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Biomedical subjects

H Wesseling

Publications and source records attributed to H Wesseling.

At least 55 records · Page 3Linked to original sources
PubMed1991

Investigating drug use in pregnancy. Methodological problems and perspectives.

In this study the use of prescribed drugs before, during and after pregnancy is described. The study is based on data obtained from pharmacy records of 1,948 women who delivered a live-born infant. Different measures to evaluate drug exposure are used. During the nine months of pregnancy 86% of the women used on average 4.2 prescriptions. During the course of pregnancy the use of gastro-intestinal and blood-forming drugs increased, whereas the use of cardiovascular, antiphlogistic and central nervous system drugs decreased. Anti-emetics were predominantly used in the first trimester, and antacids in the last trimester, whereas laxatives were especially used after delivery. The percentage of women who used a treatment for vaginal infections increased from 2 to 7 during pregnancy. Most of the women (73%) received one or more iron prescriptions during the course of pregnancy, however, the prescribed daily dose was low (prescribed daily dose/defined daily dose = 0.6). At least 1% of the women filled a new prescription for anticonceptives in the first trimester of pregnancy. Most likely, our data reflect the general prescribing pattern for Dutch pregnant women who delivered a live-born baby. Therefore, they form a good and detailed base for further studies, for instance, on the exposure to drugs with known or suspected risks or on the use of drugs in patients with chronic concomitant diseases. Such studies may lead to recommendations that may improve prescribing behaviour.

Adult↗
PubMed1991

The effects of alpha-adrenoceptor blockade on dopamine-induced renal vasodilation and natriuresis.

To establish the effects of alpha-adrenoceptor blockade on dopamine-induced changes in renal hemodynamics and sodium excretion, dopamine dose-response curves were performed without and with pretreatment with the selective postsynaptic alpha 1-adrenoceptor antagonist prazosin in normal volunteers and in patients with renal disease and moderately impaired renal function. Prazosin (1 mg p.o. every 4 h) in 7 volunteers did not significantly affect baseline values but impaired the response of effective renal plasma flow (ERPF) and filtration fraction (FF) to infusions of dopamine in doses ranging from 0.5 to 8 micrograms/kg per minute and completely abolished the dopamine-induced increase in sodium excretion. In 7 patients with renal disease and a glomerular filtration rate (GFR) ranging from 38-85 ml/min pretreatment with prazosin did not affect baseline ERPF, GFR or FF or their response to dopamine infusion, but sodium excretion and its response to dopamine infusion were reduced (fractional excretion of sodium at baseline 1.78 without and 0.89 with prazosin pretreatment). We conclude that alpha 1-adrenoceptor blockade with prazosin abolishes the effects of exogenous dopamine on sodium excretion in normal man. Prazosin also impairs the renal vasodilatory action of dopamine. However, the effect on sodium excretion is not directly related to inhibition of dopamine-induced renal vasodilation since in patients with renal disease prazosin also markedly reduces sodium excretion but does not influence the renal hemodynamic effects of dopamine.

Adult↗
PubMed1991

Coronary vasodilation induced by captopril and zofenoprilat: evidence for a prostaglandin-independent mechanism.

In this study, the vasodilating properties of captopril and zofenoprilat, two angiotensin-converting enzyme (ACE) inhibitors containing the sulfhydryl group, are investigated in the isolated rat heart. It is demonstrated that both compounds increase coronary flow in a dose-dependent manner. However, the mean pD2 of zofenoprilat appears to be significantly higher than the mean pD2 of captopril (4.55 +/- 0.06 and 3.35 +/- 0.02 respectively), indicating that zofenoprilat is about ten times more potent in increasing coronary flow than captopril. Possibly this difference in potency between captopril and zofenoprilat can be explained by their physicochemical properties. Since zofenoprilat is more lipophilic than captopril, its concentration in cardiac and vascular tissues at distribution equilibrium is thought to be higher than the tissue concentration of captopril, which may result in a more pronounced vasodilatory action. The precise mechanism of coronary vasodilation induced by ACE inhibitors containing the sulfhydryl group is not yet understood. Several factors have been proposed, such as stimulation of prostacyclin production. However, in this study, concomitant administration of 10(-6) mol/l acetylsalicylic acid shows no antagonism, indicating that under normoxic conditions the vasodilatory effects of captopril and zofenoprilat are independent of the production of vasodilating prostaglandins. Therefore, other factors than stimulation of prostacyclin synthesis seem to be involved, such as prevention of bradykinin breakdown and/or potentiation of endothelium derived relaxing factor (EDRF). Furthermore, despite a marked inhibition of prostacyclin production, 10(-6) mol/l acetylsalicylic acid itself has no effect on coronary flow. These results suggest that prostacyclin does not play an important role in the regulation of coronary flow, at least in the normoxic isolated rat heart.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Impact of clinical trials on the adoption of new drugs within a university hospital.

