摘要:

We describe a variation on an approach to simultaneous modeling of pharmacokinetics (PK) and pharmacodynamics (PD). Both approaches model the often‐observed time lag between plasma drug concentration (Cp) and drug effect (E) in non‐steady‐state experiments by postulating an E site whose concentration (Ce) is kinetically linked to Cp by a first‐order process. With the linking model, the time lag can be removed from the data and the underlying concentration‐response (Ce‐E) relationship can be estimated. The original method requires the analyst to postulate a particular parametric form for the Ce‐E model, whereas ours does not. It estimates the rate constant of the linking model as the value that causes the hysteresis curve (Ce vs E points connected in time order) to collapse to a single curve that represents the (empirical) Ce‐E relationship. The method is presented as an algorithm and is tested by means of simulation and a real‐world example. The results suggest that the method can faithfully estimate the Ce‐E curve for a variety of PD models and degrees of experimental error when its basic assumption of time‐invariant PD holds.Clinical Pharmacology and Therapeutics(1984)35, 733–741; d

ISSN:0009-9236    

DOI:10.1038/clpt.1984.104

年代:1984

数据来源: WILEY

摘要:

Kinetics and pharmacologic effects of three formulations of nifedipine were examined in six healthy young men in a crossover design. Each subject received intravenous nifedipine, 0.015 mg/kg body weight, 20 mg in a capsule, and 20 mg in a slow‐release tablet. Changes in heart rate (HR), blood pressure, heart dimensions, and plasma norepinephrine levels (PNE) were examined serially. Plasma concentrations of nifedipine (Cp) and urinary metabolite concentrations were measured by liquid chromatography. After intravenous injection the elimination t½ was 1.7 ± 0.4 hr, systemic clearance was 26.7 ± 5.4 l/hr, and volume of distribution was 0.8 ± 0.2 l/kg. After the capsule, Cprose rapidly, to a maximum concentration (Cmax) of 117 ± 15 ng/ml at a maximum time (tmax) of 1.4 ± 0.5 hr. After the sustained release tablet tmaxwas 4.2 ± 0.7 hr and Cmaxwas 26 ± 10 ng/ml. Nifedipine bioavailability was 56% ± 25% for the capsule and 52% ± 13% for the tablet, but there were large interindividual differences. Urinary excretion was 58% ± 13% 24 hr after intravenous injection, and after 32 hr was 55% ± 13% after capsules and 32% ± 8% after tablets. HR increased briefly after intravenous injection and after capsules (15 to 20 bpm), but not significantly after tablets. Diastolic blood pressure (DBP) fell briefly after capsules (8 to 10 mm Hg), but there was a sustained effect after tablets. Cardiac dimensions were unchanged. PNE levels paralleled plasma drug levels in the three experiments. There was a hyperbolic correlation between nifedipine Cpand changes in DBP (r2= 0.86), with a minimal effective concentration of about 15 ng/ml. It is concluded that nifedipine kinetics correlate directly with the effect on blood pressure and HR. Side effects from a high Cmaxcan be avoided with the tablet. It is likely that twice‐daily dosing will induce a continued effect.Clinical Pharmacology and Therapeutics(1984)35, 742–749; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1984.105

年代:1984

数据来源: WILEY

摘要:

Digoxin doses required to maintain therapeutic serum concentrations rose substantially in two patients dependent on dialysis with the commencement of rifampin therapy. When rifampin was discontinued, doses fell to requirements before rifampin. Serum digoxin concentration may fall to ineffective levels with rifampin therapy and rise to potentially toxic levels when rifampin is discontinued.Clinical Pharmacology and Therapeutics(1984)35, 750–754; doi:10.1038/clpt.1984.1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.106

年代:1984

数据来源: WILEY

摘要:

Our objective was to determine the kinetics of (+)‐ and (–)‐propranolol after intravenous doses of racemic drug. Five normal subjects received 0.1 mg/kg of a pseudoracemate of propranolol that consisted of deuterium‐labeled (+)‐propranolol and unlabeled (–)‐propranolol. Plasma concentrations of (+)‐ and (–)‐propranolol as measured by gas chromatography‐mass spectrometry demonstrated enantiomeric differences in systemic clearance (Cls) [(+)‐propranolol, 1.21 ± 0.15 l/min; (–)‐propranolol, 1.03 ± 0.12 l/min; P<0.01] and apparent volume of distribution (Vd) [(+)‐propranolol, 4.82 ± 0.34 l/kg; (‐)‐propranolol, 4.08 ± 0.33 l/kg; P<0.001], but no difference in distribution or elimination t½s (t½β 3.5 hr). The higher Clsof (+)‐propranolol suggests stereoselective hepatic elimination. The higher apparent Vd of (+)‐propranolol is mainly related to its lower plasma binding [(–)‐propranolol, 20.3 ± 0.8% unbound; (–)‐propranolol, 17.6 ± 0.7% unbound; P<0.001]. There was no stereoselective uptake by red blood cells. These findings demonstrate that multiple stereoselective mechanisms are involved in the disposition of propranolol and determine the access of the drug to active sites.Clinical Pharmacology and T

ISSN:0009-9236    

DOI:10.1038/clpt.1984.107

年代:1984

数据来源: WILEY

摘要:

We examined echocardiographically in a single‐blind crossover trial the circulatory effects of an inhaled selective β2‐adrenergie bronchodilator, fenoterol. Eight healthy subjects were studied on the first and fourteenth day after randomly assigned therapy with either no drug or 400 μg fenoterol by metered dose inhaler four times a day. Heart rate (HR) and systolic (SBP) and diastolic (DBP) blood pressure responses to fenoterol were small (X± SE; HR: +4 ± 1.3 bpm; SBP: +6 ± 1.3 mm Hg; DBP: —3 ± 1.4 mm Hg). In contrast, mean cardiac output increased 26% (1.1 ± 0.2 l/min), accompanied by an 18% fall in total peripheral vascular resistance (–6 ± 1.3 U), a 16% increase in stroke volume (+12 ±2.5 ml), and an 18% increase in the mean velocity of circumferential shortening (+0.2 ± 0.04 els). Responses varied widely among subjects; maximum observed increase in cardiac output was 117% (+5.48 l/min) in one subject. There was no evidence to suggest development of tolerance to these hemodynamic effects, as the response of measured variables did not differ after 2 wk of regular fenoterol therapy. We conclude that selective β2‐bronchodilators are not without potential for hemodynamically significant effects when taken by metered inhalers in recommended therapeutic doses and that the magnitude of such effects is underestimated when measured by HR and blood pressure changes.Clinical Pharmacology and Therapeutics(1984)35, 762–767; do

ISSN:0009-9236    

DOI:10.1038/clpt.1984.108

年代:1984

数据来源: WILEY

摘要:

The antihypertensive effects of nitrendipine were evaluated in 12 subjects with hypertension, one of whom could not tolerate the drug for more than 3 days; hence hemodynamics were studied in the 11 subjects who were treated for 2 wk. In one patient taking 40 mg twice a day, blood pressure reduction was associated with a hemodynamic pattern of hyperkinetic circulation. Of the other 10 subjects, all of whom were taking 20 mg twice a day, two did not respond, but 8 had significant reduction in mean arterial pressure (136 ± 4.3 to 106 ± 3.2 mm Hg) resulting from a decrease in total peripheral resistance (52 ± 3.7 to 35 ± 2.6 U · m2). Changes in cardiac output, heart rate, and cardiopulmonary volume varied widely among subjects, such that average changes did not attain significance. Heart rate and cardiopulmonary volume, however, changed in the same direction, which suggests that the alterations in both were related to the degree of reflex sympathetic stimulation induced by nitrendipine. Plasma renin activity (PRA) increased during treatment (2.6 ± 1.0 to 9.3 ± 4.1 ng/ml/hr), whereas the increase in plasma aldosterone (PA) levels did not attain significance (13.7 ± 1.6 to 21.5 ± 4.5 ng/dl). As a result, PA/PRA decreased (16.1 ± 4.9 to 9.4 ± 2.6). These results suggest that calcium entry blockade might have interfered with steroidogenesis, thus blunting the effect of increased PRA. Finally, blood pressure response to nitrendipine in the whole group correlated inversely with pretreatment PRA (r = −0.88), suggesting greater activity of the drug in low‐renin hypertension.Clinical Pharmacology and Therapeutics(1984)35, 768–775; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.109

