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Biomedical subjects

P Van Brummelen

Publications and source records attributed to P Van Brummelen.

At least 19 recordsLinked to original sources
PubMed1995

Pharmacokinetic-pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa.

1. Single oral doses of the catechol-O-methyltransferase (COMT) inhibitor tolcapone (10-800 mg) or placebo were administered simultaneously with a dose of levodopa/benserazide 100/25 mg to seven sequential groups of six healthy male subjects in a two-way crossover study. 2. Plasma concentrations of tolcapone, its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa (3-OMD) were determined in conjunction with COMT activity in erythrocytes. 3. The drug combination was well tolerated at all dose levels and there were no signs indicative of an increase in dopaminergic stimulation. 4. Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes in parallel with a dose-dependent decrease in the formation of 3-OMD. Tolcapone increased the area under the concentration-time curve and elimination half-life of levodopa. The maximum effects were obtained at a dose of about 200 mg when both parameters increased approximately twofold. The drug had no influence on the maximum concentration of levodopa. 5. Tolcapone was rapidly absorbed and eliminated with, on average, a tmax of 1.5 h and a t1/2 of 2.3 h. The drug showed dose-proportional pharmacokinetics, in contrast to 3-O-methyltolcapone whose formation was relatively decreased at higher doses. 6. Plasma concentrations of tolcapone correlated with inhibition of COMT activity in erythrocytes and suppression of 3-OMD levels, but not with changes in levodopa pharmacokinetics.

Adult↗
PubMed1993

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42-5892) in hypertensive patients.

1 Three double-blind, randomized, placebo controlled, multiple oral dose studies in patients with mild to moderate hypertension were performed to study tolerability, pharmacodynamics and pharmacokinetics of remikiren. Doses of 100-800 mg remikiren or placebo were given over 8 days to altogether 144 patient volunteers. In some cases (n = 46) single i.v. doses of 100 mg were administered 4 h after the last oral dose. Plasma remikiren concentrations, plasma renin activity and immunoreactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration-effect relationship was evaluated using population pharmacometric methods. 2 In most patients no distinct absorption and disposition phase could be identified, since plasma concentrations fluctuated widely over a period of approximately 10 h. Peak plasma concentrations (Cmax) were achieved within 0.25-2 h postdose. Mean Cmax values (on the first and last day of oral treatment) were in the magnitude of 4-6 ng ml(-1) (200 mg), 23-27 ng ml(-1) (300 mg), 65-83 ng ml(-1) (600 mg) and 47-48 ng ml(-1) (800 mg). Cmax and AUC0-t values were clearly different for different doses within single studies. Intersubject variability in pharmacokinetic parameters was much higher than intrasubject variability. No drug accumulation in plasma was apparent. 3 Inhibition of the angiotensin I production rate correlated well with plasma drug concentrations according to the Emax-model. An IC50 value of 0.5 ng ml(-1) (0.8 nM) was estimated. No correlation between blood pressure changes on the last day of oral treatment and either plasma remikiren concentrations or plasma renin inhibition was found.

Administration, Oral↗
PubMed1991

No effect of misoprostol on renal function of rheumatoid patients treated with diclofenac.

Non-steroidal anti-inflammatory drugs can reversibly decrease renal function in patients with rheumatoid arthritis (RA). To test whether orally administered prostaglandins could mitigate this decrease, we studied the effect of misoprostol in 24 RA patients during treatment with diclofenac in a randomized, placebo-controlled crossover trial. At baseline, 21 patients had a creatinine clearance below 80 ml/min/1.73 m2. The two treatment phases (with either misoprostol, 600 micrograms daily, or matching placebo tablets) were separated by a washout phase in which diclofenac (150 mg daily) was continued. After treatment with misoprostol/diclofenac the glomerular filtration rate was 72 +/- 5 ml/min (mean +/- standard error), and the effective renal plasma flow was 295 +/- 21 ml/min. After treatment with placebo/diclofenac, the corresponding values were 71 +/- 5 ml/min and 296 +/- 21 ml/min, respectively. We concluded that misoprostol has no effect on the renal function of RA patients treated with diclofenac.

Adult↗
PubMed1990

Atrial natriuretic peptide and chronic renal effects of changes in dietary protein and sodium intake in man.

