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Biomedical subjects

H Wesseling

Publications and source records attributed to H Wesseling.

At least 37 records · Page 2Linked to original sources

Towards understanding treatment preferences of hospital physicians.

Seventy-two physicians working in a university hospital in The Netherlands were interviewed to clarify their decision-making process when choosing drugs of preference. Each physician was questioned about the treatment choices for either one or two general case descriptions. The physicians considered only a limited set of different treatment options, on an average 1.7-5.0. Further, the physicians expressed their expectancies as regards various treatment alternatives, and the value or weight they attached to the principle aspects of a treatment. An analytical decision model was used as a reference to gain insight into the extent to which the physicians make decisions based on their own subjective expectancies and values. This model assumes that physicians follow a maximizing strategy by choosing the treatment they personally assess as optimal. It was found that a model including only biomedical expectancies and values predicted the preferred treatment correctly in no more than 53% of the cases. Sometimes, biomedical aspects were disregarded that should have been relevant according to the physicians themselves. Adding aspects of the social environment and experiences improved the prediction of the model substantially; 3 out of 4 treatment preferences could be understood by following an analytical maximizing strategy including biomedical aspects and social aspects and experiences. In the remaining cases, the physicians were not able to describe their decision in terms of this maximizing strategy, which points at the use of alternative decision strategies. One alternative decision strategy mentioned by the physicians was a 'follow-the-routine' decision rule.

Adult↗

Selective and time related activation of the cardiac renin-angiotensin system after experimental heart failure: relation to ventricular function and morphology.

OBJECTIVE: The cardiac renin-angiotensin system is activated in experimental heart failure, but it is unknown at what stage of heart failure it becomes activated, and whether activation is related to ventricular dysfunction and dilatation. Changes in activity of cardiac, renal, and plasma angiotensin converting enzyme (ACE) were therefore examined at different stages of experimental heart failure, with simultaneous measurements of left ventricular pressure, systolic dP/dt, and inner ventricular radius. METHODS: Heart failure was induced by experimental infarction in 17 normotensive male Wistar rats; 14 rats were sham operated. Rats were killed 3, 5, or 80 d after infarction. In an isolated heart perfusion, left ventricular pressure and systolic dP/dT were measured. ACE activity was determined in samples of the left and right cardiac ventricle, kidney, and plasma. Radius of the ventricular cavity was planimetrically determined in transverse sections of the left ventricle. RESULTS: At the different stages both left ventricular pressure and systolic dP/dT progressively decreased and inner radius of the left ventricle increased in all heart failure groups. ACE activity in the left ventricle increased significantly in all heart failure groups and correlated inversely with left ventricular pressure (R = -0.81; p < 0.001) and dP/dt (R = -0.85; p < 0.001). ACE activity in the kidney was only increased 80 d after the induction of heart failure [17(SEM 1) v 11.2(0.5) nM His-Leu generated per min.mg-1, p < 0.01], while plasma ACE activity was not increased in any heart failure group. CONCLUSIONS: Cardiac ACE is activated in the early stage after induction of heart failure and is related to the amount of dysfunction. ACE in the kidney is activated only in the chronic stage. The cardiac renin-angiotensin system therefore already appears to be an important neurohumoral adjustment in the early stage of heart failure and is thereby a suitable target for early intervention by ACE inhibitors.

Acute Disease↗

Endothelium dependent relaxation in two different models of chronic heart failure and the effect of ibopamine.