To assess the influence that clinical trials may have on the introduction of new drugs into prescribing routines, the adoption of drugs has been studied in a university hospital in the Netherlands. A significant relation was found between the testing of semi-innovative drugs in clinical trials in the hospital and the introduction of these drugs into general use in the same hospital. No such relationship was found for innovative drugs. Employment in clinical trials only affected the frequency of adoption of semi-innovative drugs. It did not influence the quantity of their use once they had been adopted. The idea that the stimulating effect of clinical trials on the adoption of semi-innovative drugs is only due to acceleration of the adoption process was not confirmed. These findings support the idea that clinical trials can lower the barriers for adoption of semi-innovative drugs.

Clinical Trials as Topic↗
PubMed1991

Once daily felodipine in patients with primary Raynaud's phenomenon.

The symptomatic effects of felodipine (Plendil) have been assessed in 10 patients with primary Raynaud's phenomenon in a single blind study. After 2 weeks on placebo, the patients were treated for 6 weeks with felodipine, the dose being titrated stepwise every 2 weeks, starting with 5 mg, and increasing to 10 mg and 20 mg once daily if symptoms persisted. After the drug period the patients received placebo for 2 weeks. Objective measurement by cold exposure finger plethysmography did not show any benefit of felodipine in the higher temperature range, taking 33 degrees C as reference point. However, when using 24 degrees C as the reference point, the area under the plethysmography versus temperature curve (AUC) for 5 mg felodipine were significantly larger than the initial placebo area. The AUC during recovery from cold exposure for the maximal accepted dose of felodipine was significantly larger than for the initial placebo period. Subjective judgement by the patients showed a significant reduction in the number of Raynaud attacks and a trend to a shorter duration of attacks with the maximal dose of felodipine. Two patients became free from attacks of Raynaud's phenomenon. Felodipine 10 mg once daily was well tolerated. It was regarded as the optimal dose to treat patients with Raynaud's symptoms.

Adult↗
PubMed1991

Converting enzyme inhibition after experimental myocardial infarction in rats: comparative study between spirapril and zofenopril.

STUDY OBJECTIVE: The aim was to compare the effects of two novel angiotensin converting enzyme (ACE) inhibitors, spirapril and zofenopril, on cardiac remodelling in rats with congestive heart failure after myocardial infarction. Spirapril contains no sulphydryl group, whereas zofenopril is a sulphydryl containing ACE inhibitor. DESIGN: Experimental myocardial infarction was induced by ligation of the left coronary artery. Sham operated animals served as controls. Treatment with spirapril (2-2.5 mg.kg-1.d-1) or zofenopril (12-15 mg.kg-1.d-1) added to the drinking water was started immediately after myocardial infarction or sham operation and continued for six weeks. After the treatment period, all rats were killed. The heart was rapidly removed and perfused as described by Langendorff. Heart rate and left ventricular pressure were measured both at baseline and during stimulation with isoprenaline (6 nM). Heart and lung weights were determined. SUBJECTS: Normotensive male Wistar rats (220-240 g) were used. MEASUREMENTS AND MAIN RESULTS: Experimental myocardial infarction considerably increased left ventricular cavity volume. Chronic treatment with either spirapril or zofenopril significantly attenuated this increase in volume. In infarcted rats, the increase in total heart and lung weight was also significantly reduced by chronic treatment with spirapril and zofenopril, indicating that these compounds reduce cardiac mass and pulmonary congestion in congestive heart failure due to myocardial infarction. There were no significant differences between treatment with spirapril and zofenopril. In the isolated and perfused rat heart, myocardial infarction significantly decreased both heart rate and left ventricular pressure. Converting enzyme inhibition only affected heart rate. Heart rate was significantly higher in infarcted animals treated with spirapril and zofenopril than in untreated infarcted animals. CONCLUSIONS: Both spirapril and zofenopril attenuated ventricular enlargement and cardiac hypertrophy in rats with congestive heart failure after myocardial infarction when treatment was started in the acute phase of myocardial infarction. No additional role could be attributed to the sulphydryl moiety of zofenopril. It is also suggested that these two ACE inhibitors modify cardiac sympathetic activity in rats with congestive heart failure, but more studies are needed to confirm these findings.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

