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Biomedical subjects

W E Haefeli

Publications and source records attributed to W E Haefeli.

At least 91 records · Page 5Linked to original sources
PubMed1993

Glutathione S-transferase mu polymorphism does not explain variation in nitroglycerin responsiveness.

OBJECTIVE: To determine whether the considerable interindividual variability in nitroglycerin-induced venodilation in humans is related to the polymorphic expression of the mu class of glutathione S-transferase (GST mu). Recently vascular glutathione S-transferase (EC 2.5.1.18) of the mu-class (GST mu), a polymorphic group of enzymes present in only about 60% of the population, have been identified and shown in vitro to possess high metabolic activity toward nitroglycerin. Their clinical relevance is unknown. DESIGN: Dose-response relationships to nitroglycerin were constructed in vivo measuring changes in compliance of dorsal hand veins in 26 healthy volunteers during local infusion of small amounts of nitroglycerin. Polymerase chain reaction was applied to detect the deoxyribonucleic acid sequence that codes GST mu in whole blood samples. RESULTS: The GST mu isozyme was present in 15 subjects (58%) and deficient in 11 subjects. Values for mean maximum venodilation (Emax) and dose rates producing 50% of Emax (ED50) were not significantly different between the groups with or without GST mu. The respective values were 98% and 103% dilation for Emax and 9 and 16 ng/min for ED50. There was no gender difference in the venodilatory response to nitroglycerin. CONCLUSIONS: Subjects lacking GST mu can clearly respond normally to nitroglycerin, and the large interindividual variability in nitroglycerin potency is not related to the expression of this polymorphic enzyme. Intersubject variability is therefore more likely to be the result of differences in the presence or activity of other vascular enzymes or in steps further distal in the venodilatory cascade.

Adult↗
PubMed1993

Evidence for activation of the sympathetic nervous system by recombinant human interleukin-1 beta in humans.

Administration of interleukin-1 beta (IL-1 beta) to humans initiates a cascade of metabolic, hematologic, and cardiovascular events. To investigate the role of the sympathetic nervous system in the early cardiovascular response to IL-1 beta in humans, we recorded the heart rate, blood pressure, and changes in hand vein compliance in five patients with malignant melanoma treated with a 30-min infusion of 10,000-20,000 U/kg of human recombinant IL-1 beta. All patients developed fever, chills, and marked hemodynamic changes. During or shortly after the infusion, a dramatic decrease in hand vein compliance occurred (vasoconstriction). At the time of maximum venoconstriction (35 min after the start of the IL-1 beta infusion), the mean heart rate and systolic blood pressure were significantly increased by 30 mm Hg and 31 beats/min, respectively. Venoconstriction always preceded the onset of chills by several minutes (mean of 7 min), was closely correlated with the heart rate, and could be reversed by local administration of the alpha-antagonist phentolamine, indicating involvement of catecholamines. Our study shows that cardiovascular responses that occur early after IL-1 beta administration in humans are most likely the result of adrenergic stimulation possibly through its effect on the central nervous system.

Adult↗
PubMed1993

Lack of role of endothelium-derived relaxing factor in effects of alpha-adrenergic agonists in cutaneous veins in humans.

In some blood vessels, the alpha 2-adrenergic agonist clonidine simultaneously activates vasoconstrictive alpha-adrenoceptors on smooth muscle cells and endothelial alpha 2-adrenoceptors mediating release of endothelium-derived relaxing factor (EDRF), with the net vascular response representing a balance between these two counteracting pathways. To investigate whether clonidine's modest constrictor effect in human veins is due to simultaneous release of EDRF, the dorsal hand vein compliance technique was used to measure vascular responses in healthy volunteers. Clonidine-induced venoconstriction was not potentiated by methylene blue, an inhibitor of EDRF-mediated relaxation. After preconstriction with angiotensin II, clonidine did not cause venodilation but rather promoted further constriction, which could be reversed by the alpha 1-antagonist labetalol. However, in veins preconstricted with the full alpha 1-agonist phenylephrine, clonidine induced venodilation, suggesting that clonidine is a partial agonist at venous alpha 1-adrenoceptors. In conclusion, we found no evidence for endothelial alpha 2-adrenoceptor-mediated release of EDRF in human hand veins. The results further suggest that postjunctional alpha 1-adrenoceptors participate in clonidine-induced venoconstriction in humans.