年代:1984

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1984)35, 775–775; doi:10.1038/clpt.1984.1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.110

年代:1984

数据来源: WILEY

摘要:

The relative chronotropic and inotropic activity of preferential β1‐ and β2‐ adrenoceptor Stimulation was investigated in seven healthy male subjects in a randomized within‐subject, single‐blind study. Two doses of β1selective agonist prenalterol (1 mg/hr or 2 mg/hr) and of β2‐selective agonist salbutamol (300 µg/hr or 600 µg/hr) were infused intravenously in four separate sessions, with intervals of at least 48 hr between sessions. At each session cuff blood pressure and heart rate (HR) were measured and some hemodynamic information on the inotropic state were derived by echocardiography. Both prenalterol and salbutamol induced increases in HR, but tachycardia was greater after salbutamol, whereas the positive inotropic response to β‐stimulation was greater after prenalterol. At comparable HR rises (prenalterol, from 66.0 ± 5.5 to 72.2 ± 4 bpm; salbutamol, from 64.6 ± 6 to 70.0 ± 7 bpm), inotropic response seemed to be greater after prenalterol than after salbutamol (systolic blood pressure [SBP]: 133.5 ± 8 and 120.7 ± 8 mm Hg; mean velocity of circumferential fiber shortening [Vcf]: 1.54 ± 0.13 and 1.31 ± 0.12 c/s; ejection fraction [EF]: 72.4% ± 5% and 69.5% ± 4%; stroke index: 47.4 ± 4 and 41.7 ± 3 ml/m2). In presence of a chronotropic effect (HR from 64.6 ± 6 to 70.0 ± 7 bpm), the low salbutamol dose did not induce any changes in the indices of inotropism (SBP: from 119.2 ± 6 to 120.7 ± 8 mm Hg; mean Vcf: from 1.28 ± 0.11 to 1.31 ± 0.12 e/s; EF: from 68.1% ± 5% to 69.5% ± 4%; stroke index: from 40.2 ± 3 to 41.7 ± 3 ml/m2. On prenalterol, HR increases were accompanied by changes in all the indices of inotropism. Results would appear consistent with animal data in suggesting some heterogeneity of cardiac β‐adrenergic receptors. Inotropic response to β‐stimulation would appear to be mediated mostly by β1‐ adrenoceptors, whereas β1‐ and perhaps β2‐ adrenoceptors share a mediating action on chronotropic response to cardiac β‐adrenoceptor stimulation.Clinical Pharmacology a

ISSN:0009-9236    

DOI:10.1038/clpt.1984.111

年代:1984

数据来源: WILEY

摘要:

A single oral dose of 300 mg labetalol was given to 10 subjects with uncomplicated primary hypertension; its effects on blood pressure, heart rate (HR), plasma renin activity (PRA), and plasma concentration of catecholamines and of their major metabolites, octopamine (OTP), and dopamine‐β hydroxylase (DbH) were investigated. Although HR did not change after dosing, both systolic and diastolic blood pressure decreased in 2 hr and remained below control up to 12 hr. There was symptomatic orthostatic hypotension in two subjects in the first 2 hr after dosing. PRA decreased in the first 2 hr and followed a gradual rise that became significant at 24 hr. Although DbH did not change, plasma concentrations of norepinephrine (NE) and its major metabolites and of OTP increased between 2 and 4 hr after dosing and remained elevated up to 12 hr. There was no correlation between change in blood pressure and control levels or changes of PRA or NE concentrations.Clinical Pharmacology and Therapeutics(1984)35, 782–787; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1984.112

年代:1984

数据来源: WILEY

摘要:

Potassium balance was followed in 12 subjects with hypertension during treatment either with timolol and hydrochlorothiazide or with timolol, hydrochlorothiazide, and amiloride. Subjects treated with the beta‐blocker and thiazide developed potassium depletion, which was prevented by concomitant treatment with amiloride. Thiazide augments timolol‐induced potassium loss and it is suggested that the renal handling of potassium is changed by other mechanisms. The decrement in potassium loss during concomitant amiloride treatment cannot be explained.Clinical Pharmacology and Therapeutics(1984)35, 788–791; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1984.113

年代:1984

数据来源: WILEY