OBJECTIVES: The purpose was to relate endothelium dependent relaxation to neurohumoral and haemodynamic changes in rats with chronic heart failure. METHODS: Rats were submitted to either coronary ligation causing myocardial infarction or banding of the abdominal aorta (aortic stenosis), and comparisons were made with normal rats (n = 20 per group). Starting six weeks after surgery, half of the experimental animals received ibopamine and the other half served as controls and were given saline for another three weeks. After this, haemodynamic and neurohumoral variables were determined and the rats were killed. Rings of both the thoracic and abdominal aorta were studied in organ baths to measure their response to vasoactive agents. RESULTS: Increased plasma noradrenaline concentrations in rats with myocardial infarction and aortic stenosis were reduced by ibopamine. Blood pressure and heart rate, which were higher in rats with aortic stenosis than in rats with myocardial infarction and in normal rats, were unaffected by ibopamine. The maximal relaxation to sodium nitrite was depressed in the thoracic aorta from rats with myocardial infarction. The pIC50 of metacholine induced relaxation was smaller in the thoracic aorta from rats with myocardial infarction and aortic stenosis. By contrast, both pIC50 and the maximal relaxation (Emax) were increased in the abdominal aorta from rats with aortic stenosis, whereas Emax was smaller in rats with myocardial infarction. Ibopamine had no significant effects on these responses. CONCLUSIONS: Endothelium dependent relaxation to metacholine was selectively altered in rats with chronic heart failure due to aortic stenosis, probably because of differences in regional haemodynamics. In rats with myocardial infarction, however, endothelium dependent relaxation was impaired in both the thoracic and abdominal aorta. Ibopamine acted as a neurohumoral modulator by reducing increased noradrenaline concentrations but had no significant effect on either endothelium dependent or independent relaxation.

Animals↗

Sustained atrial flutter around the tricuspid valve in pigs: differentiation of procainamide (class IA) from flecainide (class IC) and their rate-dependent effects.

The wavelength theory considers two determinants of reentry, i.e., refractoriness and conduction velocity. It does not take excitability into account primarily. We evaluated frequency-dependence of excitability and refractoriness before and after flecainide or procainamide administration in relation to termination of reentrant atrial flutter. After making a Y-shaped lesion in the right atrium, we induced 62 flutters (cycle length 171 +/- 15 ms) by electrical stimulation in 15 pigs. Strength-interval curves were determined to assess excitability and refractoriness. Multiple cycle lengths were used to establish rate-dependent changes. Flutter cycle length increased after flecainide (to 290 +/- 67 ms) or procainamide (to 295 +/- 54 ms). The flutters always terminated abruptly (flecainide dose 103 +/- 104 mg, plasma concentration 370 +/- 21 ng/ml; procainamide dose 1,150 +/- 686 mg, concentration 51 +/- 24 mg/l). Flecainide caused an increase in diastolic thresholds from 0.3 +/- 0.2 to 0.8 +/- 0.5 mA (p < 0.006) and procainamide from 0.5 +/- 0.3 to 0.9 +/- 0.5 mA (p < 0.02). The increase in threshold was frequently dependent. Procainamide increased refractoriness at longer cycle lengths (> or = 250 ms), but this effect was abolished at shorter cycle lengths, indicating that only after significant slowing of the rate, prolongation of refractoriness may appear. Thus, both drugs interrupt reentrant flutter mainly by reducing excitability. Subclassification into IA and IC may be less relevant at high rates. Construction of strength-interval curves and assessment of rate-dependent "postrepolarization refractoriness" should be considered when one studies drugs that influence excitability.

Animals↗

Drug expectations and drug choices of hospital physicians.