Adrenergic alpha-Agonists↗
PubMed1993

Responsiveness to bradykinin in veins of hypercholesterolemic humans.

BACKGROUND: Hypercholesterolemia impairs endothelium-dependent dilation in arteries. We tested the hypothesis that hypercholesterolemia impairs endothelium-dependent vasodilation by an interaction between elevated plasma lipoproteins and a presumably normal endothelium using human veins in vivo; veins do not generally develop atherosclerosis and are appropriate for testing functional alterations. METHODS AND RESULTS: Full dose-response curves were constructed in 13 hypercholesterolemic and 12 normocholesterolemic subjects by infusing bradykinin (0.25 to 508 ng/min) into hand veins preconstricted with the alpha-adrenergic agonist phenylephrine. The maximal relaxation induced by bradykinin was 80 +/- 38% in the controls and 103 +/- 40% in subjects with hypercholesterolemia (P = .08). Responsiveness to bradykinin was also determined after infusion of indomethacin (5.4 micrograms/min), a cyclooxygenase inhibitor, to block the contribution of prostaglandins; maximal responsiveness was greater in hypercholesterolemic subjects (112 +/- 41%) than in controls (81 +/- 31%) (P = .03). Hypercholesterolemic subjects were more sensitive to bradykinin, with an ED50 of 4.2 ng/min versus 10.9 ng/min in controls (P = .05); a similarly increased sensitivity was found in the presence of indomethacin. The response to a maximally effective dose of nitroglycerin was greater in hypercholesterolemic subjects (142 +/- 31%) versus 106 +/- 28% in controls (P = .007). In five hypercholesterolemic subjects, treated with lovastatin to normalize serum cholesterol concentrations, maximal responsiveness to bradykinin decreased from 103 +/- 52% to 80 +/- 28%. CONCLUSIONS: These results demonstrate that hypercholesterolemia in humans does not impair endothelium-derived relaxing factor-mediated venodilation.

Adult↗
PubMed1993

Evaluation of conventional chest tube therapy for iatrogenic pneumothorax.

STUDY OBJECTIVE: To assess conventional, large chest tube therapy in iatrogenic pneumothorax and to determine the optimal moment when to use more invasive procedures. DESIGN: Retrospective chart review. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Forty-seven patients with needle-induced iatrogenic pneumothorax. Twenty-four patients had an underlying pleural or pulmonary disorder. INTERVENTIONS: After insertion of a 20- to 24-French plastic chest tube connected to an underwater seal, suction was maintained until gas egress stopped or up to 10 days in patients with a persisting gas leak. RESULTS: In 96 percent, a definite occlusion of the pneumothorax was achieved. In all patients without an underlying lung disorder, gas egress stopped definitely after 72 h. In the presence of an underlying lung disorder, 92 percent of the pneumothoraces were healed after 10 days of continuous suction therapy. At 72 h, only 71 percent of the latter group were healed (p < 0.05 vs patients without lung disease). No major complication of chest tube therapy occurred. CONCLUSION: Conventional chest tube therapy is a safe and effective treatment for iatrogenic pneumothorax. In patients with an underlying lung disease, gas egress may last for up to 10 days. In these patients, the earlier use of a more invasive approach may be justified if the air leak persists.

Adult↗
PubMed1992

[Drug-induced hyperprolactinemia and galactorrhea].

