摘要:

We have applied a new method for quantitative measurement of bronchial beta adrenoceptor blockade to a new beta adrenoceptor antagonist, bevantolol. Dose‐response curves to a beta agonist, albuterol, were obtained in six normal subjects by measuring specific airway conductance (sGaw) after increasing doses of inhaled albuterol. These were repeated on three separate occasions 2 hr after subjects had taken oral placebo or bevantolol (75 or 150 mg), double‐blind in random order. The dose‐response curves after bevantolol 75 mg were displaced to the right of placebo in four subjects and after 150 mg were displaced to the right of placebo in all subjects. The mean dose ratios for bevantolol 75 and 150 mg were 1.02 and 2.77, much the same as those obtained in the same subjects after practolol 100 and 200 mg and considerably less than that after propranolol 40 mg. The mean reductions in exercise heart rate were 25% and 29% after bevantolol 75 and 150 mg. Our data show that bronchial beta blockade after a beta blocking drug can be assessed quantitatively in man by a double‐blind technique.Clinical Pharmacology and Therapeutics(1981)29,1–6; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1981.1

年代:1981

数据来源: WILEY

摘要:

Prazosin was given for 10 to 14 days to eight hypertensive patients on a fixed intake of dietary salt. Except as limited by side effects, the dose was increased from 2 mg/day to a maximum dose of 24 mg/day. During treatment, when subjects were studied in supine and upright positions, mean arterial pressure (MAP) fell 6% and 12% (p<0.025 and p<0.005), heart rate rose 3% and 9% (p<0.05 and p<0.005), and plasma norepinephrine increased 95% and 107% (p<0.01 and p<0.001) over control. Daily excretion of the norepinephrine metabolites methoxyhydroxyphenyl glycol (MHPG) and vanillylmandelic acid (VMA) increased 42% and 17% (p<0.05 for each) during treatment. There were no changes in average body weight or plasma renin for the group, but patients whose body weight increased tended to show less reduction in blood pressure (correlation coefficient, r = 0.72, p<0.05) and smaller increases in heart rate (r = −0.73, p<0.05) during treatment with prazosin. These data suggest that expansion of extracellular fluid and activation of the sympathetic nervous system oppose the hemodynamic effects of prazosin.Clinical Pharmacology and Therapeutics(1981)29,7–11; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1981.2

年代:1981

数据来源: WILEY

摘要:

We studied the effect of a single oral dose of the neuronal norepinephrine uptake blocker, desipramine 125 mg, on norepinephrine kinetics. Desipramine reduced the plasma norepinephrine clearance by approximately 20%, from 1.33 ± 0.22 to 1.08 ± 0.19l/m2/min (p<0.01). Similarly, plasma norepinephrine clearance was slowed in patients with sympathetic nerves damaged by disease (idiopathic peripheral autonomic insufficiency). Desipramine also reduced the rate of spillover of norepinephrine to plasma, from 0.27 ± 0.07 to 0.15 ± 0.04 µg/m2/min, leaving the plasma norepinephrine concentration unchanged. Disappearance of tritiated norepinephrine from plasma, after infusion to steady state, was biexponential, with half‐time of the rapid‐removal phase (t1½) = 2.0 ± 0.4 min and half‐time of the second exponential (t2½) = 34 ± 10 min. The rapid‐removal phase was sensitive to disturbances in the neuronal uptake of norepinephrine, the t1½ being prolonged by desipramine and lengthened in the patients with peripheral autonomic insufficiency. In contrast, the selective extraneuronal norepinephrine uptake blocker, cortisol, 500 mg intravenously, had no effect in normal subjects on either plasma norepinephrine clearance or the t1½ value. Neuronal uptake of norepinephrine contributes to the overall removal of norepinephrine from plasma. Extraneuronal uptake of norepinephrine could not be demonstrated at existing plasma norepinephrine concentrations.Clinical Pharmacology and Therapeutics(1981)29,12–20; do

ISSN:0009-9236    

DOI:10.1038/clpt.1981.3

年代:1981

数据来源: WILEY

摘要:

Verapamil plasma protein binding was studied in four groups of 12 subjects each: (1) normal subjects; (2) patients with moderate renal insufficiency and patients requiring dialysis; (3) patients 1 to 4 days after coronary artery surgery; and (4) patients undergoing cardiac catheterization. In normal subjects, plasma protein binding of verapamil was 89.6 ± 0.17% and was concentration independent over a range of 35 to 1,557 ng/ml, which includes the usual clinical plasma range. In normal subjects, plasma protein binding of verapamil was not affected by addition of its major metabolite, norverapamil, in ratios of 1.2 to 26.3 (norverapamil/verapamil) or by the addition of 10 µg of warfarin. The plasma protein binding of verapamil was not altered in the postsurgical state or in the dialysis patients. Verapamil protein binding was initially lower in the cardiac catheterization patients (x̄ = 86.34 ± 2.13%, p<0.001) than in normal subjects and was still lower (x̄ = 83.29 ± 3.04%, p<0.02) after heparinization. There was also a small increase in binding in the patients with renal insufficiency (p<0.05). Plasma protein binding of verapamil in mongrel dogs (x̄ = 90.7%) was of the same order. We found verapamil to be approximately 90% bound in man and dogs and not markedly changed by any of the conditions studied.Clinical Pharmacology and Therapeutics(1981)29,21–26; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1981.4

年代:1981

数据来源: WILEY

摘要:

Verapamil kinetics have been determined in liver disease (mainly in cirrhotic patients), in intensive‐care patients, and in healthy control subjects. Areas under the concentration‐time curves (AUCs) after intravenous 5‐mg and oral 80‐mg doses were used to calculate systemic blood clearance, intrinsic blood clearance, and bioavailability of verapamil in patients and to calculate apparent hepatic blood flow. Intravenous data showed that verapamil clearance was reduced in all patients with liver disease (x̄ = −66%), but intensive‐care patients were a more heterogenous group in which some patients had increases (five patients; x̄ = +72%) and others had decreases (two patients; x̄ = −57%) in verapamil clearance. The changes in clearance corresponded to changes in the half‐time for the β‐phase (t½β). Verapamil bioavailability is low, and in the intensive‐care patients and healthy subjects examined it ranged from 13% to 21%. There was considerable variation in liver disease subjects, in whom verapamil bioavailability ranged from 3.8% to 64%. The systemic clearance of verapamil correlated linearly with calculated apparent hepatic blood flow (r = 0.99; regression coefficient = 0.87). In the case of one liver patient the kinetic results could be used to confirm the clinical diagnosis of hepatic shunts. It is concluded that there are clinically significant changes in verapamil elimination in liver disease and in intensive‐care patients. For patients with normal hepatic vascular anatomy, these changes can be explained in terms of differences in hepatic blood flow.Clinical Pharmacology and Therapeutics(1981)29,27

ISSN:0009-9236    

DOI:10.1038/clpt.1981.5

年代:1981

数据来源: WILEY

摘要:

The bioavailability of oral, sublingual, and chewable tablets of erythrityl tetranitrate (ETN) was evaluated in 15 normal men. In a randomized, complete crossover investigation with nitroglycerin and placebo controls, drug‐induced changes in the diastolic amplitude response intensity were measured with a digital plethysmogram. Values for area under the response intensity curve (AUC), maximum response intensity (Imax), and time lapse from dosing to peak response (tmax) were obtained by computer processing and converted to intensity values and AUC segments for specific time intervals. Sublingual nitroglycerin induced a response (p<0.05) from placebo within the first hour. Although somewhat slower in reaching peak intensity, all forms of ETN induced significant responses over placebo (p<0.05) for 2 hr, with oral (swallowed) ETN different for 6 hr. Our results indicate that all the ETN dosage forms were bioavailable, with the longest duration of effect by the oral form.Clinical Pharmacology and Therapeutics(1981)29,35–39; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1981.6

年代:1981

数据来源: WILEY

摘要:

Potentially serious cardiovascular changes occur in alcoholics as a result of carbimide‐ethanol reactions (CERs). Hypotension and tachycardia often occur when blood acetaldehyde levels increase. Hypotension with bradycardia can also occur secondary to vagal stimulation, the result of retching or vomiting. Conservative procedures (e.g., modified Trendelenburg's position) are usually effective in reversing the hypotension but in severe reactions active treatment (intravenous fluids, O2, and drugs) may be indicated. Three case reports are presented to illustrate cardiovascular responses during CERs; for comparison, changes for one subject during a disulfiram reaction are also presented. Caution is recommended in screening alcoholics before treatment with carbimide or disulfiram so as to rule out cardiovascular, hepatic, or renal diseases.Clinical Pharmacology and Therapeutics(1981)29,40–46; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1981.7