OBJECTIVES: To assess whether differences in drug choices of hospital physicians are related to differences in the underlying decision-making process. DESIGN: A survey study was conducted addressing drug choices in six therapeutic fields with existing interprescriber variations; prescribers and non-prescribers of drugs of which the merits were not sufficiently proven (i.e. the 'target drugs') were compared. SETTING: A 1000-bed university hospital in The Netherlands. SUBJECTS: All 85 hospital physicians working in specialities involving one of the selected fields were asked to participate; 72 physicians completed the interviews. MAIN OUTCOME MEASURES: Comparisons were made regarding three elements of the decision-making process: (1) the physicians' expectations of the target drugs and frequently used alternatives, (2) the weights attached to the principal treatment aspects, and (3) the extent to which their actual choice is based on these expectations and weights. RESULTS: In three fields, i.e. anti-emetics, vasodilators, and platelet inhibitors, the prescribers of the less desirable target drugs had higher expectations of these drugs in comparison to the non-prescribers. In the other therapeutic fields, choosing target drugs was related either to attaching less importance to side-effects and costs, or to attaching less importance to reports from clinical trials. Twenty of the 46 treatment choices of the prescribers of target drugs could not be predicted from their expressed views as opposed to 5 of the 36 choices of the non-prescribers (P < 0.05). CONCLUSIONS: Choosing less desirable drugs is not always related to having too high expectations of the drug. Assigning a different importance to certain aspects of the drug and resorting to decision strategies that do not include the weighing of all pros and cons provide alternative explanations for such treatment choices.

Decision Making↗

Characterization of hypertensive subjects who become normotensive during three months of office BP follow-up: comparison with subjects with sustained hypertension and normotensives, and follow-up after two years.

After an observation period of three months, 83% of new hypertensives (n = 84), identified in a population survey, became normotensive. Those with sustained hypertension (n = 14) were compared with 14 initially hypertensives who became normotensive and 14 normotensives, matched for age and sex, using ambulatory and exercise BP and echocardiography (both M-mode and Doppler). The initially hypertensive group (n = 11) was re-examined after two years follow-up. The 24h mean ambulatory and submaximal systolic exercise BP did not differ between sustained (139/92 and 210 mmHg) and initially hypertensives (143/95 and 217 mmHg), being significantly lower in the normotensive group (129/85 and 198 mmHg). Left ventricular mass did not differ between the initially hypertensive and the normotensive groups, being significantly higher in the sustained hypertensives. In both hypertensive groups, as compared with normotensives, the ratio between flow velocity in early and late diastole (E/A ratio) tended to be lower and the early diastolic deceleration time (DT) was significantly shorter. After two years, in the untreated initially hypertensives, office DBP had increased to hypertensive values, without change in ambulatory BP, left ventricular mass or early diastolic deceleration time. The E/A ratio had decreased to a level < 1. We conclude that the subjects who became normotensive after three months office BP follow-up have a BP load and signs of compromised left ventricular diastolic function similar to that of the sustained hypertensives, but without increased left ventricular mass.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Acitretin (Neotigason). A review of pharmacokinetics and teratogenicity and hypothesis on metabolic pathways.

Acitretin was introduced as a replacement for etretinate, the ethyl ester of acitretin. Acitretin is eliminated at a much faster rate than etretinate. Although both drugs are teratogens, the replacement was important especially as it allowed for a much shorter post-medication period in which pregnancy should be precluded. Recent findings showed the presence of etretinate in the plasma of acitretin-treated patients. This article gives a review of known metabolic pathways of the retinoids and tries to elucidate the possible conversion of acitretin into etretinate after acitretin ingestion.

Abnormalities, Drug-Induced↗

Handling of risk-bearing drugs during pregnancy. Do we choose less risky alternatives?

The drug use of nearly 2,000 pregnant women was evaluated at the level of the individual patient for the drugs belonging to the Australian risk categories B3, C and D. The pattern of changes in the use of these drugs is studied in terms of women who discontinue (d), continue (c) or begin (b) using the drug during pregnancy. The ratios d/(c+b) and d/b were the highest for the drugs belonging to the high-risk groups and the lowest for drugs from the low-risk categories. This suggests a congruence between theoretical knowledge and daily practice. Patients who had already been using a drug for a long time before pregnancy, more frequently continued using that drug than patients who had been using the drug only incidentally before. The described daily dose for the riskful drugs was approximately 20% lower in patients who started to use a drug during pregnancy compared to those who continued drug use. The data from this analysis indicate that the prescribing physician is generally aware of the possible risks of drug use during pregnancy. The d/(b+c) and d/b ratios are shown to be a good measure of prescribing behaviour in relation to pregnancy and can be used to compare knowledge of theory and daily practice.