A 21 year old female treated for recurring gastric troubles with dopamine-antagonists (domperidone, metoclopramide) developed a clinically manifest hyperprolactinemia (3055 microU/l; normal value < 650 microU/l) with galactorrhea only two days after a new two day course of metoclopramide. The drug was withdrawn and within days mastodynia and galactorrhea subsided. A control of plasmatic prolactin two weeks later yielded a normal value (358 microU/l). After administration of metoclopramide or domperidone hyperprolactinemia is regularly observed and galactorrhea has been described earlier. It is unclear why this patient inspite of repeated administration of one dopamine antagonist remained asymptomatic whereas the other after a short time and only a few doses led to galactorrhea. It is conceivable that differences in passage into the cerebrospinal fluid or the better penetration of the blood-brain barrier favored the development of galactorrhea under metoclopramide. This case served to discuss the pathophysiologic background of drug-induced hyperprolactinemia.

Adult↗
PubMed1992

Possible risk for cardiac arrhythmia related to intravenous erythromycin.

OBJECTIVE: To evaluate the incidence of prolongation of the rate-corrected electrocardiographic QT interval (QTc) and of ventricular arrhythmia associated with intravenous administration of erythromycin lactobionate. DESIGN: A consecutive series of 7 critically ill patients treated with intravenous erythromycin for severe pneumonia. SETTING: A medical intensive care unit of a university hospital. MEASUREMENTS AND RESULTS: Registration of QTc duration before and after intravenous administration of erythromycin as a short infusion. Blood chemistry, hemodynamic variables, arrhythmias, and co-medications were recorded. Evaluation of at least 10 ECG intervals by 2 experienced investigators who were blinded as to the time of drug administration. If several measurements were performed in the same patient, only the mean value was used for further analysis. During 12 of 13 drug administrations studied in 7 patients QTc prolongation was observed. The extent of QTc prolongation was significantly correlated with the infusion rate (mg/min, r = 0.765, p = 0.05). In 3 patients ventricular arrhythmia occurred in close temporal relation to the erythromycin infusion; two of them developed ventricular fibrillation shortly after the first and second dose of erythromycin, respectively, and died within 3 h. CONCLUSION: In critically ill patients erythromycin-induced QTc prolongation is a frequent pharmacologic effect correlated with erythromycin infusion rate. To avoid changes in electrocardiographic intervals and thereby possibly potentially life-threatening ventricular arrhythmia administration with the lowest possible infusion rate and close cardiac rhythm monitoring are advisable in these patients.

Aged↗
PubMed1992

Comparison of vasodilatory responses to nitroglycerin and its dinitrate metabolites in human veins.

Independent of the route of nitroglycerin administration, substantial amounts of 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl dinitrate (1,3-GDN) metabolites accumulate in humans. Thus far their pharmacologic activity in comparison to nitroglycerin in humans is unknown. To compare the venodilatory potency of nitroglycerin and of 1,2-GDN and 1,3-GDN in vivo, cumulative dose-response curves were established in nine healthy volunteers by use of the dorsal hand vein compliance technique. Separated by a washout period, two of the three venodilators were infused in randomized order after preconstriction with phenylephrine. Values for maximum vasodilation were similar for all compounds: nitroglycerin, 109%; 1,2-GDN, 100%; and 1,3-GDN, 106%. The respective values for the dose rate exerting 50% of maximum vasodilation were 5.1, 43, and 60 ng/min, indicating that the dinitrates were about 10 times less potent than nitroglycerin (p < 0.001) but not significantly different from each other. The findings support the hypothesis that activity of nitroglycerin metabolites is related to the number of nitrate groups in the molecule and are in agreement with lower dinitrate potencies found in animal experiments.

Adult↗
PubMed1991

Concentration-effect relations of 5-hydroxypropafenone in normal subjects.

