摘要:

Four healthy subjects and six patients with congestive heart failure (CHF) were given 3 mg oral and intravenous doses of bumetanide in a random crossover fashion. Bumetanide was analyzed by HPLC, and sodium and potassium was analyzed by flame photometry. Aside from a modest reduction in renal clearance, the kinetics of bumetanide in CHF were similar to those in healthy subjects. The extent of bioavailability was 81%, with a variability of 20% to 25% about the mean for both groups. The cumulative dynamic responses to bumetanide, whether administered orally or intravenously, were essentially the same in each group. Pharmacodynamic modeling showed that there were no significant differences between healthy subjects and patients with CHF in either ER50(bumetanide urinary excretion rate producing 50% of maximum drug effect) or S (slope), although the baseline effect was 15 times lower in CHF. The maximum effect attributable to bumetanide was twofold higher in healthy subjects and there was a significant correlation between this parameter and creatinine clearance (r= 0.964;p<0.001). Overall, these results indicate that a predictable transition from 3 mg intravenous to oral doses of bumetanide is possible in CHF.Clinical Pharmacology and Therapeutics(1988)44,487–500; doi:10.1038/clpt.1988.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.186

年代:1988

数据来源: WILEY

摘要:

Clinical, pharmacologic, and immunologic effects of 2'‐deoxycoformycin (dCF) were evaluated in 15 patients with advanced malignancies. Toxicity was less severe with a low dose (4 mg/m2) of dCF, but this dose still resulted in suppression of cellular adenosine deaminase activity, skin test reactivity, and lymphocyte responses to mitogens. Improvement in cutaneous T cell lymphoma plaques was seen after dCF. Further investigations of antitumor efficacy with the use of this low dosage schedule should continue in patients with hematologie neoplasms, and additional preliminary studies of the combination of an adenosine deaminase inhibitor with an adenosine analog should also be considered.Clinical Pharmacology and Therapeutics(1988)44,501–509; doi:10.1038/clpt.1988

ISSN:0009-9236    

DOI:10.1038/clpt.1988.187

年代:1988

数据来源: WILEY

摘要:

To evaluate the effect of hyperthyroidism on the protein binding and metabolism of prednisolone, eight subjects with hyperthyroidism were investigated before and after thyroid status returned to normal. Hyperthyroidism was associated with a reduced volume of distribution of prednisolone, a decreased systemic availability of prednisolone after oral prednisone, a displacement of the prednisolone ⇄ prednisone equilibrium toward prednisone, and an increased nonrenal clearance of unbound prednisolone in the presence of an impaired 6β‐hydroxyprednisolone formation. After oral prednisone or intravenous prednisolone, patients with hyperthyroidism had lower albumin‐bound, transcortin‐bound, and unbound concentrations of prednisolone but normal affinities of albumin and transcortin for prednisolone binding. These differences in prednisolone plasma concentrations were biologically relevant, because the capacity of these plasma samples to inhibit allogeneically stimulated lymphocytes was lower by 70% in the hyperthyroid than in the euthyroid state. Thus hyperthyroidism reduces the biologic effect of prednisolone and exhibits a differential effect on various enzymes involved in the catabolism of prednisolone.Clinical Pharmacology and Therapeutics(1988)44,510–521; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1988.188

年代:1988

数据来源: WILEY

摘要:

The effect of age on theophylline kinetics was examined in six normal young men and six elderly men. There were no age‐associated differences in theophylline volume of distribution, total clearance, or t½. The unbound fraction of theophylline was significantly raised in the elderly (mean 77.7% vs. 62.3%,p<0.001) and was correlated with the serum albumin level (r= −0.7,p<0.01). Theophylline nonrenal clearance was not changed, but the total unbound clearance was significantly reduced in the elderly subjects as compared with the young ones (mean 0.744 vs. 1.085 ml/min/kg,p<0.05). Creatinine clearance was reduced in the elderly and was significantly correlated with unbound renal clearance (r= 0.6,p<0.04). There were no age‐related differences in the urinary excretion of theophyUine, 1‐methyluric acid, 3‐methylxanthine, or 1,3‐dimethyluric acid. However, significant reduction in unbound renal theophyUine clearance (p<0.002) as well as the unbound metabolic clearance of 1,3‐dimethyluric acid (p<0.03), 3‐methylxanthine (p<0.04), and 1‐methyluric acid (p<0.02) were observed in the elderly subjects. These observations indicate that both renal and metabolic elimination processes for theophyUine are less active in the normal elderly.Clinical Pharmacology and Therapeutics(1988)44,522–530; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1988.189

年代:1988

数据来源: WILEY

摘要:

The mechanism by which nonsteroidal antiinflammatory drugs interfere with the action of loop diuretics is not clear. We studied the renal response to an acute challenge of piretanide superimposed on pretreatment with either placebo, probenecid, indomethacin, or piroxicam in seven maximally hydrated subjects. No change was seen in glomerular filtration rate, as measured by creatinine clearance, throughout the experiments. When compared with responses to piretanide challenge after placebo pretreatment, probenecid reduced by 65% the peak fractional excretion of sodium (FENa), with a corresponding reduction in diuretic excretion. Pretreatment with indomethacin reduced peak FENa by 35%, but urinary delivery of piretanide was not altered. In contrast, piroxicam did not influence FENa but significantly reduced the delivery of both sodium and piretanide into urine. We conclude that the activity of nonsteroidal antiinflammatory drugs within the renal tubule varies among individual drugs and cannot be explained solely by their common mechanism of antiinflammatory action.Clinical Pharmacology and Therapeutics(1988)44,531–539; doi:10.1038/clpt.1988.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.190

年代:1988

数据来源: WILEY

摘要:

By use of an interview, return tablet count, and a pharmacologic indicator (low‐dose phenobarbital), we compared compliance with tablets prescribed to be taken once, twice, or three times daily. One hundred seventy‐nine patients with type II diabetes were randomly allocated to take one 2 mg phenobarbital tablet once, twice, or three times daily for 28 days. Phenobarbital level/dose ratios indicated that compliance was similar with once‐ and twice‐daily regimens, and both were better than thrice‐daily dosing. Mean return tablet counts suggested that compliance was best with the once‐daily regimen; both twice‐ and thrice‐daily regimens were similarly inferior. This difference between the techniques may be explained by the inadequacies of the residual tablet count, which identified only 13% of cases identified by phenobarbital. We conclude that compliance with the once‐daily regimen was best, but that compliance with a twice‐daily regimen was very similar, and both were superior to dosing three times a day.Clinical Pharmacology and Therapeutics(1988)44,540–545; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1988.191

年代:1988

数据来源: WILEY

摘要:

The aim of this study was to determine the effect of 1 week of antacid dosing on the aspirin‐induced potential differences (PDs) across the gastric mucosa. The study design was double blind and randomized with crossover. Ten healthy subjects received aluminum hydroxide gel, 8 gm t.i.d., or placebo for 1 week. They then received 1 gm aspirin after an overnight fast and the PD across the mucosa was measured. Baseline potentials were the same before both treatment periods. Antacids reduced the aspirin‐induced PDs. The mean (± SD) maximal PD was 27.4 ± 1.7 mV with placebo vs. 10.7 ± 2.2 mV with antacids (p<0.001). Recovery time was 65.5 ± 5.2 minutes with placebo vs. 29.0 ± 6.7 minutes with antacids (p<0.001). These results suggest the effect is due to a longer‐term cytoprotective property of antacids rather than to acid‐neutralizing activity.Clinical Pharmacology and Therapeutics(1988)44,546–549; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1988.192

年代:1988

数据来源: WILEY

摘要:

Cerebrospinal fluid (CSF) and plasma levels of verapamil and its two metabolites, norverapamil and D‐620, were measured in seven patients with schizophrenia under steady‐state conditions. Simultaneous sampling of CSF and plasma just before the dose during week 4 of the trial showed that verapamil, norverapamil, and D‐620 partition in the CSF and reflect 7%, 5%, and 12% of the corresponding levels in plasma, respectively. There was a significant decrease in the mean unbound fraction of verapamil in schizophrenic patients as compared with normal subjects (0.058 vs. 0.11;p<0.001). Estimates of the mean unbound fraction obtained from CSF/plasma verapamil concentrations and the pH partition hypothesis showed excellent agreement with that measured by equilibrium dialysis (0.055 vs. 0.058) in these patients. Although systemic pool protein concentrations in schizophrenic patients were within normal range, an excellent positive correlation was observed between the ratio of the bound/ free verapamil concentration and α1‐acid glycoprotein levels (r= 0.86;p<0.05). Determination and development of correlations between plasma and GSF may enhance our understanding of the central nervous system effects of verapamil.Clinical Pharmacology and Therapeutics(1988)44,550–557; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1988.193

年代:1988

数据来源: WILEY

摘要:

The pharmacokinetics of both enantiomers of vigabatrin after a single oral dose in healthy young subjects (mean creatinine clearance 120 ml/min) were compared with kinetics in two groups of elderly subjects, one group aged 60 to 75 years (mean creatinine clearance 86 ml/min) and one group aged 76 to 97 years (mean creatinine clearance 30 ml/min). At a dose of 1500 mg, the group with the eldest subjects and the lowest creatinine clearance values showed mean increases of 3.3‐fold in the time to reach the maximum concentration, 2.7‐fold in the maximum concentration, and 9.8‐fold in the AUC; a twofold prolongation of the t½; and reduced urinary excretion of the biologically and pharmacologically activeS(+)‐enantiomer. Changes in the intermediate group were qualitatively similar but quantitatively less. Parallel observations were made for the inactiveR(−)‐enantiomer. Most of these changes can be related to decreased renal clearance of vigabatrin. No interference of either enantiomer in the renal clearance of the other was noted. A nonlinear relationship between renal clearance and creatinine clearance for both enantiomers is suggested. Knowledge of the patient's renal function and an appropriate dose adjustment will minimize side effects during vigabatrin therapy, especially in elderly patients.Clinical Pharmacology and Therapeutics(1988)44,558–565; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1988.194

年代:1988

数据来源: WILEY

摘要:

The pharmacokinetics of flecainide were studied in six patients with cirrhosis of the liver and in six healthy subjects after a single 2 mg/kg intravenous dose. Hepatic biotransformation capability before flecainide dosing was assessed by antipyrine challenge. The mean plasma antipyrine t½for patients (42.2 hours) was longer (p<0.01) than that for subjects (11.7 hours). For control subjects, the plasma t½of flecainide (9.5 hours) was shorter (p<0.01), plasma clearance (9.1 ml/min/kg) was faster (p<0.01), and volume of distribution (7.5 L/kg) was smaller (p0.05) between the two groups. The mean ratio of renal clearance to plasma clearance for subjects (0.4) was smaller (p<0.05) than that for patients. The slower rate of flecainide elimination from plasma in patients is likely due to reduced hepatic biotransformation. In patients with cirrhosis, plasma levels of flecainide may accumulate to unacceptably high levels with usual dosage regimens.Clinical Pharmacology and Therapeutics(1988)44,566–572; doi:10.1038/clpt.1988

ISSN:0009-9236    

DOI:10.1038/clpt.1988.195

年代:1988

数据来源: WILEY