The influence of infusion rate on the pharmacokinetics and haemodynamic effects of nisoldipine in man.

Harten, J. Van; Brummelen, P. Van; Zeegers, R. R. E. C. M.; Danhof, Meindert; Breimer, D. D.

doi:10.1111/j.1365-2125.1988.tb05257.x

Cited by 24 publications

(5 citation statements)

References 17 publications

(19 reference statements)

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“…This was suggested to be caused by stronger counter‐regulation in baroreceptor reflex activation of the higher infusion rate. Similar observations have been reported for other calcium antagonists such as nisoldipine [ 22] and other vasodilator agents such as prazosin [ 23]. On the other hand, a slow and constant drug input rate has been found disadvantageous for the anti‐anginal effect of nitrates, because tolerance occurs after several doses [ 24].…”

Section: Discussionsupporting

confidence: 69%

The influence of drug input rate on the development of tolerance to frusemide

Wakelkamp

Alván

Scheinin

et al. 1998

Brit J Clinical Pharma

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Aims Understanding the impact of drug input rate on its pharmacokineticpharmacodynamic relationship may lead to a more optimal drug therapy. The aim of the present study was to investigate the influence of the rate of administration on tolerance development to frusemide, by giving the drug at four different infusion rates. Methods Eight healthy volunteers were given 10 mg of frusemide on four different occasions, as a constant-rate intravenous infusion during 10, 30, 100 and 300 min, respectively. Urinary volume and contents of frusemide and sodium were measured in samples collected over 8 h. Results The four different infusion rates systematically influenced the frusemide excretion rate versus diuretic and natriuretic response relationship. Counter-clockwise hysteresis occurred for the most rapid infusion rate, whereas a progressive clockwise hysteresis was observed for the slower infusions, indicating development of tolerance. For each subject, diuresis and natriuresis were modeled for all four treatments simultaneously, using a feedback tolerance model. It was not possible to describe the data using a model without tolerance. The time course of tolerance development showed remarkable differences between the infusion rates. The intensity of maximum tolerance development was significantly less for the slowest infusion rate compared with the more rapid infusions and it appeared significantly later. However, no differences in diuretic or natriuretic response were found between the treatments. Conclusions The direction of the hysteresis loop is dependent on the input rate of frusemide. After the administration of a single low dose of frusemide, the time course of tolerance, rather than the integrated time course of tolerance, is influenced by the drug input rate.

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Section: Discussionsupporting

confidence: 69%

The influence of drug input rate on the development of tolerance to frusemide

Wakelkamp

Alván

Scheinin

et al. 1998

Brit J Clinical Pharma

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“…Indeed, a similar observation had been made more than 30 years ago when using hydralazine-type vasodilatators [7,8]. More recent studies with nitrendipine [9] and nisoldipine [10] have confirmed the phenomenon. New galenic forms have been employed, therefore, in the hope of reducing the unwanted effects.…”

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confidence: 51%

Influence of input rates on (�)-isradipine haemodynamics and concentration-effect relationship in healthy volunteers

Carrara

Porchet

Dayer

1994

Eur J Clin Pharmacol

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Since the magnitude of the response to a drug may depend upon the drug input rate, the concentration-effect relationship of the new dihydropyridine (+/-)-isradipine was investigated using different administration modalities. Ten normotensive healthy volunteers were given, double-blind and in a crossover fashion, isradipine as a 1 mg iv infusion, 5 mg oral solution, 5 mg standard tablet, 10 mg slow release formulation, and a placebo. Blood pressure, heart rate, and plasma isradipine concentrations were recorded for 24 h. The maximal fall in diastolic blood pressure was similar after the infusion (-11.40 mmHg), the oral solution (-15.20 mmHg), and the standard tablet (-12.50 mmHg). In healthy volunteers the slow release form had no significant effect on blood pressure. The concentration-effect plots showed an increasing slope in the order infusion, solution, and table, and anticlockwise hysteresis. This was partly due to marked heart rate counter-regulation, the corresponding mean maximal heart rate increases being 24, 19, and 17 beats.min-1. The pronounced counter-regulation of the heart rate implies that a slow isradipine input rate would be more effective in decreasing blood pressure.

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“…The present study is a sequel to previous studies (van Harten et al, 1988b, c), in which it was found that liver blood flow appeared to be increased by nisoldipine only during its absorption phase. It was also found that the absolute value of calculated systemic availability was positively correlated with the observed increase in apparent liver blood flow during the absorption Figure 2 Relationship between increase in liver plasma flow (dQp) during the absorption phase of nisoldipine and the calculated AUC due to the increase in liver flow (dAUC), based on the mean value of AUC (AUCav) on days 1 and 8. phase of nisoldipine (van Harten et al, 1988c).…”

Section: Discussionsupporting

confidence: 67%

The contribution of nisoldipine‐induced changes in liver blood flow to its pharmacokinetics after oral administration.

Harten

Burggraaf

Danhof

et al. 1989

Brit J Clinical Pharma

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1. The pharmacokinetics of nisoldipine (10 mg) was assessed in 10 healthy subjects after single dose and multiple dose oral administration. Apparent liver blood flow was measured, using ICG before and during the absorption phase of nisoldipine. 2. Apparent liver blood flow was increased both on acute and short‐term administration of nisoldipine, basal flow being lower on multiple dosing than on acute administration (P less than 0.02). 3. A positive relationship was found between the increase in apparent liver blood flow during absorption of nisoldipine and the flow‐dependent part of the total AUC of nisoldipine. 4. The findings of this study indicate that a variable liver blood flow response during the absorption phase of nisoldipine contributes to the pharmacokinetic variability of the drug, both on acute and multiple dose administration.

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The influence of infusion rate on the pharmacokinetics and haemodynamic effects of nisoldipine in man.

Cited by 24 publications

References 17 publications

The influence of drug input rate on the development of tolerance to frusemide

The influence of drug input rate on the development of tolerance to frusemide

Influence of input rates on (�)-isradipine haemodynamics and concentration-effect relationship in healthy volunteers

The contribution of nisoldipine‐induced changes in liver blood flow to its pharmacokinetics after oral administration.

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