To evaluate the pharmacologic activity of 5-hydroxypropafenone, electrocardiographic changes (PQ and QRS duration) and blood pressure levels were measured in 6 healthy extensive metabolizers of debrisoquine after a single oral dose of 300 mg of this metabolite as a solution in a placebo-controlled, double-blind crossover study. Well-absorbed, with a lag time of 4.4 to 9.8 minutes, 5-hydroxypropafenone reached peak concentrations of 153 to 337 ng/ml after 20 to 51 minutes. The terminal half-life was 506 to 963 minutes. To describe the temporal aspects of the concentration-effect relation, a pharmacokinetic-pharmacodynamic model with a hypothetical effect compartment was applied. The relation between electrocardiographic changes and drug concentration at the effect site could be described by a linear regression model. Significant prolongations of PQ and QRS duration were found in 5 of 6 subjects. There were no changes in QTc interval, blood pressure measurements and heart rate in the supine position. However, blood pressure measurements in the upright position revealed a greater percent decrease of systolic blood pressure than with placebo (mean +/- standard deviation -25.6 +/- 13.8% vs -3.4 +/- 13.1%, p less than 0.05). It is concluded that 5-hydroxypropafenone exerts significant pharmacologic activity in humans as well as animals. Because QRS prolongation in patients treated with class IC antiarrhythmic drugs correlates with the antiarrhythmic effect, our data suggest that 5-hydroxypropafenone may contribute to the therapeutic activity of propafenone in humans.

Administration, Oral↗
PubMed1991

Timing of invasive procedures in therapy for primary and secondary spontaneous pneumothorax.

Timing of invasive procedures during chest tube therapy in spontaneous pneumothorax is undefined. Evaluation of 115 patients with primary and secondary spontaneous pneumothorax treated with tube thoracostomy revealed nearly maximal healing rates after 48 hours without a relevant increase if drainage was maintained for up to 10 days. In secondary spontaneous pneumothorax, a significantly lower healing rate was observed after 48 hours compared with primary spontaneous pneumothorax (60% vs 82%). Therapeutic success was not predictable by single clinical variables available at admission (eg, age, gender, and smoking habits) nor by their combinations. Recurrence rates were 30% in both primary and secondary spontaneous pneumothorax. Hospital stay averaged 6 days in primary and 15 days in secondary spontaneous pneumothorax. Considering their efficacy and the low incidence of complications, the early use of invasive procedures such as surgical pleurectomy, after 48 hours of persistent gas leaking, seems justified. Shorter in-patient care and lower recurrence rates may result.

Adult↗
PubMed1990

[Tattooing and its significance in Switzerland. A representative study of 2177 20-year-old Swiss subjects].

To investigate the incidence, significance and symbolism of tattooing in Switzerland, a representative group of 2177 young males (all liable for military service, age 19-21 years) were examined in 1988. All tattoos were sketched, the location was recorded and the individual meaning was discussed with the bearer. 135 subjects (6.2%) had 1-9 tattoos per person, showing 155 different marks. Only 13% of all tattoos were professional, moderate to large in size and most often located in the area of the upper arm and the shoulder. 87% of tattoos were self-inflicted or placed by a friend and the left side was therefore preferred (66%). In general, these were small to moderate in size, simple in design, and usually located on the forearm and the hand. The dominant significance of all tattoos was related to mental attitude (29%) and love affairs (14%). 13% were pictorial. Some were related to drug abuse, criminality of gangs, or contained magic symbolism or personal data such as zodiac signs and initials (about 4% each). Only 20% had no conventional or private meaning or involved concealed symbolism. For further understanding of the individuals' social history, it should be noted that some tattoos were characterized by minor differences of meaning, such as the "man-in-4-walls" mark (= prison), the "fuck-the-police" mark, the leaf of cannabis sativa or different cross motifs. Even greater consistency related to tattoos located in the web space between the thumb and the forefinger or on the back of the fingers. The location in itself may therefore provide additional personal information on individual circumstances at the time of tattooing.

Adult↗
PubMed1990

[Clinical aspects of severe digitalis poisoning and its treatment with and without digoxin-specific antibodies. 3 case reports].

