摘要:

We report on changes in echocardiographic parameters of left ventricular muscle mass in 20 hypertensive patients during short‐term therapy with hydrochlorothiazide. In the group as a whole, blood pressure fell, but septal thickness and posterior wall thickness did not change. Septal thickness decreased in nine patients, and in all of these patients calculated left ventricular cross‐sectional area also decreased. Septal thickness did not change or increased in 11 patients and in only one of these patients did cross‐sectional area increase. These increases in septal thickness usually were associated with decreases in left ventricular transverse dimension. We therefore conclude that the increases in left ventricular wall and septal thickness during diuretic therapy probably reflect an adaptive change of cardiac muscle tissue around a smaller left ventricle.Clinical Pharmacology and Therapeutics(1982)32,283–288; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1982.161

年代:1982

数据来源: WILEY

摘要:

The effects of the beta‐adrenoceptor blockers atenolol, metoprolol, pindolol, and propranolol on the ventilatory response to carbon dioxide rebreathing have been determined in a double‐blind randomized manner. Eight healthy, male, nonsmoking subjects received cumulative doses of each drug over a 10‐hr period. The effects of each drug on heart rate and carbon dioxide sensitivity were determined at intervals of 2 hr and were related to plasma concentrations of each drug. Maximum reduction of exercise heart rate was achieved with all four beta blockers and plasma concentrations were in the usual therapeutic range for these drugs. There was considerable intersubject and within‐subject variability in ventilatory responsiveness to inhaled carbon dioxide, but we were not able to discern any alteration in central sensitivity to increasing carbon dioxide concentrations.Clinical Pharmacology and Therapeutics(1982)32,289–294; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1982.162

年代:1982

数据来源: WILEY

摘要:

Altered concentrations of serum proteins often accompany malignant disease. The effect of these changes on drug binding was studied with lidocaine, a basic drug, and tolbutamide, an acidic drug. Patients with cancer had increased serum concentrations of the acute‐phase protein α1‐acid glycoprotein (AAG) and lowered serum concentration of albumin. In association with these changes lidocaine binding was increased at all concentrations studied (predialysis concentrations 2, 6, and 10 μg · ml−1) and that of tolbutamide was decreased at the highest concentration (200 μg · ml−1). Not all of the increase in lidocaine binding was explicable on the basis of increased serum AAG concentration. Estimation of binding parameters with a model with two independent sites showed increased affinity at the high affinity site in cancer patients with no change in the calculated number of binding sites. Therefore, in cancer there is increased lidocaine binding in association with increased AAG concentrations. We also record the novel observation of a change in the intrinsic properties of the high affinity binding site.Clinical Pharmacology and Therapeutics(1982)32,295–302; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1982.163

年代:1982

数据来源: WILEY

摘要:

Furosemide kinetics were studied in 25 patients with congestive heart failure. The elimination half‐life (t½) was longer and the elimination rate constant and the plasma clearance smaller in patients with advanced (n = 15) than in those with moderate (n = 10) failure. Furosemide kinetics with and without hydralazine were compared in eight patients with advanced heart failure. Furosemide t½ in patients receiving both drugs fell from 96 ± 16 to 81 ± 15 min (P<0.02), elimination rate constant increased from 0.0186 ± 0.0056 to 0.0214 ± 0.0068 min−1(P<0.05), and plasma clearance rose from 72.6 ± 18.5 to 88.1 ± 26.9 ml/min (P<0.01). Renal clearance rose from 45.4 ± 12.0 to 60.9 ± 19.0 ml/min (P<0.01) and creatinine clearance was unchanged. We conclude that hydralazine affects furosemide kinetics.Clinical Pharmacology and Therapeutics(1982)32,303–306; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1982.164

年代:1982

数据来源: WILEY

摘要:

The effects of Captopril (C) in doses of up to 450 mg/day, placebo (P), and hydrochlorothiazide (H) in doses of 50 to 100 mg/day were compared in double‐blind studies in 38 black patients. Mean blood pressure response to C was only slightly greater than to P (systolic response difference only). Mean blood pressure responses to H were greater than to C. Results were compared to available data on 185 white and black patients treated similarly. In white patients, response to C was greater than to P, but response to H was approximately equal to that to C. In black patients, results were of the same order as those reported here; the systolic response to C was greater than that to P and the response to H was greater than that to C. These data suggest that black and white patients differ in response to certain antihypertensive drugs.Clinical Pharmacology and Therapeutics(1982)32,307–312; doi:10.1038/clpt.1982

ISSN:0009-9236    

DOI:10.1038/clpt.1982.165

年代:1982

数据来源: WILEY

摘要:

The value of bretylium for long‐term therapy of arrhythmias is slight because of the almost universal development of orthostatic hypotension induced by adrenergic neuron blockade. Blockade of neurotransmission by bretylium depends on its uptake into adrenergic neurons by the norepinephrine pump. The effects of inhibiting the pump with protriptyline were evaluated in five patients with ventricular tachycardia (VT) resistant to conventional therapy but responsive to bretylium. Adrenergic blockade was assessed by measuring the venous reflex response (VRR) and change in blood pressure on standing. Before bretylium, VRR was present and standing blood pressure was normal. The patients received intravenous bretylium in increasing doses until VT was suppressed, at which time the VRR was blocked and all patients were bedridden due to orthostatic hypotension. The dosage of bretylium was tapered as oral treatment was begun and the dosage gradually increased to maintain VT suppression. Protriptyline was then given orally in slowly increasing doses in an attempt to reverse intolerable orthostatic hypotension. Five to 7 days later the VRR was restored and the blood pressure in the standing position returned toward normal, enabling the patients to become ambulatory. In these patients the antiarrhythmic efficacy of bretylium was not altered by protriptyline and was therefore not dependent on adrenergic neuron blockade. As bretylium was withdrawn and protriptyline continued, recurrence of arrhythmia established that protriptyline did not contribute to bretylium's antiarrhythmic efficacy. These findings do not, however, constitute sufficient evidence to support the routine application of this approach to therapy. Rather, it provides a pharmacologic rationale for more extensive evaluation of the safety and efficacy of the combination. The demonstration of dissociation between the antiarrhythmic and adrenergic effects of bretylium in man suggests that structural modification of the molecule might yield an antiarrhythmic drug free of undesirable effects on the adrenergic nervous system.Clinical Pharmacology and Therapeutics(1982)32,313–321; doi:10.1038/clpt.1982

ISSN:0009-9236    

DOI:10.1038/clpt.1982.166

年代:1982

数据来源: WILEY

摘要:

Single oral dose kinetics of nortriptyline and of its two major metabolites, conjugated and unconjugated 10‐hydroxynortriptyline, were studied in eight healthy subjects and 15 patients with chronic renal failure, five of whom were being treated with hemodialysis. Nortriptyline kinetics were unaltered, but the elimination of the metabolites was reduced in both groups of patients. In chronic renal failure the excretion of nortriptyline metabolites appeared to be the rate‐limiting step in nortriptyline elimination. Three depressed hemodialysis patients were treated with nortriptyline (75 mg at night) for 6 wk. The ratios of the steady‐state plasma concentrations of unconjugated 10‐hydroxynortriptyline to nortriptyline (0.74 to 2.30) were in the same range as those in a control group of depressed patients with adequate renal function (0.53 to 4.08) who were also receiving nortriptyline. Conjugated 10‐hydroxynortriptyline in renal failure patients was slow to reach steady‐state concentrations and these were 10 to 20 times as high as those of the control depressed patients. Conjugated 10‐hydroxynortriptyline in dialysis fluid during treatment showed that a mean 43 ± 7% (SD) of the dose was removed by a 10‐hr dialysis. Dialysis clearance of conjugated 10‐hydroxynortriptyline was 58 ± 8 (SD) ml min−1, but nortriptyline and unconjugated 10‐hydroxynortriptyline were not appreciably removed by dialysis. Hemodialysis is not likely to be of value in the management of acute nortriptyline poisoning.Clinical Pharmacology and Therapeutics(1982)32,322–329;