年代:1981

数据来源: WILEY

摘要:

The elimination half‐life (t½E) of lithium carbonate in red blood cells, plasma, and urine was measured in 30 patients hospitalized for primary affective disorder. Duration of Li treatment at time of sampling was found to have a direct effect on lengthening time course. Patients on their initial course of Li had the lowest t½s: 1.12 (urine), 1.28 (plasma), and 1.22 days (red blood cells); those less than 1 yr on Li had intermediate values: 1.85, 1.65, and 1.75 days; and those more than 1 continous year on Li had the longest mean t½s: 2.40, 2.43, and 2.24 days. These results for urine (p<0.01) and plasma (p<0.05) are further evidence that Li may stimulate the production of an endogenous regulator of Li efflux. This regulator may prove to be an important factor in planning of long‐term Li prophylaxis.Clinical Pharmacology and Therapeutics(1981)29,47–50; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1981.8

年代:1981

数据来源: WILEY

摘要:

Toxic electrophilic metabolites of acetaminophen are detoxified by conjugation with glutathione. Cellular glutathione content of patients with glutathione synthetase deficiency (5‐oxoprolinuria) is 10% to 20% of normal. These patients might be at increased risk for acetaminophen toxicity. The hypothesis was tested by challenging lymphocytes from normals and a patient with glutathione synthetase deficiency in vitro with acetaminophen metabolites generated by a mouse hepatic microsomal drug‐metabolizing system. For toxicity to be manifested in normal cells, glutathione content had to be depleted to<20% of control values at high acetaminophen concentrations (500 and 1,500 µg/ml), concentrations similar to blood levels in massive overdose and associated with hepatotoxicity in vivo. The patient's cells had only 14% of normal glutathione content, and exhibited more toxicity at 12.5 µg/ml acetaminophen (within the therapeutic range) as normals at maximum concentrations. The in vitro system may be of value in screening drugs potentially hazardous for glutathione synthetase–deficient patients, for exploring the role of glutathione in the detoxification of xenobiotics, and for examining glutathione protective mechanisms in patients with idiosyncratic cytotoxic drug reactions.Clinical Pharmacology and Therapeutics(1981)29,51–55; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1981.9

年代:1981

数据来源: WILEY

摘要:

Ten healthy adult subjects took a single daily dose of phenytoin for 9 days to achieve a steady‐state serum phenytoin concentration in the therapeutic range. While continuing on phenytoin, subjects took increasing doses of salicylate in a step‐wise fashion, each dose (325, 650, and 975 mg) given every 4 hr for 48 hr. Serum (total) and salivary (free) phenytoin concentrations and serum salicylate concentrations were measured before and after each dose level of salicylate. Protein binding displacement of phenytoin by salicylate occurred only at the highest salicylate dose. Serum phenytoin control levels fell from 13.5 ± 1.2 to 10.3 ± 0.8 µg/ml (p<0.01), salivary phenytoin levels rose from 0.97 ± 0.09 to 1.13 ± 0.12 µg/ml (p<0.05), and phenytoin free fraction (salivary/serum ratio) increased from 7.14 ± 0.34% to 10.66 ± 0.57% (p<0.01) in the highest salicylate dose periods. There was no difference in these parameters during low‐dose or intermediate‐dose salicylate therapy. Linear‐regression analysis failed to show a relationship between serum salicylate concentration and serum or salivary phenytoin concentration. Although high‐dose salicylate induced protein binding displacement of phenytoin, it is unlikely that this is of clinical importance since the rise (16%) in the free (salivary) phenytoin concentration was small. Serum total phenytoin concentration may fall during salicylate therapy but the dose of phenytoin should not be altered unless there are overt signs of toxicity.Clinical Pharmacology and Therapeutics(1981)29,56–60; do

ISSN:0009-9236    

DOI:10.1038/clpt.1981.10

年代:1981

数据来源: WILEY