In vivo effect of bradykinin during ischemia and reperfusion: improved electrical stability two weeks after myocardial infarction in the pig.

In this study, the effect of bradykinin or saline infusion during ischemia and reperfusion on electrical stability, 2 weeks after myocardial infarction, was assessed. Acute myocardial infarction was induced in 21 pigs by a transluminal occlusion of the left coronary artery with a catheter balloon, inflated for 45 min. Bradykinin was administered by a 30-min infusion that started after 30 min of coronary occlusion and was continued until 15 min after reperfusion. Although creatine kinase levels in bradykinin-treated animals were significantly lower (p less than 0.001), 2 week survival was not different between groups. In survivors, the filtered QRS (ventricular deflection) duration (detected using signal-averaged electrocardiography) was significantly prolonged in saline-treated pigs, whereas in bradykinin-treated pigs this prolongation was prevented. The terminal voltage of the QRS complex was significantly lower in saline-treated pigs than in bradykinin-treated pigs. These two parameters signify an improved electrical stability after bradykinin treatment. Refractory periods in saline-treated hearts were longer than in bradykinin-treated hearts (106 +/- 10% vs. 95 +/- 13%, p less than 0.05). Also, current thresholds in the infarct border zones showed a greater variance in saline-treated hearts (p less than 0.001), pointing toward more tissue heterogeneity of the infarct border zone. Programmed electrical stimulation showed a trend toward reduced inducibility of sustained ventricular tachycardia in bradykinin-treated hearts. Therefore, bradykinin improves electrical stability weeks after experimental myocardial infarction.

Animals↗
PubMed1991

Effects of bradykinin on inducible sustained ventricular tachycardia two weeks after myocardial infarction in pigs.

We studied the in vivo effect of bradykinin infusion on inducible sustained ventricular tachycardia (VT) 2 weeks after myocardial infarction in pigs, based on the assumption that the antiarrhythmic effect of angiotensin-converting enzyme (ACE) inhibitors may, apart from their angiotensin-II lowering effect, also be due to elevation of endogenous bradykinin levels. Of the six pigs with inducible VT in the control state, four were noninducible during subsequent bradykinin infusion (p less than 0.05). The ventricular effective refractory period (VERP) did not change during bradykinin infusion (from 237 +/- 37 to 239 +/- 42 ms), nor did intraventricular conduction change (filtered QRS duration was 45 +/- 17 ms before and 43 +/- 19 ms during infusion). Bradykinin caused both a significant systolic blood pressure (SBP) decrease (from 79 +/- 14 to 49 +/- 4 mm Hg, p less than 0.001) and diastolic BP (DBP) decrease (from 41 +/- 10 to 27 +/- 4 mm Hg, p less than 0.01). In conclusion, exogenous bradykinin reduced the inducibility of sustained VT 2 weeks after myocardial infarction. Because refractory periods or conduction velocity were not affected, the mechanism of action might be associated with the BP decrease, which can decrease wall stress. The previously reported antiarrhythmic effect of ACE inhibitors may be due in part to elevation of endogenous bradykinin levels.

