.32 ± 0.45 and 5.70 ± 0.21 ml/ml/kg). In both cases the increase in ClAPwas a result of induction of acetaminophen glucuronidation and oxidation; clearance of the glucuronic acid conjugate was 26% and 59% greater and clearance of the glutathione‐derived conjugates (reflecting the activity of the oxidative pathway) was 43% and 60% greater in the groups given sulfinpyrazone and anticonvulsants, respectively.Clinical Pharmacology and Therapeutics(1984)35,480–486; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1984.64

年代:1984

数据来源: WILEY

摘要:

Single‐dose ranitidine kinetics were studied in 10 patients with cirrhosis as proved by liver biopsy. All were clinically stable. After an overnight fast, ranitidine was given in a randomized crossover order as a bolus intravenous injection (50 mg) or was taken by mouth (150 mg). Terminal t½ was 2.7 ±0.4 hr after oral dosing and 2.9 ±0.4 hr after intravenous injection. Total plasma clearance was 470 ±170 mi/min and the steady‐state volume of distribution was 1.2 ± 0.2 l/kg. There was considerable intersubject variability in the ranitidine serum concentration‐time profile after oral dosing. Systemic availability as assessed by AUC analysis was 58% ± 11%. Not all of the dose could be recovered in the urine as unchanged ranitidine and its known metabolites after intravenous injection. At 0.5 µg/ml the serum protein binding of ranitidine was 4.6% ± 1.3%. It is concluded that disposition of ranitidine in these 10 stable subjects with cirrhosis was not significantly altered. The minor changes observed in some were as likely to be the result of secondary perturbations in physiologic status as to effects of cirrhosis on drug metabolism.Clinical Pharmacology and Therapeutics(1984)35,487–494; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.65

年代:1984

数据来源: WILEY