Female↗

Late potentials in a bradycardia-dependent long QT syndrome associated with sudden death during sleep.

The purpose of this study was to determine the incidence of late potentials and their relation to QT prolongation in a family with a high incidence of sudden death during sleep at a young age and bradycardia-dependent QT prolongation (n = 9) and to compare the findings with those in consanguineous family members without QT prolongation (n = 13). Six (67%) of the 9 family members with QT prolongation had late potentials on the signal-averaged electrocardiogram (ECG) compared with 1 of the 13 normal subjects (p less than 0.007). Positive predictive accuracy of the signal-averaged ECG for the detection of subjects with QT prolongation was 86%; negative predictive accuracy was 80%. During exercise testing, the QT interval normalized, whereas late potentials did not change significantly. Exercise testing did not reveal the presence of coronary artery disease as a possible cause of late potentials. It is concluded that 1) compared with family members with a normal QT interval, patients with this type of bradycardia-dependent QT prolongation have a high incidence of late potentials; 2) late potentials persist despite normalization of the QT interval at high heart rates, indicating that there is no direct relation between late potentials and QT prolongation; and 3) late potentials are not caused by coronary artery disease in these subjects. Therefore, the detection of late potentials might be a new aid in the detection and risk stratification of patients with the long QT syndrome. Late potentials possibly indicate a substrate for ventricular tachyarrhythmias in this type of bradycardia-dependent QT prolongation.

Adolescent↗

Effects of early angiotensin-converting enzyme inhibition in a pig model of myocardial ischemia and reperfusion.

In a blind, randomized study, the effects of perindopril, a nonsulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, were compared with those of placebo in a closed-chest pig model of myocardial infarction. In anesthetized pigs, myocardial ischemia and reperfusion were induced by inflation and deflation of a catheter balloon in the left anterior descending coronary artery (LAD), respectively. Thirty minutes after induction of ischemia and 15 min before reperfusion, a bolus injection of 0.06 mg/kg perindoprilat (n = 12), the active compound of perindopril, or placebo (n = 12) was administered in the pulmonary artery of these animals. After the acute phase of myocardial infarction, treatment with 12 mg/day perindopril or placebo was continued orally for 2 weeks. During the entire treatment period, 7 of 12 animals died in the placebo group versus 2 of 12 animals in the perindopril group (Fisher's exact test p less than 0.04). This beneficial effect of perindopril on mortality could not be attributed to salvage of myocardial tissue because the increases in creatine phosphokinase and coronary venous purine levels were similar in perindopril- and placebo-treated animals. Neither were there any significant between-treatment differences in the hemodynamic and (neuro)humoral parameters during the acute phase of myocardial infarction. The difference in mortality was observed within 24 h after myocardial infarction. Prevention of acute pump failure and, especially, life-threatening ventricular arrhythmias may explain this improvement in survival by perindopril. Retrospectively, logistic regression analysis showed that, irrespective of treatment, survival was inversely correlated to plasma renin activity (PRA) before induction of ischemia (r = -0.33; p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

Late potentials in a porcine model of anterior wall myocardial infarction and their relation to inducible ventricular tachycardia.