Animals↗
PubMed1991

Converting enzyme inhibitors and the role of the sulfhydryl group in the potentiation of exo- and endogenous nitrovasodilators.

In this study, the effect of bradykinin on coronary flow in the isolated rat heart was significantly potentiated when cysteine or the sulfhydryl-containing converting enzyme inhibitors captopril and zofenoprilat were administered simultaneously. In contrast, the effect of concomitant administration of enalaprilat only slightly increased the effect of bradykinin on coronary flow. In nitrate-tolerant hearts of rats pretreated with isosorbide dinitrate (15 mg daily), the increase in coronary flow by nitroglycerin and bradykinin was significantly less when compared to control hearts. The effect of captopril was not affected by pretreatment. The involvement of endothelium-derived relaxing factor (EDRF) in the effect of captopril was apparent from experiments with L-arginine, the precursor of EDRF, and L-NMMA, the "false" precursor of EDRF. L-Arginine increased the effect of captopril, whereas L-NMMA showed a competitive antagonism for the effect of captopril on coronary flow in the isolated rat heart. Clinically, the effect of captopril was studied in 10 patients with stable, exercise-induced angina pectoris that had been treated for 3 weeks with slow-release isosorbide dinitrate (20 mg four times daily). At day 7, a baseline exercise test was obtained. Subsequently, patients with chest pain and at least 1-mm ST-segment depression on the ECG during exercise were included. They received on day 14 and 21 either captopril (25 mg) or placebo 1 h before exercise testing in a randomized, double-blind, crossover design. Captopril significantly improved the combined score of maximal ST-segment depression, maximal workload, and time to angina when compared to placebo. No differences in the pressure-rate index at rest and during exercise were seen. These results indicate that the sulfhydryl group of certain angiotensin converting enzyme inhibitors can potentiate their effect on the endogenous nitrovasodilator EDRF. In the clinical situation, this may lead to an improved exercise performance in patients with stable angina pectoris during chronic nitrate treatment, independent of its systemic vascular effects.

Aged↗
PubMed1991

The acute hemodynamic, hormonal, and pharmacokinetic properties of oral spirapril in patients with moderate to severe heart failure.

The acute hemodynamic, hormonal, and pharmacokinetic responses to the oral angiotensin-converting enzyme (ACE) inhibitor spirapril were studied in 15 patients with moderate to severe congestive heart failure in a baseline controlled dose-ranging study. Doses of 0.3, 1.0, 1.5, 3.125, and 6.25 mg were investigated for 24 h in three groups of five patients each. All doses demonstrated a significant reduction in serum ACE, even after 24 h. Significant reductions in mean arterial pressure, systemic vascular resistance, and pulmonary capillary wedge pressure were observed with doses greater than 1.0 mg spirapril. Maximal significant hemodynamic effects occurred approximately 4-6 h after drug administration. The plasma concentrations of spirapril and its metabolite spiraprilate were dose-dependent. After administration of spirapril, the quick rise to the peak level of spiraprilate suggests rapid metabolism of spirapril into spiraprilate and a slow elimination of this metabolite. No severe hypotension or other serious side effects occurred in the patients studied. The results indicate that spirapril may be expected to be an effective drug in the treatment of congestive heart failure. From our findings we conclude that 1.5 mg spirapril is an optimal starting dose in patients with moderate to severe congestive heart failure.

Aged↗
PubMed1991

Prescribing pattern in a Dutch university hospital.

In many countries, including The Netherlands, little is known about the overall prescribing patterns within hospitals. While individual hospitals have some data available, these are not pooled on a regional or national level. The available data consist of dispensing data that are neither patient-linked nor diagnosis-linked. We report the results of a study in a Dutch university hospital which show that despite the limitations, such data can be used for a general evaluation of prescribing patterns. Using three categories of undesirable or irrational drug prescribing the dispensing data were screened. The categories were 'inferior or dubious' drugs, 'semi-innovative' drugs, and 'inappropriately used' drugs. The results show that most problems are seen with the use of new drugs. In the first instance, this involves the use of semi-innovative drugs whose adoption may be stimulated by clinical trials in the hospital concerned. Secondly, innovative drugs seem to be used on too large a scale, i.e., for indications for which their use is not warranted. Based on these findings, a follow-up study has been initiated to study some of these suboptimal drug choices in detail.

