摘要:

Plasma and erythrocyte digoxin concentrations from patients on digoxin maintenance therapy were measured and the results from patients with toxic and those with nontoxic drug levels were compared. Digoxin cumulation and release in plasma and erythrocyte were also studied. Our results indicate that erythrocyte digoxin concentration may be useful in distinguishing toxic and nontoxic drug levels.Clinical Pharmacology and Therapeutics(1982)31,541–547; doi:10.1038/clpt.1982.

ISSN:0009-9236    

DOI:10.1038/clpt.1982.75

年代:1982

数据来源: WILEY

摘要:

Cardioactivity due to elevated serum digoxin concentration (SDC) after quinidine (Q) and digoxin (D) was evaluated in six healthy subjects by means of measurement of systolic time intervals (STIs). Each subject randomly received basic treatments with 0.2 mg D and placebo (PL1). Randomized coadministrations with Q (1 gm/day), sparteine (SP) (0.8 gm/day), and placebo (PL2) were given for 7‐day periods. A steady‐state dose of 0.4 mg D was added. Mean SDC increased from 0.48 nglml during 0.2 mg D + PL2to 1.13 ng/ml on 0.2 mg D + Q (P<0.05); it was unchanged by SP. On 0.4 mg D there were further shortenings of STIs compared to those on 0.2 mg D + PL2. Q markedly prolonged STIs; the SP effects were similar but less pronounced. When given with Q or SP, the effect of D was obscured by opposing inotropic properties; consequently, despite increasing SDC, measurable STIs were unchanged. The true glycoside effect was determined by comparing the effects of the pure antiarrhythmic to those of the antiarrhythmic with D. These calculations showed that the glycoside effect of the elevated SDC during Q + D dosing was much the same as the effect of 0.4 mg D.Clinical Pharmacology and Therapeutics(1982)31,548–554; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1982.76

年代:1982

数据来源: WILEY

摘要:

It has recently been reported that the β‐adrenergic receptor‐blocker acebutolol accelerates the development of antinuclear antibodies (ANAs) in hypertensive patients. We examined data from over 1500 hypertensive patients to determine whether this effect is associated with other beta blockers. Groups of patients treated with acebutolol, atenolol, labetalol, and pindolol all displayed increased development of ANAs relative to patients on other medication. When patients taking methyldopa (a drug associated with a high ANA incidence) were excluded from the analysis, only acebutolol retained an association (P<0.001) with ANA production. Sequential studies to assess the development of AN As in patients during the course of beta‐blocker treatment revealed a similar pattern. With methyldopa patients excluded, the fraction of patients developing AN As was less than 10% for all but atenolol (10.9%), labetalol (13.8%), and acebutolol (33%). Thus, although some of the beta blockers may be associated with an increase in ANA incidence, the dramatic effects of acebutolol do not appear to be a group property.Clinical Pharmacology and Therapeutics(1982)31,555–558; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1982.77

年代:1982

数据来源: WILEY

摘要:

Alterations in propylthiouracii (PTU) disposition after long‐term use in patients treated for alcoholic liver disease (ALD) have not been reported. We gave PTU (3.3 mg / kg / day intraperitoneally) for 24 days to naive male Sprague‐Dawley rats (n = 10). Clearance of PTU in these animals (1.11 ± 0.04 ml / min / kg, x̄ ± SEM) was slightly less than in controls (1.28 ± 0.05 ml/min/kg, n = 8, P = 0.02) as a consequence of drug‐induced hypothyroidism (thyroid weight in PTU‐treated rats = 78.0 ± 7.2; controls = 29.6 ± 2.1 mg/kg, P<0.01). PTU clearance in thyroidectomized rats (0.74 ± 0.04 ml/min/kg, n = 12; thyroid‐stimulating hormone [TSH] = 3.3 ± 0.2; μIU/ml) was less (P<0.01) than in sham‐operated controls (1.47 ± 0.12 ml/min/kg; n = 9; TSH = 1.9 ± 0.2 μIU/ml). Neither plasma free fraction (25.0 ± 0.8%) nor apparent volume of distribution (0.72 ± 0.02 l/kg) in thyroidectomized rats differed from control values (26.4 ± 1.4%, 0.73 ± 0.02 l/kg). In ALD patients (four men; two women) tested with PTU (300 mg IV) before and after PTU therapy (150 mg b.i.d. orally) for 28 days, TSH rose from 3.6 ± 1.0 to 7.0 ± 2.6 μIU/ml (P = 0.03), but free PTU clearances rose in all patients (range 2.2% to 48.4%, P = 0.03). Free clearance before treatment was 1047 ± 131 and after treatment it was 1223 ± 139 ml/min; in 14 healthy subjects it was 1454 ± 86 ml/min. The alteration in clearance correlated positively (r = 0.91, P<0.02) with the severity of disease as assessed by a composite clinical and laboratory index; in the more severely diseased patients there was the most alteration in both clearance and severity of ALD. There are two opposing events that determine net PTU disposition; biochemical hypothyroidism reduces PTU clearance, but improvement in hepatic function overcomes such an effect. The net increase in PTU free clearance reduces efficacy during long‐term dosing.Clinical Pharmacology and Therapeutics(1982)