Although elevated digitalis concentrations are often observed, symptomatic intoxications occur less frequently. We report the course in three patients with extremely elevated digitalis concentrations as examples of the poor correlation between measured serum levels and symptoms. In view of the cost of treatment by fab-fragments and the lack of a close dose-related effect of digitalis, we suggest restricting the use of fab-fragment therapy to patients with severe hyperkalemia or hemodynamically relevant arrhythmias.

Adult↗
PubMed1990

Potent inhibition of cytochrome P450IID6 (debrisoquin 4-hydroxylase) by flecainide in vitro and in vivo.

Flecainide acetate, a class Ic antiarrhythmic agent, is eliminated to a larger extent by renal excretion and to a minor extent by the liver. In patients with impaired renal function or with elevated urinary pH, however, its elimination is dominated by hepatic metabolism. Recent evidence suggests that the in vivo metabolism of flecainide is controlled by the genetic polymorphism of the debrisoquin/sparteine type; i.e., it is a substrate of cytochrome P450IID6. We investigated the inhibitory effect of flecainide on bufuralol 1'-hydroxylation in human liver microsomes in vitro and on the metabolic dextromethorphan urinary ratio in eight healthy male volunteers. Both bufuralol and dextromethorphan are well-known substrates of cytochrome P450IID6. Microsomal bufuralol 1-hydroxylation was competitively inhibited by flecainide with an apparent Ki of 0.954 mumol/L. Moreover, a statistically significant increase in the urinary metabolic ratio (MR) of dextromethorphan/dextrorphan after 1 week of administration of oral flecainide was observed (p = 0.013) in all subjects. One individual increased the urinary MR to a value consistent with the poor metabolizer phenotype. We conclude that flecainide is a potent inhibitor of cytochrome P450IID6 in vitro and in vivo and that careful drug monitoring is required with respect to renal function, debrisoquine phenotype, and concomitant drug administration.

Adult↗
PubMedDate not supplied

Influence of intensive physical training on urinary nitrate elimination and plasma endothelin-1 levels in patients with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) is associated with increased peripheral vascular resistance. Exercise-induced shear stress may release endothelial relaxing factors, such as nitric oxide (NO), and inhibit the production of vasoconstrictors such as endothelin-1 (ET-1) thereby modulating vascular tone. We examined the effect of intensive training on ET-1 plasma concentrations and NO-metabolite elimination in patients with CHF after acute myocardial infarction. METHODS: Seventeen patients with CHF after a myocardial infarction were randomized to an exercise group (n = 9), who performed physical training for 8 weeks, or a control group (n = 8) who received usual care. A physical examination, pulmonary function test, and a maximum exercise test were performed, and 24-hour urinary nitrate elimination and ET-1 in plasma were determined before and at the end of the study period. RESULTS: Maximal oxygen uptake remained unchanged in controls (17.9 +/- 1.4 to 18.1 +/- 1.5 mL/(kg min) but increased in the exercise group (from 20.4 +/- 0.75 to 26.7 +/- 1.4 mL/(kg min). After 8 weeks the urinary nitrate elimination in controls was significantly decreased (1.25 +/- 0.20 to 1.03 +/- 0.22 mmol/24 hours; P < 0.001), while it was unchanged in the exercise group (1.26 +/- 0.23 to 1.39 +/- 0.28; P = 0.71). Plasma ET-1 levels did not change after 8 weeks (7.87 +/- 0.62 versus 7.57 +/- 0.75 and 7.13 +/- 0.6 versus 7.35 +/- 0.7 pg/mL for control and exercise groups, respectively). CONCLUSION: In patients with CHF after acute myocardial infarction nitrate elimination decreases over the subsequent 2 months. This trend was reversed by training. Because nitrate elimination mirrors endogenous NO production, these results suggest that training may positively influence endothelial vasodilator function.

Endothelin-1↗