Drug Prescriptions↗
PubMed1991

The effects of short- and long-term treatment with an ACE-inhibitor in rats with myocardial infarction.

It has been shown that converting enzyme inhibitors (CEI) attenuate ventricular dilatation and hypertrophy after myocardial infarction. In most studies, CEI treatment was started when ventricular dilatation and hypertrophy were already well under way. Therefore, we studied the effects on ventricular dilatation and hypertrophy, when CEI treatment was started in the acute phase of myocardial infarction. Immediately after a sham-operation or myocardial infarction in rats (sham: n = 8; MI: n = 17), treatment with zofenopril, a novel ACE-inhibitor, was started and continued during 42 days (long-term treatment). In a second group of rats, zofenopril was administered only during the first 5 days after myocardial infarction (short-term treatment); these rats were not treated with zofenopril during the remaining period of 37 days (sham: n = 5; MI: n = 13). Untreated rats served as controls (sham: n = 9; MI: n = 24). The results from this study showed that long-term treatment with zofenopril caused a significant reduction of left ventricular cavity volume in rats with moderate-to-large infarctions, which was accompanied by a significant reduction in the ratio of total heart weight to body weight. However, short-term treatment with zofenopril did not significantly reduce ventricular volume or total heart weight. Finally, both long- and short-term treatment resulted in a small, but statistically significant, reduction of septal wall thickness in sham-operated and infarcted rats. We conclude that CEI therapy decreases ventricular dilatation and hypertrophy after myocardial infarction, only when treatment is continued during the chronic phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Captopril compared to atenolol in mild to moderate hypertension in a randomized double-blind controlled trial.

After screening a local population in the northern part of The Netherlands for hypertension, 125 patients (116 of whom had not previously used antihypertensive drugs) with a five times elevated diastolic pressure (DP) of between 95 and 130 mmHg were randomized and treated daily either with atenolol 50 mg o.d. (n = 62) or with captopril 25 mg b.i.d. (n = 63) for 2 months under double-blind conditions. During this period the DP fell by 9 mm under atenolol (from 107 +/- 8 to 98 +/- 8) and by 8 mm under captopril (from 107 +/- 7 to 99 +/- 9). The number of responders with a DP = less than 90 mmHg was 21% and 20%, respectively. After 2 months the double-blind period was ended and the patients were submitted to a medication protocol for another 4 months in which an increased dose and additional nifedipine were given to non-responders. The response rate rose to 76% (atenolol/nifedipine combination) and to 60% (captopril/nifedipine combination) - NS. It is concluded that low doses of atenolol and captopril are equally effective in lowering blood pressure in uncomplicated mild to moderate hypertension.

Adult↗
PubMed1990

Dissociation of renal vasodilator and natriuretic effects of dopamine during sulpiride infusion in normal man.

The effect of sulpiride on dopamine-induced changes in renal function in man has been investigated. Dopamine dose-response studies were performed in 7 healthy volunteers before and after sulpiride 200 mg i.v. The same investigations were performed in 15 healthy volunteers after pretreatment with the selective alpha-1-adrenoceptor antagonist prazosin (n = 7) and the non-selective alpha-adrenoceptor-blocker phentolamine (n = 8). Infusion of dopamine 0.25 to 8 micrograms.kg-1.min-1 resulted in a dose-dependent increase in effective renal plasma flow (ERPF) and glomerular filtration rate (GFR), and a fall in filtration fraction (FF) in 7 normal volunteers. Sulpiride had no effect on base-line ERPF or GFR and did not influence the dopamine-induced renal vasodilatation in those volunteers. It did cause a fall in the fractional sodium excretion (FENa+%) from 1.7 to 1.38, and shifted the dose-response curve of the natriuretic response to a subsequent infusion of dopamine. Sulpiride enhanced the fall in diastolic blood pressure during infusion of dopamine. In 7 other volunteers pretreated with prazosin, sulpiride did not influence base-line ERPF, GFR or FF or their response to dopamine, but the sodium excretion fell markedly (FENa+% changed from 1.13 to 0.63). Administration of sulpiride to 8 volunteers after phentolamine pretreatment 20 mg.h-1 i.v. in the first hour followed by 10 mg.h-1 i.v. resulted in a fall in sodium excretion (FENa+% from 1.09 to 0.53) without affecting ERPF or FF, and it did not affect the dose-response curve in the subsequent DA infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Clinical pharmacology and primary health care in Europe--a gap to bridge. The WHO Working Group on Clinical Pharmacology in Europe.

