摘要:

Clinical Pharmacology and Therapeutics(1990)47,553–556; doi:10.1038/clpt.1990.

ISSN:0009-9236    

DOI:10.1038/clpt.1990.75

年代:1990

数据来源: WILEY

摘要:

To assess the safety, pharmacokinetics, and erythropoietic responses to human recombinant erythropoietin (epoetin beta), single intravenous doses (10, 50, 150, and 500 IU/kg) were administered at monthly intervals to 16 healthy subjects in a two‐panel, placebo‐controlled, double‐blind ascending‐dose trial. A 1000 IU/kg dose was subsequently administered in an open manner. Epoetin concentrations were determined in serum and urine by radioimmunoassay. Reticulocyte, hemoglobin, and hematocrit values were serially measured after each dose. Mean epoetin apparent half‐lives ranged from 4.42 to 11.02 hours. The apparent volume of distribution was between 40 and 90 ml/kg, consistent with plasma water, and the apparent clearance values ranged from 4 to 15 ml/kg/hr, with both parameters having the highest values at the 10 IU/kg dose level. Clearance tended to decrease as a function of dose. Maximum reticulocyte counts were dose‐dependent and occurred 3 to 4 days after the epoetin dose. Epoetin was well tolerated, and no antibodies were detected.Clinical Pharmacology and Therapeutics(1990)47,557–564; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1990.76

年代:1990

数据来源: WILEY

摘要:

To determine the relationship between changes in plasma methadone concentration and pharmacodynamic effects, plasma methadone profiles and pharmacodynamics (analgesia and sedation) were measured during and after the continuous infusion of methadone for 180 to 270 minutes in 15 patients with pain caused by cancer. An increase in plasma methadone concentration resulted in a rapid increase in pain relief or sedation. The estimates of values of 50% of maximum effect (Css50) for pain relief and sedation obtained with a pharmacokinetic‐pharmacodynamic model varied tenfold to twentyfold among patients; the mean Css50 value for pain relief (0.359 ± 0.158 [SD] μg/ml) was virtually the same as the mean Css50 value for sedation (0.336 ± 0.205 [SD] μg/ml). Similarly, the mean γ (slope function) for pain relief (4.4 ± 3.8 [SD]) and sedation (5.8 ± 5.4 [SD]) did not differ. Examination of hysteresis plots of data obtained during the infusion and for 4 to 5 hours after cessation of the infusion revealed a very rapid equilibration between plasma methadone values and the sites mediating pain relief. There was no indication of the development of tolerance to the pharmacodynamic effects of methadone during the study. This report describes a method for quantitating the pharmacokinetic‐pharmacodynamic relationships of the desirable and undesirable effects of opioid analgesics.Clinical Pharmacology and Therapeutics(1990)47,565–577; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1990.77

年代:1990

数据来源: WILEY

摘要:

The β1‐ and β2‐adrenoreceptor blockade by means of the systemic diffusion of three β‐blocker eyedrops—timolol, carteolol, and betaxolol—was evaluated in a randomized, single‐blind, three‐way crossover study in 18 volunteers. The blockade was evaluated by analyzing the variations of the β1‐ and β2‐blockade effects of isoproterenol before and after instillation of one drop in each eye. The β1‐blockade effect was judged on the variation of heart rate, and the β2‐blockade effect was judged on the change in peripheral blood flow measured by veno‐occlusive plethysmography. Comparison of the blockade by these drops showed that carteolol and timolol totally inhibited the β1and β2effects of a dose of isoproterenol able to increase heart rate by 50% (placebo eyedrops were used as a control). Betaxolol differ significantly because it allowed the same effects with the same dose of isoproterenol. Intensity of the blockade was measured by comparison of the effective doses of isoproterenol. Carteolol and timolol were shown to be four times more inhibitory.Clinical Pharmacology and Therapeutics(1990)47,

ISSN:0009-9236    

DOI:10.1038/clpt.1990.78

年代:1990

数据来源: WILEY

摘要:

Diltiazem and verapamil inhibit oxidative drug metabolism both in vivo and in vitro. We compared their effects on the stereoselective pharmacokinetics and protein binding of propranolol in 12 subjects. After 6 days of coadministration with racemic propranolol, diltiazem caused decreases of 27% and 24% in d‐propranolol and 1‐propranolol oral clearances, respectively (p<0.05 versus control). With verapamil, d‐propranolol oral clearance decreased 32% (p<0.05), and 1‐propranolol oral clearance decreased 26% (p<0.05). The unbound fraction of d‐propranolol was higher than that of 1‐propranolol (p<0.05), but the protein binding was not altered by diltiazem or verapamil. Both drugs therefore decreased the unbound oral clearance of each propranolol enantiomer (p<0.05). Verapamil caused a stereoselective effect and increased the d/1 ratio of propranolol serum concentrations (p<0.05) and decreased the d/1 ratio of oral clearance (p<0.05).Clinical Pharmacology and Therapeutics(1990)47,584–591; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1990.79

年代:1990

数据来源: WILEY

摘要:

The pharmacokinetics of nitroglycerin and the formation of its dinitrate metabolites (1,2‐glyceryl dinitrate and 1,3‐glyceryl dinitrate) were determined in six healthy volunteers after administration of six oral solution doses ranging from 0.4 mg to 13 mg. ANOVA analysis indicated significant differences between subjects for all Cmax/dose and AUC/dose measurements. No significant difference between doses were noted for these parameters except for AUC/dose for 1,3‐glyceryl dinitrate. The ratio of metabolites (1,2‐metabolite/1,3‐metabolite) for the 0.4 mg dose was significantly different from the ratios for the doses of 1.6 mg or higher. Measurements of the combined residence time parameter suggest nonlinearity in nitroglycerin absorption and metabolism processes of AUMC/AUC between the 0.4 and the 13 mg doses. Consistent results were observed in the AUC ratios of metabolites for 0.4 mg doses of nitroglycerin between oral and sublingual administrations, suggesting that the increased metabolite ratio noted for sublingual nitroglycerin may reflect differences in dose, rather than differences in route of administration.Clinical Pharmacology and Therapeutics(1990)47,592–598; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1990.80

年代:1990

数据来源: WILEY

摘要:

Cardiovascular and sympathoadrenal effects of short‐term oral treatment with β1‐blockade (atenolol, 50 mg, administered two times) and β2‐blockade (ICI 118,551, 50 mg, administered three times) were compared with placebo during actual flying in subjects with flight phobia (n= 34). β1‐Blockade lowered resting blood pressure and heart rate and prevented a heart rate response but not a blood pressure response to this psychologic stress. β2‐Blockade minimally lowered resting heart rate and prevented a heart rate response, but it failed to lower resting blood pressure or blood pressure response to the stress. Plasma epinephrine increased with all three treatments and more with β1‐blockade than with placebo. Plasma norepinephrine decreased with administration of β2‐blockade. Thus neither β1‐ nor β2‐blockade prevents an increase in blood pressure during acute flight phobia stress. Increased plasma epinephrine seems to be the sympathetic variable that is closest related to this increase in blood pressure. Norepinephrine may be less consistently related to the blood pressure rise during flight phobia stress as shown by the decrease in plasma norepinephrine with administration of β2‐blockade.Clinical Pharmacology and Therapeutics(1990)47,599

ISSN:0009-9236    

DOI:10.1038/clpt.1990.81

年代:1990

数据来源: WILEY

摘要:

This study evaluated the blood pressure effects of administration of once daily oral benazepril hydrochloride, a new angiotensin‐converting enzyme (ACE) inhibitor, for mild‐to‐moderate hypertension. After a 2 to 4 week placebo baseline period, patients with diastolic blood pressure between 95 and 114 mm Hg, were randomized to receive either placebo or benazepril hydrochloride, 5, 10, 20, or 40 mg, once daily in double‐blind fashion for 28 days. Blood pressure was measured predose and at 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after the dose during inpatient observation days at the end of the placebo baseline period, and on the first and last day of the double‐blind treatment period; and 24 hours after the dose at weekly outpatient visits. All doses of benazepril hydrochloride resulted in clinically important reductions in diastolic and systolic blood pressures that lasted between 12 and 24 hours after both the first dose, and following the last dose after 4 weeks of treatment. The findings indicate that benazepril hydrochloride may be clinically useful as once‐daily monotherapy in many patients with hypertension.Clinical Pharmacology and Therapeutics(1990)47,608–617; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1990.82

年代:1990

数据来源: WILEY

摘要:

Thirteen patients with cystic fibrosis and 12 healthy control volunteers received a single oral 800 mg dose of fleroxacin and 800 mg every day for 5 days. Interstitial fluid penetration was studied by the suction‐induced blister technique. Fleroxacin and its two major metabolites,N‐demethyl andN‐oxide, were analyzed in plasma and urine by HPLC. Single‐dose absorption parameters (absorption rate constant, normalized peak plasma drug concentration, and time to reach peak concentration) and total urinary excretion indicated that fleroxacin was absorbed more slowly and more completely in patients with cystic fibrosis than in control subjects. Fleroxacin volume of distribution tended to be smaller in patients with cystic fibrosis and it reached statistical significance after a single dose when normalization for lean body mass was applied. When normalized for lean body mass, the formation clearance ofN‐demethyl fleroxacin andN‐oxide fleroxacin was significantly greater in patients with cystic fibrosis than in control subjects (p<0.05). These data concur with those of others showing an induction of drug‐metabolizing enzymes in cystic fibrosis. Renal clearances of fleroxacin and its metabolites were significantly increased in cystic fibrosis (p<0.05), and this seems to be explained by a decreased tubular reabsorption of these compounds. The differences seen in the pharmacokinetics of fleroxacin in cystic fibrosis support the theories of generalized induction of drug metabolism and of a defective renal tubular reabsorptive process of drugs in cystic fibrosis.Clinical Pharmacology and Therapeutics(1990)47,618–628; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1990.83

年代:1990

数据来源: WILEY

摘要:

In patients with azotemia, urea excretion, urea clearance, and urea/creatinine clearance ratio were increased by pyrazinoylguanidine in a dose‐related manner. Urine volume and excretion of sodium>chloride>potassium tended to increase during administration of pyrazinoylguanidine. Systemic arterial pressure declined while pyrazinoylguanidine was given at 300 or 600 mg b.i.d. for 3 days. At both doses pyrazinoylguanidine reduced plasma renin activity during the first 2 hours. Between days 1 and 3 only the high dose of pyrazinoylguanidine decreased plasma renin activity and plasma aldosterone levels. These findings with pyrazinoylguanidine are consistent with those of secretion of urea in human subjects across the renal tubules and indicate that this process is susceptible to pharmacologic alteration, even in the presence of severe renal insufficiency.Clinical Pharmacology and Therapeutics(1990)47,629–638; doi:10.1038/clpt.199

ISSN:0009-9236    

DOI:10.1038/clpt.1990.84

年代:1990

数据来源: WILEY