1. Plasma levels of atrial natriuretic peptide and several other hormones were measured and related to the renal responses to chronic changes in the dietary intake of protein and sodium, alone and in combination. Eight healthy subjects consumed four diets for 1 week: a basal diet containing 140 mmol of sodium/day and 1 g of protein day-1 kg-1, the same diet with isocaloric addition of 1 g of meat protein day-1 kg-1, the basal diet with addition of 170 mmol of sodium chloride/day and the basal diet with both additions. 2. Creatinine clearance was increased significantly both by protein and, to a smaller extent, by sodium. Plasma atrial natriuretic peptide and the urinary excretion of guanosine 3':5'-cyclic monophosphate were increased significantly by sodium but were not affected by protein. Protein induced a significant rise in plasma glucagon levels, whereas the rise in somatomedin C (insulin-like growth factor I) just failed to reach statistical significance. 3. These findings demonstrate that atrial natriuretic peptide does not mediate chronic protein-induced hyperfiltration, although it may contribute to the renal effects of sodium. Glucagon and somatomedin C (insulin-like growth factor I) may have contributed to chronic protein-induced hyperfiltration.

Adult↗
PubMed1989

Clinical pharmacology of cilazapril.

In clinical pharmacology studies cilazapril, after its bioactivation to cilazaprilat, was characterized as a potent, reversible angiotensin-converting enzyme (ACE) inhibitor with a terminal half-life of 30 to 50 hours consistent with saturable binding to ACE. Despite the arterial vasodilation, only slight increases in heart rate were found. Cilazapril had no acute effect on cardiovascular reflexes. Cilazapril increased effective renal plasma flow slightly. Glomerular filtration rate remained unaltered. A close and steep correlation between cilazaprilat plasma concentration and ACE inhibition was found. The potency of cilazaprilat, defined as the concentration of cilazaprilat causing 50 percent ACE inhibition, was approximately 1 ng/ml plasma. In short-term studies in hypertensive patients, it appeared that more than 90 percent of plasma ACE inhibition is needed to obtain blood pressure reduction. The result of various dose-response studies established the indirect relationship between dose, plasma concentration of the drug, and the blood pressure response and identified the dose producing maximal effect (i.e., 5 mg). Cilazapril had relatively long-lasting effects on ACE inhibition. In patients with severe chronic renal impairment or hepatic failure, the duration of ACE inhibition of cilazapril was prolonged. In these patients a reduction of the dose and/or less frequent dosing is recommended. There was no clinically relevant interaction of cilazapril with food or furosemide. The effects of hydrochlorothiazide on sodium and chloride excretion were potentiated by cilazapril. An additive effect of propranolol and nitrendipine on the blood pressure response to cilazapril was observed. An interaction with nonsteroidal anti-inflammatory drugs and cilazapril might occur, potentially reducing the blood pressure lowering effect. In general cilazapril was well tolerated.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Effects of posture and saline infusion on atrial natriuretic peptide and haemodynamics in patients with Bartter's syndrome and healthy controls.

In order to explore the role of atrial natriuretic peptide (ANP) in Bartter's syndrome, five patients and five healthy controls matched for age and sex were studied. The study was designed to stimulate and suppress ANP secretion by manipulation of right atrial pressure with different body positions and mild volume expansion with saline. Other vasoactive hormones were also measured, and heart rate and blood pressure were recorded at 5-min intervals. Plasma ANP levels increased after head-down tilt and returned to baseline in the upright position. Infusion of saline failed to increase plasma ANP both in the control group and in four of the patients. No significant differences were found in plasma atrial natriuretic peptide concentrations between both groups. In view of previously reported elevated plasma ANP levels, Bartter's syndrome may be heterogeneous in this respect. Plasma renin activity was higher in the patients, but plasma aldosterone, adrenaline and noradrenaline were similar in both groups. Mean arterial blood pressure was similar in both groups, but rose significantly in the upright position in the control group only, while changes in heart rate were similar in both groups. We conclude that atrial natriuretic peptide does not seem to play a causal role in our patients with Bartter's syndrome.

Adult↗
PubMed1987

Postsynaptic alpha 1- and alpha 2-adrenoceptors in human blood vessels: interactions with exogenous and endogenous catecholamines.

The relative efficacy of epinephrine and norepinephrine on vascular alpha 1- and alpha 2-adrenoceptors and also the difference in vasoconstriction induced by exogenous norepinephrine as opposed to neuronally released norepinephrine were studied in the forearm of healthy volunteers. Intra-arterial cumulative dose infusions of epinephrine and norepinephrine (0.6, 1.6 and 4.0 ng kg-1 min-1) were given in the presence of saline, the selective alpha 1-antagonist doxazosin (0.1 microgram kg min-1) the selective alpha 2-antagonist yohimbine (1.0 microgram kg min-1) and the combination of both antagonists. beta-Adrenoceptor-mediated effects were prevented by a concomitant i.a. infusion of propranolol (1.0 microgram kg-1 min-1). Forearm blood flow (FBF) was measured before each infusion and at the end of each dose step. Neuronal norepinephrine was released by i.a. infusion of tyramine in three cumulative doses (0.25, 0.50 and 1.25 micrograms kg-1 min-1) and by lower body negative pressure (LBNP, -40 mmHg for 5 min). Changes in FBF were measured without and with concomitant i.a. infusions of the aforementioned doses of doxazosin and yohimbine. In the LBNP experiment the opposite arm was used as a control. Forearm blood flow was measured by plethysmography. Epinephrine and norepinephrine induced an equal and dose-dependent vasoconstriction, which was significantly inhibited by doxazosin as well as yohimbine and to a greater extent by the combination of the antagonists. No differences were found between epinephrine and norepinephrine in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed1984