In this study, normal values for signal averaged electrocardiographic parameters were assessed in healthy pigs (n = 100) and the development of late potentials after myocardial infarction (n = 41) in relation to inducible ventricular tachycardia was investigated. Normal values are: filtered QRS duration (QRS) < or = 78 msec; root mean square voltage of the averaged QRS complex (V(tot)) > or = 51 microV, and duration of terminal activity below 30 microV (D30) < or = 37 msec. The distribution of the root mean square voltage in the last 30 msec (V30) was biphasic. Two weeks after myocardial infarction, QRS was prolonged from 55 +/- 10 to 66 +/- 19 msec (P < 0.002). D30 was prolonged from 19 +/- 6 msec to 28 +/- 13 (P < 0.002). V30 was decreased from 107 +/- 135 microV to 45 +/- 77 (P < 0.02). The total voltage (V(tot)) was decreased from 195 +/- 78 to 123 +/- 61 microV (P < 0.002). In four pigs (19%) late potentials developed. Sustained ventricular tachycardia was inducible in 11 pigs (52%), ventricular fibrillation in two pigs (10%) and eight pigs (38%) were noninducible. Three of 11 inducible pigs and one of the noninducible pigs had a late potential. The incidence of late potentials and their relation to inducible sustained ventricular tachycardia is comparable to the situation in man. Therefore, this pig model is an attractive alternative to the commonly used dog models.

Animals↗

[Dry mouth; possible cause--pharmaceuticals].

Many elderly complain about oral dryness. This complaint can be the result of the use of drugs, because many drugs, such as anti-depressives, anti-psychotics and anti-hypertensives, have an anti-cholinergic or anti-adrenergic action. Knowledge of this potential side-effect of drugs as well as adjustment of schedules of drug usage may result in (partly) relief of dryness-related complaints. In this paper first of all mechanisms that underly negative regulation of salivary secretion are discussed. An overview is given of drugs with an salivary secretion inhibitory action. In addition, suggestions are presented to manage drug-induced hyposalivation.

Aged↗

The angiotensin converting enzyme inhibitor perindopril improves survival after experimental myocardial infarction in pigs.

In this randomized, blinded study the effect of the angiotensin converting enzyme inhibitor perindopril on electrical stability after myocardial infarction in pigs was compared to placebo. The left anterior descending artery was occluded for 45 min. Perindoprilat (0.06 mg/kg, n = 12) or saline (n = 12) was injected 15 min before reperfusion. Treatment was continued till day 13 with perindopril (12 mg, once daily) or placebo. At day 14 an electrophysiologic study was performed. The release of creatine phosphokinase did not differ significantly. During the subsequent days, seven of 12 placebo-treated pigs died (six within 24 h), whereas two of the 12 perindopril-treated pigs died (one within 24 h; p less than 0.04). Sustained ventricular tachycardia was inducible in one of five placebo-treated pigs versus three of 10 perindopril-treated survivors (NS). Late potentials had developed in one placebo-treated pig but not in pigs that received perindopril. Characteristics of infarct border zone heterogeneity (percentages of a reference electrode in viable myocardium) such as a dispersion of current thresholds (127 +/- 96 vs. 238 +/- 463% in perindopril-treated pigs, NS) and refractoriness (9.8 +/- 8.4 vs. 11.9 +/- 6.0% in perindopril-treated pigs, NS) were comparable. This treatment with perindopril significantly improved survival while electrical stability was comparable between survivors. The latter indicates that a comparable electrical stability 2 weeks after myocardial infarction is obtained in perindopril-treated pigs at a significantly higher survival rate.

Angiotensin-Converting Enzyme Inhibitors↗

Captopril modifies the response of infarcted rat hearts to isoprenaline stimulation.

In this study the effect of the angiotensin converting enzyme (ACE) inhibitor captopril on beta-receptor responsiveness was investigated in failing rat hearts after experimental myocardial infarction. Infarcted rats were treated for 8 weeks with either captopril added to the drinking water (100 mg/kg/day; n = 5) or drinking water alone (n = 7). Treatment was started 2-3 days before myocardial infarction. A third group of untreated rats without myocardial infarction served as control (n = 6). At the end of the treatment period the hearts were perfused as described by Langendorff, and a cumulative dose-response curve of isoprenaline was obtained in each heart. In comparison with noninfarcted hearts, the response of heart rate and peak pressure rate (dP/dt) to isoprenaline stimulation was significantly depressed in hearts of infarcted rats. Chronic treatment with captopril significantly attenuated the reduced responsiveness to isoprenaline stimulation. This improved responsiveness in captopril-treated rat hearts might be due to prevention of "down-regulation" of myocardial beta-adrenoceptors. Other factors should also be considered, such as prevention of structural alterations in the noninfarcted myocardium, e.g., myocardial hypertrophy and fibrosis. Differences in infarct size did not play an important role, since infarct size was comparable in both groups of infarcted rats. This partial preservation of beta-adrenergic responsiveness was accompanied by a significant reduction in right ventricular weight and lung weight, suggesting that captopril also improved the signs of heart failure. Therefore, the results of this study indicate that early ACE inhibition in myocardial infarction may be useful in preventing deterioration of cardiac function.