ISSN:0009-9236    

DOI:10.1038/clpt.1982.167

年代:1982

数据来源: WILEY

摘要:

Free platinum urinary excretion kinetics after a 30‐min infusion of 60 mg/m2IVcis‐diamminedichloroplatinum (C) were studied during 51 monthly courses of C therapy in 11 patients suffering from a variety of advanced malignancies. Each patient received half of his or her treatment course at 6:00 A.M. and 6:00 P.M. Initial treatment time was randomly assigned and subsequent treatment times were alternated. Each C infusion was accompanied by 4100‐ml 5% dextrose and 0.45% NaCl solution given intravenously. Evening C infusion resulted in greater urine output, lower peak urinary platinum concentrations, and lower areas under the curve of cisplatin concentration. While the normal circadian rhythm characteristics of body temperature were not altered by changing the C infusion time, the circadian rhythm characteristics of urine volume 1 mo after treatment were significantly disrupted by morning, but not by evening, C. We conclude: (1) that since the kinetics of certain drugs may be affected by the time of administration, kinetic studies should be performed and reported in a time‐qualified fashion, and (2) that it is reasonable to expect that, since kinetic parameters are important in determining drug toxicity and effect, these too may vary predictably during the day.Clinical Pharmacology and Therapeutics(1982)32,330–339; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1982.168

年代:1982

数据来源: WILEY

摘要:

Antipyrine clearance was measured during occupational exposure and after an exposure‐free interval of 3 wk in 26 spray painters, 44 workers in a herbicide‐producing (phenoxyacids) plant, and 10 pesticide‐exposed greenhouse gardeners. A control group of 39 workers were investigated simultaneously. A noninvasive simplified antipyrine clearance was used. Antipyrine clearance was greater by 15% in workers exposed to phenoxyacids and chlorophenols and 21% greater in pesticide‐exposed persons, but it was 15% less in workers exposed to spray paints compared to 3 wk after discontinuation of exposure. Clearance was unchanged in the control group examined at the same interval. Thus, the combined action of different spray paints, grinding dust, and cleaners may inhibit, and phenoxyacids, chlorophenols, and various pesticides may induce, the microsomal enzyme function. The workers had been exposed to the chemicals for years, but the change in antipyrine clearance apparently was reversible.Clinical Pharmacology and Therapeutics(1982)32,340–346; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1982.169

年代:1982

数据来源: WILEY

摘要:

A three‐way crossover study was undertaken in 10 healthy subjects to characterize the reported disulfiram‐like activity of moxalactam and to assess its influence on ethanol and acetaldehyde metabolism. On different occasions separated by at least 2 wk subjects were given in random order: 0.5 gm/kg ethanol orally, 0.5 gm/kg ethanol followed in 1 hr by 1.0 gm IV moxalactam, and 1.0 gm IV moxalactam every 8 hr for four doses followed by 0.5 gm/kg ethanol. Mean ethanol elimination rates of 13.1 ± 0.76, 10.1 ± 1.11, and 10.9 ± 1.06 mg/dl/hr (mean ± SEM) were observed in the three protocols, respectively. Corresponding mean estimated acetaldehyde clearance rates were 103.7 ± 15.55, 93.8 ± 13.79, and 97.3 ± 10.41 l/min (mean ± SEM). While no consistent moxalactam effect on ethanol or acetaldehyde elimination was observed, two subjects experienced mild disulfiram‐like reactions to ethanol after moxalactam pretreatment. In one subject this reaction was associated with markedly elevated blood acetaldehyde concentrations. We conclude that moxalactam pretreatment may induce a disulfiram‐like reaction after ethanol ingestion in some, probably due to inhibition of aldehyde dehydrogenase, and that alcoholic beverages are contraindicated in patients receiving moxalactam. We suggest, however, that such reactions will not occur when moxalactam is given after ethanol ingestion.Clinical Pharmacology and Therapeutics(1982)32,347–355; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1982.170

年代:1982

数据来源: WILEY