Role of alpha adrenoceptors in hypertension and in antihypertensive drug treatment.

Recent plethysmographic experiments suggest that both postsynaptic alpha 1 and alpha 2 adrenoceptors in human resistance vessels play an important role in the maintenance and regulation of vascular tone. Central alpha 2 adrenoceptors are assumed to be involved in the central regulation of blood pressure. Radioligand binding studies on the density and characteristics of alpha adrenoceptors have not revealed consistent differences between normotensive and hypertensive subjects, with the exception of pheochromocytoma, in which a consistent down regulation of alpha 2 adrenoceptors in thrombocytes has been demonstrated. The radioligand binding studies are limited, since they cannot be performed on vascular tissues. Alpha adrenoceptors are vitally important as targets of several antihypertensive drugs; the activities of these agents and the principles and clinical relevance of mechanisms involving alpha adrenoceptors are reviewed.

Adrenergic alpha-Agonists↗
PubMed1984

Liquid chromatographic determination of nifedipine in plasma and of its main metabolite in urine.

A high-performance liquid chromatographic method was developed for the assay of nifedipine in plasma and its main metabolite (M-I) in urine. After liquid-liquid extraction nifedipine was chromatographed in a reversed-phase system with ultraviolet detection at 238 nm. The method was sensitive to 2 ng nifedipine per ml plasma and the standard curve was linear to at least 400 ng/ml. Standard deviations did not exceed 8.5%. There was no interference with photodecomposition products or metabolites. M-I was determined in urine after liquid-liquid extraction by ion-pair chromatography with ultraviolet detection at 290 nm. The method was sensitive to 0.02 micrograms M-I per ml urine and the standard curve was linear to at least 5 micrograms/ml. Standard deviations did not exceed 5.0%. The methods were used to study nifedipine disposition in healthy volunteers.

Chromatography, Liquid↗
PubMed1984

Plasma lipid fractions during long-term monotherapy with the ISA-containing beta-adrenoceptor blocker bopindolol in hypertensive patients.

The influence of bopindolol monotherapy on blood pressure and plasma lipid fractions was investigated in 24 hypertensive patients. Bopindolol lowered blood pressure and heart rate significantly. When compared with placebo no changes were found in the plasma concentrations of total cholesterol, LDL cholesterol and HDL cholesterol. Plasma triglycerides were significantly increased after 4 and 8 weeks but not after 12 weeks of bopindolol. It is concluded that bopindolol is an effective and well tolerated beta-adrenoceptor blocker in hypertensive patients. The fact that it does not lower HDL cholesterol could be a potential advantage.

Adult↗
PubMed1984

Direct and indirect measurement of urinary kallikrein excretion in patients with essential hypertension and normotensives: relation to age and plasma renin and aldosterone levels.

The relevance of age and activity of the renin-angiotensin-aldosterone system to the excretion of urinary kallikrein (Ukal) was studied in twenty-five patients with essential hypertension and forty normotensive controls. The age range for both study groups was 20-60 years. Ukal was measured by radioimmunoassay and by an amidolytic assay. Results of both assays correlated closely (r = 0.93, n = 65, P less than 0.001). For all hypertensives Ukal excretion was not significantly different from that of controls. However, older hypertensives (greater than 40 years, n = 13) had a significantly lower Ukal excretion than normotensives of the same age (n = 20) (radioimmunoassay 67.2 (SEM 7.2) v. 105.1 (SEM 8.4) micrograms (24 h)-1; and amidolytic method 0.84 (SEM 0.10) v. 1.13 (SEM 0.08) U (24 h)-1). No correlation was found between Ukal excretion and plasma renin or aldosterone. In fact, the aldosterone level was highest in older hypertensives. In conclusion, the lower Ukal excretion in hypertensives over 40 is likely to be secondary to the long-standing high blood pressure. Under basal conditions, Ukal excretion seems little influenced by the activity of the renin-angiotensin-aldosterone system.

Adult↗
PubMed1983

Carcinoma of the adrenal cortex causing primary hyperaldosteronism. A case report and review of the literature.