Administration, Oral↗

Effects of converting enzyme inhibitors on coronary flow and myocardial ischemia.

The regulation of coronary hemodynamics is a complex process. One important factor that interferes with the regulation of coronary tone is the pathophysiological state of the vessels: stimuli that in normal vessels provoke no or only a slight vasoconstriction may cause a severe vasoconstriction in diseased vessels. This effect is related to the function of the endothelium and its ability to produce nitric oxide and prostaglandins. The presence of a local renin-angiotensin system implies the possibility of influencing the coronary flow via interference with this local system. Therefore, it is interesting to determine the effects of converting enzyme inhibitors on coronary flow. In animal experiments, a bradykinin-dependent coronary vasodilation by angiotensin-converting enzyme (ACE) inhibitors is suggested. However, reports on the effect of converting enzyme inhibitors in patients with angina pectoris are not consistent. Some authors found an increase in coronary flow and others found no change or a decrease. The importance of the activation of the renin-angiotensin system is discussed. Moreover, it is shown that captopril reduces sympathetic-mediated coronary vasoconstriction during the cold pressor test and that captopril enhances the parasympathetic-mediated bradycardia during the diving response. In conclusion, the effects of converting enzyme inhibitors on coronary flow is an interesting but not fully understood topic. Therefore, the multifactorial mechanism of action of converting enzyme inhibitors deserves further investigation. There are probably subgroups of anginal patients who may benefit from converting enzyme inhibitor therapy. These subgroups have to be defined. Especially, the finding that a converting enzyme inhibitor reduces sympathetically induced coronary vasoconstriction seems promising.

Angiotensin-Converting Enzyme Inhibitors↗

Differences in vasomotor control between human gastroepiploic and left internal mammary artery.

BACKGROUND: Internal mammary artery grafts have a greater long-term patency rate than do saphenous vein grafts. This has in part been attributed to the difference in endothelial function of arterial and venous vessels. The use of the gastroepiploic artery in coronary artery bypass grafting has become popular recently because of its similarity to internal mammary artery. In this study, we compared the endothelial responses of gastroepiploic and left internal mammary arteries to vasoactive substances. METHODS AND RESULTS: Gastroepiploic and left internal mammary arteries were obtained during surgery from patients undergoing elective coronary artery bypass surgery. Vascular rings of both graft types were studied in organ bath experiments. Relaxation responses to metacholine and sodium nitrite were similar in rings of both arteries. In contrast, bradykinin induced potent relaxations in rings of the gastroepiploic artery but not in rings of the left internal mammary artery. Furthermore, there was a inverse correlation of maximal metacholine-induced relaxations with increasing age. CONCLUSIONS: The resemblance of relaxations induced by metacholine and sodium nitrite in both gastroepiploic and left internal mammary arteries suggests a similar activation and behavior of the L-arginine pathway in both arteries. The difference in bradykinin-induced relaxations may reflect a prostaglandin metabolism in the gastroepiploic artery different from that in the left internal mammary artery. Furthermore, maximal metacholine-induced relaxation in rings of the left internal mammary artery shows an age dependency that was not observed in rings of the gastroepiploic artery.

Arteries↗