ISSN:0009-9236    

DOI:10.1038/clpt.1982.78

年代:1982

数据来源: WILEY

摘要:

Abrupt withdrawal of some beta‐adrenergic blockers has resulted in clinical syndromes suggestive of adrenergic hyper sensitivity that may be due to an adaptive increase in cardiac beta‐receptor responsiveness. It was postulated that the partial agonist activity of pindolol might limit enhanced responsiveness of cardiac beta receptors and prevent or diminish withdrawal manifestations. Pindolol was given to 10 hypertensive patients in doses of 10 mg b.i.d. for at least 4 wk, then abruptly replaced with placebo for 20 days. Cardiac chronotropic responsiveness to isoproterenol was decreased on pindolol and gradually returned to normal over 10 to 20 days with no evidence of enhanced responsiveness. In contrast, both resting and exercise heart rate showed rebound increase in responsiveness between the second to sixth day after pindolol (P<0.05). Resting and exercise blood pressures gradually rose to stable values without rebound. Plasma norepinephrine and epinephrine and serum thyroxine and triiodothyronine did not change. These data show that abrupt withdrawal of pindolol after long‐term dosing leads to transient cardiac hyperresponsiveness of resting and exercise heart rate at the same time as persistent cardiac hyporesponsiveness to isoproterenol. These opposite effects may indirectly reflect different effects of pindolol on subsets of cardiac beta‐adrenergic chronotropic receptors.Clinical Pharmacology and Therapeutics(1982)31,564–571; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1982.79

年代:1982

数据来源: WILEY

摘要:

Trimazosin was given for periods of at least 6 mo to 25 patients with mild to moderate essential hypertension. In doses of 300 to 900 mg daily trimazosin alone led to blood pressure control (supine diastolic blood pressure<90 mm Hg with a fall of at least 10 mm Hg) in 16 patients (64%). Despite the decrements in blood pressure there were no changes in body weight or creatinine clearance. There were also no changes in plasma renin activity or urinary aldosterone excretion rate. Although patients with high control renin values appeared to have greater blood pressure decreases than those with low renin values, responsiveness to treatment was not associated with consistent effects of trimazosin on the renin‐angiotensin system. Trimazosin induced a small decrease in plasma total cholesterol concentration. In seven patients whose blood pressures were not controlled by trimazosin alone, the addition of polythiazide led to decreased blood pressure and in five control of pressure was achieved. Thus, trimazosin is an effective antihypertensive when given by itself or in combination with a diuretic. Its mechanism of action has not been established, but its ability to induce vasodilation without concomitant sodium retention or stimulation of the renin axis may be an important factor in its effectiveness.Clinical Pharmacology and Therapeutics(1982)31,572–578; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1982.80

年代:1982

数据来源: WILEY

摘要:

The kinetics and the effects on the ventilatory function peak expiratory flow rate (PEFR) of a single 600‐mg oral dose of theophylline were investigated in 46 adult patients with bronchial asthma (BA) and in 16 adult patients with chronic airflow obstruction (CAO). In the former, theophylline induced an early and potent broncho dilatation (60% rise in PEFR), the kinetics of which correlated with plasma concentration. Theophylline was also effective in patients with CAO, but the magnitude of its bronchodilator effect was less than in those with BA; this was despite plasma concentrations of much the same order. In adult patients with BA (but not with CAO) theophylline plasma levels and bioavailability are higher after simultaneous erythromycin dosing.Clinical Pharmacology and Therapeutics(1982)31,579–586; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1982.81

年代:1982

数据来源: WILEY

摘要:

Nine healthy subjects (7 men; 2 women) received single 20‐mg IV injections of 4‐aminopyridine (4‐AP). Six of the subjects received the same dose in the form of enteric‐coated tablets and four the same dose in uncoated tablets; treatments were at least 2 wk apart. Blood, saliva, and urine were assayed for 4‐AP using a high‐performance liquid chromatography. Kinetic analysis of serum concentrations after intravenous dosing resulted in the best fitting of a triexponential model in five and a biexponential model in four subjects. The apparent volume of distribution (V) was 2.6 ± 0.9 (mean ± SD) l/kg−1, the terminal half‐life (t½) 3.6 ± 0.9 hr, and the total serum clearance 0.61 ± 0.14 lhr−1kg−1. Saliva concentrations were higher than those in serum after 5 min, with a mean correlation coefficient of 0.989 (n = 5). The t½ and V calculated from serum and saliva concentrations were of the same order. The total urinary excretion of unchanged 4‐AP was 90.6 ± 7.8% after intravenous doses and 88.5 ± 4.8% after oral doses of enteric‐coated tablets. The bioavailability of the enteric‐coated tablets calculated from the area under the serum concentration curve (95 ± 29%) did not differ from that calculated from urinary excretion (98 ± 8%). Protein binding of 4‐AP was found to be negligible. Biotransformation is unlikely.Clinical Pharmacology and Therapeutics(198

ISSN:0009-9236    

DOI:10.1038/clpt.1982.82

年代:1982

数据来源: WILEY

摘要:

Acyclovir (ACV) is almost entirely eliminated by the kidneys and has a terminal plasma half‐life (t½) of 2 to 3 hr in subjects with normal renal function. To determine the drug's kinetics and tolerance in patients with severe renal failure, six anuric subjects on long‐term hemodialysis were studied. Each received a 1‐hr infusion of 2.5 mg/kg IV ACV. The kinetics are well described by a two‐compartment open model. ACV terminal plasma t½ and the total body clearance were 19.5 ± 5.9 hr (x̄ ± SD) and 28.6 ± 9.5 ml / min / 1.73 m2. Peak (end of infusion) and 8‐ and 24‐hr plasma ACV concentrations were 37.5 ± 23.3, 10.3 ± 2.9, and 6.4 ±2.4 μM. Approximately 48 hr after the start of the infusion the subjects were hemodialyzed for 6 hr. The pre‐ and posthemodialysis ACV plasma levels were 2.74 ± 1.38 and 1.11 ± 0.60 μM. The terminal ACV t½ during hemodialysis was 5.7 ± 0.85 hr. During hemodialysis paired arterial and venous samples showed that ACV was readily dialyzed, with a mean coefficient of extraction of 0.45 ± 0.12. The dialysis clearance of acyclovir was 81.8 ± 12.6 ml / min. None of the patients had any ACV‐related adverse effects. Since ACV elimination is markly reduced in end‐stage renal failure and because ACV is readily hemodialyzible, dosage modifications are needed to avoid cumulation and to replace dialyzed drug.Clinical Pharmacology and Therapeutics(1982)3

ISSN:0009-9236    

DOI:10.1038/clpt.1982.83

年代:1982

数据来源: WILEY

摘要:

Cefsulodin kinetics were determined after a 500‐mg dose to normal subjects and patients with varying degrees of renal insufficiency, including those requiring hemodialysis. Elimination kinetics were described by a two‐compartment model. Steady‐state volume of distribution was 0.26 l/kg regardless of renal function. When glomerular filtration rate (GFR) was more than 80 ml/min, elimination half‐life (t½) was 1.9 hr, total body clearance (ClT) was 2.01 ml/kg/min, and renal clearance (ClR) was 1.09 ml/kg /min. When GFR ranged from 79 to 53 ml/min, t½ was 2.9 hr, ClTwas 1.17 ml/kg/min, and ClRwas 0.65 ml/kg/min. In subjects with moderate renal failure in whom GFR was 32 to 22 ml/min, t½ was 5.7 hr, ClTwas 0.66 ml/kg/min, and ClRwas 0.26 ml/kg/min. In anuric patients t½ was 13.0 hr and ClTwas 0.19 ml/kg/min or 9.5% of ClTin normal subjects. There was a linear relationship between ClTand GFR such that ClT= 0.19 + 0.017 GFR (r = 0.95). During hemodialysis the average plasma flow was 122 ml/min, dialyzer plasma clearance was 50.9 mllmin, plasma drug concentration was reduced by 60%, and t½ fell to 2.1 hr. After dialysis the elimination rate appeared to return to that in nondialysis studies. Therefore, renal failure reduces the ClTof cefsulodin. In hemodialysis patients the maintenance dose of cefsulodin should be reduced to 10% of normal and 60% of the dose should be given after hemodialysis.Clinical Pharmacology and Therapeutics(1982)31,602–608; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1982.84

年代:1982

数据来源: WILEY