A group of senior European clinical pharmacologists presents a position paper on the possible role of clinical pharmacology (CP) in bridging the gap between academic drug evaluation and drug prescribing in primary health care (PHC). As a teaching, research and service discipline CP has developed in academic or other major hospitals while 80% of all drugs are prescribed in PHC. CP therefore has to extend its functions to PHC. Examples are given of how joint ventures between clinical pharmacologists and PHC physicians may improve the quality of drug research and increase the clinical relevance of drug information in PHC, thereby contributing towards rational drug utilization in PHC. Colleagues in PHC are invited to respond to this call for collaboration.

Drug Prescriptions↗
PubMed1990

Digoxin infusion versus bolus injection in rapid atrial fibrillation: relation between serum level and response.

Using available data on time-concentration and time-effect relationships in normal persons the results of infusion of digoxin in various time periods were simulated and compared with administration of digoxin by bolus injections, using a three-compartment pharmacokinetic model to which a separate small side-effect compartment was subsequently added. The validity of the simulations was tested in 11 patients with rapid atrial fibrillation. Serum digoxin concentrations, ventricular rate and side effects were monitored in a double-blind study comparing an infusion of 1.5 mg digoxin over 6 h with administration of three bolus injections of 0.5 mg digoxin 8 h apart. In agreement with the predictions of the model, the maximal fall in ventricular rate was reached after 8-9 h in the infusion group and after 19-20 h in the bolus injection group, without any detectable difference in side effects. There were certain discrepancies between the results of the clinical study and the predictions of the model, e.g. in serum digoxin concentrations, perhaps due to impaired clearance in the patients. However, it is concluded that the tested model is valid in elderly patients with rapid atrial fibrillation.

Adult↗
PubMed1990

The effects of oral pretreatment with zofenopril, an angiotensin-converting enzyme inhibitor, on early reperfusion and subsequent electrophysiologic stability in the pig.

The effects of oral zofenopril pretreatment were investigated in a chronic closed-chest pig model of ischemia and reperfusion. Pigs (25-35 kg) were pretreated orally with zofenopril (15 mg/day) on the 2 days prior to ischemia, which was evoked by the inflation of a catheter balloon in the left anterior descending coronary artery over 45 minutes. The catheter was then removed and the myocardium was reperfused. After 2 weeks, infarct properties were assessed by signal averaging of the body surface electrocardiogram and the inducibility of malignant ventricular tachyarrhythmias was tested with a programmed electrical stimulation protocol. A significant increase in the pressure-rate product (43 +/- 11%, mean +/- SEM), indicating the oxygen demand of the heart, was prevented by zofenopril (19 +/- 8%, p less than 0.05). Zofenopril reduced the peak efflux of adrenaline (1302 +/- 213 vs. 3201 +/- 760 pg/ml; p less than 0.05), noradrenaline (402 +/- 54 vs. 902 +/- 282 pg/ml; p less than 0.05), and of the adenosine catabolites inosine and hypoxanthine (56 +/- 4 vs. 78 +/- 9, pg/ml; p less than 0.05) in the coronary venous effluent. The efflux of the cytoplasmatic enzyme creatine phosphokinase was not significantly reduced after zofenopril (p = 0.08). No difference in plasma renin levels between the groups were found. After 2 weeks, late potentials were found only in the surviving animals from the untreated group, i.e., the voltage vector magnitude was more reduced, and a prolongation of the QRS duration and of the terminal low-amplitude part of the high-frequency QRS were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