A male patient presenting with primary hyperaldosteronism after a three-year delay, was found to have an aldosterone producing adrenocortical carcinoma. Evidence is presented that aldosterone was the only steroid produced in excess. Only six other patients with adrenocortical carcinoma and isolated primary hyperaldosteronism could be traced in the literature. The relation between histology and endocrine functions of the tumor cells is discussed.

Adrenal Cortex Neoplasms↗
PubMed1983

Effect of captopril on sympathetic neurotransmission in pithed normotensive rats.

Captopril significantly diminished the basal diastolic blood pressure and the vasopressor response to electrical stimulation of the thoracic-lumbar spinal cord in pithed normotensive rats. The reduction of the hypertensive response to electrical stimulation was more pronounced after bilateral adrenalectomy. Captopril also diminished the vasopressor response to intravenously administered (-)-noradrenaline. Pretreatment of the animals with indomethacin had no effect on the vasopressor response to electrical stimulation and did not affect the sympathoinhibition of captopril. After bilateral nephrectomy, 18-24 h previously, the basal diastolic blood pressure and the vasopressor response to electrical stimulation were reduced and captopril had no additional inhibitory effect on these parameters. In indomethacin-pretreated animals with intact kidneys, restoration of the basal diastolic blood pressure with angiotensin II (AII) completely abolished the sympathodepressive effect of captopril. When the reduction in basal diastolic blood pressure with captopril was prevented by vasopressin, converting enzyme inhibition had no depressive effect on the hypertensive response to intravenously administered (-)-noradrenaline and did not influence sympathetic neurotransmission in animals with intact adrenals. However, a small, but significant reduction of the hypertensive response to electrical stimulation by captopril was still detectable in bilaterally adrenalectomized rats. The results suggest that endogenous AII facilitates sympathetic neurotransmission in vascular smooth muscle of pithed normotensive rats. However, the modulatory action of endogenous AII largely results from an effect on basal arteriolar smooth muscle tone and should, therefore, be considered as non-specific facilitation. Genuine prejunctional facilitation of the sympathetic neurotransmission in vascular smooth muscle can only be observed after bilateral adrenalectomy but this effect of endogenous AII appears of minor significance, at least in pithed normotensive rats.

Animals↗
PubMed1979

Plasma noradrenaline correlates with alpha-adrenoreceptor-mediated vasoconstriction and blood pressure in patients with essential hypertension.

1. The relationships between plasma noradrenaline concentration at rest and blood pressure, as well as increase in forearm blood flow in response to a brachial artery infusion of the alpha-adrenoreceptor-blocking agent phentolamine, were investigated in hypertensive and normotensive subjects of similar age. 2. In 44 hypertensive patients plasma noradrenaline correlated with systolic, diastolic and mean blood pressures, but no difference in the mean plasma noradrenaline concentration was found. 3. In 11 patients and 14 normotensive subjects alpha-adrenoreceptor blockade resulted in a similar increase in forearm blood flow. Only in the patients, however, was this increase related to plasma noradrenaline and blood pressure. 4. In patients with established essential hypertension plasma noradrenaline can be considered to be a marker of alpha-adrenoreceptor-mediated vasoconstriction, which, in part, determines the height of the blood pressure.

Adolescent↗
PubMed1979

Haemodynamics during long-term thiazide treatment in essential hypertension: differences between responders and non-responders.

1. Blood pressure, systemic haemodynamics, plasma volume, renin and aldosterone were measured during placebo treatment and after 1, 4 and 12 weeks of hydrochlorothiazide in 13 patients with uncomplicated essential hypertension. Nine of these patients were also studied after 24 and 36 weeks of treatment. 2. Mean arterial pressure was lowered significantly during hydrochlorothiazide treatment. In seven patients the fall in mean arterial pressure was lowered significantly during hydrochlorothiazide treatment. In seven patients the fall in mean arterial pressure was greater than 10% (responders); four of these were studied for 36 weeks. The remainder were considered non-responders. 3. Hydrochlorothiazide lowered cardiac output. The maximal decrease was observed after 12 weeks of treatment (P less than 0.01). In responders this was followed by a return to pretreatment values and a significant decrease in total peripheral resistance, whereas in non-responders cardiac output remained reduced and total peripheral resistance was permanently elevated. 4. Changes in plasma volume, renin and aldosterone were not significantly different in responders and non-responders although non-responders tended to show a greater degree of plasma volume depletion and a more pronounced increase in plasma aldosterone. 5. Thus it is unlikely that the initial decrease in cardiac output is an important determinant of the long-term haemodynamic effect of thiazide diuretics.

Adult↗