摘要:

Clinical Pharmacology and Therapeutics(1984)36,573–573; doi:10.1038/clpt.1984.2

ISSN:0009-9236    

DOI:10.1038/clpt.1984.223

年代:1984

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1984)36,574–583; doi:10.1038/clpt.1984.2

ISSN:0009-9236    

DOI:10.1038/clpt.1984.224

年代:1984

数据来源: WILEY

摘要:

Nadolol and propranolol effects on lidocaine elimination were followed in six healthy men and women. Each received three separate 30‐hr infusions of lidocaine (2 mg/min): one alone, one after 3 days pretreatment with nadolol (160 mg daily), and one after 3 days pretreatment with propranolol (80 mg every 8 hr). Liver blood flow was determined by the systemic clearance of indocyanine green. Steady‐state plasma lidocaine levels were increased by nadolol (2.1 ± 0.2 to 2.7 ± 0.3 μg/ml) and by propranolol (2.1 ± 0.2 to 2.5 ± 0.3 μg/ml). Lidocaine plasma clearance was decreased by nadolol (1030 ± 81 to 850 ± 82 ml/min) and by propranolol (1030 ± 81 to 866 ± 75 ml/min). Hepatic blood flow was decreased by nadolol (1275 ± 77 to 902 ± 102 ml/min) and propranolol (1275 ± 77 to 957 ± 119 ml/min). The hepatic extraction ratio for lidocaine was increased by nadolol (0.86 ± 0.06 to 0.91 ± 0.05) and by propranolol (0.86 ± 0.06 to 0.90 ± 0.06). Lidocaine intrinsic clearance was not changed by nadolol (8.19 ± 1.87 to 9.52 ± 2.36 l/min) or propranolol (8.19 ± 1.87 to 9.50 ± 3.13 l/min). Our data indicate that both nadolol and propranolol reduce lidocaine clearance by their effects on hepatic blood flow and not by inhibition of lidocaine metabolism.Clinical Pharmacology and Therapeutics(1984)36,584–58

ISSN:0009-9236    

DOI:10.1038/clpt.1984.225

年代:1984

数据来源: WILEY

摘要:

Daily doses of 0.3 mg clonidine and 3 mg guanfacine were equiactive in decreasing blood pressure and heart rate in 17 subjects with essential hypertension. Clonidine decreased cardiac output and guanfacine decreased total peripheral resistance, while clonidine had no effect on stroke volume but guanfacine increased it. Both clonidine and guanfacine decreased plasma renin activity. Naloxone, 0.4 mg iv, reversed the antihypertensive effect of clonidine but was ineffective even at higher doses (1.6 mg iv) when subjects were treated with placebo or guanfacine. It is suggested that the hemodynamic differences between the two centrally acting α2‐adrenoceptor agonist antihypertensive drugs may at least in part result from the involvement of opioid mechanisms only in the action of clonidine.Clinical Pharmacology and Therapeutics(1984)36,588–594; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1984.226

年代:1984

数据来源: WILEY

摘要:

Levels of hydralazine in blood are log‐linearly related to its vasodepressor effect. We examined the effect of oral dose size on the proportion of hydralazine that reaches systemic circulation. Nine subjects with hypertension were given hydralazine in oral doses in the therapeutic range. Blood hydralazine levels, effective liver blood flow, blood pressure, and heart rate were measured. As the hydralazine dose increased, the ratios of the AUC of hydralazine to hydralazine dose and of peak blood hydralazine concentration to hydralazine dose increased, indicating an increase in the proportion of the dose in blood. Liver blood flow tended to increase (maximum 40%) as dose increased above 0.5 mg/kg. Vasodepressor response and degree of tachycardia increased disproportionately with increasing hydralazine dose. There were strong log‐linear relationships between peak hydralazine levels and both vasodepressor response and tachycardia that did not change with increasing hydralazine dose. Thus blood hydralazine and vasodepressor response increase disproportionately with increasing hydralazine doses in hypertension.Clinical Pharmacology and Therapeutics(1984)36,595–600; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1984.227

年代:1984

数据来源: WILEY

摘要:

The kinetics of digitoxin and two of its metabolites, the bis‐ and monodigitoxosides of digitoxigenin, were determined in six normal subjects. Mean t½s and total body clearances were 134.4, 15.4, and 0.59 hr and 2.66, 27.3, and 1071 ml/min. Mean renal clearance of the monodigitoxoside was more rapid (7.24 ml/min) than those of digitoxin (0.81 ml/min) or the bisdigitoxoside (0.94 mi/min). The volumes of distribution were of the same order, 0.45 l/kg for digitoxin, 0.57 l/kg for the bisdigitoxoside, and 0.83 l/kg for the monodigitoxoside. The short t½ of monodigitoxoside would make it unsuitable for clinical use, but the bisdigitoxoside of digitoxigenin has a t½ of an intermediate length and may have significant therapeutic advantages.Clinical Pharmacology and Therapeutics(1984)36,601–606; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.228

年代:1984

数据来源: WILEY

摘要:

The kinetics of digitoxin and two of its major metabolites, the bis‐ and monodigitoxosides of digitoxigenin, were determined in six subjects with renal insufficiency and compared to those in six age‐ and sex‐matched normal control subjects. No significant differences between the two groups were found in elimination t½, total body clearance, or volume of distribution. Average renal clearances of all three drugs were reduced in subjects with renal failure, but the differences were significant only in the case of digitoxin. The bis‐digitoxoside of digitoxigenin has kinetic properties that offer clinical advantages.Clinical Pharmacology and Therapeutics(1984)36,607–612; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1984.229

年代:1984

数据来源: WILEY

摘要:

Oral cibenzoline kinetics were followed in 36 healthy subjects aged from 22 to 78 yr divided into groups of six subjects per decade between 20 and 80 yr. Each received a single, oral, 160‐mg dose of cibenzoline. Blood and urine samples were collected for 72 hr. Cibenzoline plasma and urine concentrations were measured by HPLC. Maximum plasma cibenzoline concentrations (Cmax) ranged from 283 to 1100 ng/ml and occurred 1 to 2.5 hr after dosing. Apparent oral clearance (ClT) ranged from 401 to 1677 ml/min and the t½ ranged from 5.9 to 13.4 hr. Nonrenal clearance (ClNR) ranged from 65 to 1113 ml/min, renal clearance (ClR) ranged from 165 to 645 ml/min, and 31% to 86% of the dose was recovered unchanged in urine (Xu). The volume of distribution (Vd) was large, ranging from 236 to 948 l. There was a significant relationship between age and the following kinetic parameters: Cmax, Xu, t½ (all of which increased with age), ClT, ClR, ClNR, the terminal elimination rate constant β, and Vd (which decreased with age). Mean ClTwas 999 ± 371 ml/min in the 20‐ to 30‐yr age group and was 465 ± 78 ml/min in the 70‐ to 80‐yr age group. The change in ClTwith age resulted from a decrease in both ClRand ClNR. Mean t½ varied from 7 hr in the youngest group to 10.5 hr in the oldest group. The age‐related changes in cibenzoline kinetics occurred over the entire age range studied and the relationship between age and these kinetic parameters appeared to be linear. Multiple regression analyses showed that ClT, ClR, and Vd were related to sex, age, and serum creatinine concentration, which suggests that these variables may be essential in the clinical individualization of cibenzoline dosing.Clinical Pharmacology and Therapeutics(1984)36,613–619; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.230

年代:1984

数据来源: WILEY

摘要:

The tolerance and prolactin (PRL) release‐inhibiting action of the 8α‐aminoergoline mesulergine were investigated. In a blind crossover study in six subjects with hyperprolactinemia, 0.5 mg mesulergine induced fewer side effects than did 2.5 mg bromocriptine, while the PRL release‐inhibiting effect of the two was of the same order. Six different subjects with suspected PRL‐secreting pituitary adenomas who (repeatedly) had to discontinue bromocriptine because of nausea, vomiting, or symptoms of orthostatic hypotension were treated for 20 mo with mesulergine (1 to 2 mg/day). Mesulergine did not induce side effects and its actions resembled those of bromocriptine. Mesulergine induced cessation of galactorrhea and resumption of normal menstrual cycles in five subjects, while in one subject an insufficient luteal phase persisted. No abnormalities in routine blood parameter estimations were observed. In two of three subjects there was shrinkage of a pituitary tumor after 12 to 15 mo on mesulergine. Mesulergine did not directly inhibit PRL release by cultured normal rat pituitary cells and human prolactinoma cells and it antagonized the action of dopamine in a dose‐dependent manner. This suggests that the dopaminergic action is carried out by a metabolite of mesulergine, while the parent drug probably prevents the well‐known side effects of dop amine‐agonistic drugs by its dopamine receptor blocking activity. Because of its acceptability, mesulergine might be important in the treatment of hyperprolactinemia and perhaps also of acromegaly and Parkinson's disease.Clinical Pharmacology and Therapeutics(1984)36,620–627; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.231

年代:1984

数据来源: WILEY

摘要:

The incidence and pathogenesis of withdrawal phenomena with the centrally acting drugs clonidine (CLON) and tiamenidine (TIAM) were evaluated. Thirty subjects with hypertension on hydrochlorothiazide (HCTZ) were randomized to TIAM or CLON. Blood pressure and integrated plasma catecholamine levels fell equally in response to both drugs. On withdrawal, blood pressure and pulse rose in both groups with no difference between them. Three subjects had symptoms of withdrawal, four had blood pressure overshoot above pretreatment levels of 10 mm Hg or more, and eight had a rise in blood pressure of 30 mm Hg systolic or 20 mm Hg diastolic. There was no difference between TIAM and CLON in these effects. There was a direct correlation between blood pressure rise and increase in integrated plasma norepinephrine levels. We conclude that the incidence of withdrawal phenomena in subjects on TIAM or CLON is infrequent and that there is a direct relationship between the rise in blood pressure and the loss of suppression of catecholamines by these drugs.Clinical Pharmacology and Therapeutics(1984)36,628–633; doi:10.1038/clpt.1984.2

ISSN:0009-9236    

DOI:10.1038/clpt.1984.232

年代:1984

数据来源: WILEY