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Biomedical subjects

F Follath

Publications and source records attributed to F Follath.

At least 55 records · Page 3Linked to original sources

[Comparative evaluation of ACE inhibitors: which differences are relevant?].

ACE inhibitors are well established in the treatment of arterial hypertension, heart failure and diabetic and/or hypertensive nephropathy with albuminuria. The important trials for the various indications are briefly discussed. In Switzerland 11 ACE inhibitors are available for clinical use, differing mainly in their pharmacokinetic and pharmacodynamic properties. The characteristics of practical relevance regarding oral bioavailability, elimination mechanisms and half-life, as well as the necessary dosage modifications in patients with renal, hepatic and cardiac failure, are presented. All ACE inhibitors except captopril and lisinopril are administered as prodrugs. The bioavailability among ACE inhibitors varies widely with a range from 11% (trandolapril) to more than 60% (captopril). The great majority of ACE inhibitors are eliminated predominantly through the kidneys. However, benazepril, fosinopril, ramipril, spirapril and trandolapril also have a hepatic (metabolic) route of elimination. Since half-life varies from 1 h (captopril) to 30 h (spirapril) we drew up, for simplicity, a table of 3 groups with short, medium and long t1/2. In renal insufficiency dose adjustment is required only below a creatinine-clearance level of 30 ml/min. These dosage reductions are not required in liver diseases, but renally excreted drugs such as lisinopril should be preferred. Treatment with ACE inhibitors in severe heart failure should be initiated carefully, with low doses and concomitant diuretic treatment added or maintained. Most common adverse effects of ACE inhibitors are hypotension, cough, hyperkalaemia and renal failure. Less frequent adverse effects are angioedema, bone marrow suppression and also foetal damage. Thus, ACE inhibitors are contraindicated in pregnancy.

Angiotensin-Converting Enzyme Inhibitors↗

[New cardiovascular drugs: expanded therapeutic possibilities in coronary heart disease and in heart failure].

Important novel developments in the pharmacotherapy of cardiovascular diseases are briefly summarized. New results with lipid lowering statins in secondary prevention of atherosclerosis are mentionned. Atorvastatin, introduced recently, is compared to the other statins. The extended possibilities for inhibition of platelet-aggregation in coronary disease and after interventional coronary therapy with ticlopidine, clopidogrel and specific antagonists of platelet integrin IIb/IIIa receptors (abciximab, tirofibrane) as well as fibrinolysis with reteplase are covered. Among modern trends in pharmacotherapy of heart failure studies with angiotensin-II-receptor inhibition (losartane and related compounds) or betablockers (carvedilol) are worth mentioning.

Cardiovascular Agents↗

Within-patient comparison of effects of different dosages of enalapril on functional capacity and neurohormone levels in patients with chronic heart failure.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are established as first-line therapy in chronic heart failure (CHF). However, conflicting results exist regarding the dose-effect relation of ACE inhibitors. METHODS: We investigated 45 patients (age 55 +/- 10 years) with stable CHF who presented with a maintenance dosage of enalapril of either 5 mg given twice daily (E10; n = 16), 10 mg given twice daily (E20; n = 18), or 20 mg given twice daily (E40; n = 11). This dosage was changed 3 times to treat all patients with lower, higher, and the initial dosages for 4 weeks each. Neurohormones (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], and norepinephrine) and enalaprilat trough levels were measured, and ergospirometry was performed. RESULTS: Changes in enalapril dose and enalaprilat level were concordant in 82% of patients, indicating good compliance. After augmentation of enalapril to 40 mg daily, patients in the E10 group showed an increase in maximal oxygen consumption and a decrease in neurohormonal stimulation, whereas the opposite changes were observed after reduction of enalapril to 10 mg daily in patients in the E20 and E40 groups (maximal oxygen consumption: Delta1.1 +/- 2.0 vs -1.0 +/- 1.9 mL. kg(-1). min(-1), P <.01; ANP: Delta-63 +/- 106 vs 19 +/- 54 pg/mL, P <.01; BNP: Delta-62 +/- 104 vs 18 +/- 89 pg/mL, P <.05; norepinephrine: Delta-1.3 +/- 2.9 vs 0.6 +/- 1.8, P <.05). Within-patient comparison showed that neurohormone levels were higher and exercise capacity lower while patients were receiving 10 mg of enalapril per day than when they were receiving 40 mg per day (ANP: 172 +/- 148 vs 139 +/- 122 pg/mL, P <.01; BNP: 193 +/- 244 vs 152 +/- 225 pg/mL, P <.005; norepinephrine: 4.2 +/- 2.2 vs 3.5 +/- 1. 6 nmol/L, P <.05; maximal oxygen consumption 22.0 +/- 4.4 vs 21.3 +/- 4.3 mL. kg(-1). min(-1) P <.05). Similar differences were observed when comparing these variables, and patients had lowest and highest enalaprilat trough levels. CONCLUSIONS: High doses of enalapril resulted in an improvement of exercise capacity and reduction of neurohumoral stimulation, whereas these parameters worsened after reduction of enalapril dose. Thus patients with congestive heart failure may benefit from increasing dosage of ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗

Profound ECG abnormalities during emergency cesarean section in a patient with pre-eclampsia.

A case of severe ECG abnormalities occurring during pre-eclampsia is presented. Although these electrocardiographic changes were indicative of severe alterations of coronary flow, neither structural nor functional abnormalities could be documented during subsequent diagnostic workup. The pathogenetic pathways potentially involved in this case including coronary spasms are briefly discussed.

Adult↗

Nonischemic heart failure: epidemiology, pathophysiology, and progression of disease.

The prevalence of nonischemic heart failure including idiopathic dilative cardiomyopathy is not well known. It may vary considerably in different population sub-groups and geographic areas. In ambulatory and hospitalized patients with clinically manifest heart failure primary cardiomyopathy is diagnosed in 2-15%, while in recent large scale therapeutic trials the proportion of patients with nonischemic heart failure ranged from 18% to 53%. There is a relation between sex, age and etiology of chronic heart failure, nonischemic cardiomyopathy being more frequent in women and in younger individuals. In contrast to ischemic heart failure, where the severity usually correlates with the extent of coronary artery lesions, the pathophysiology of cardiomyopathy is less clear. Genetic factors, myocarditis from infectious agents, auto-immune mechanisms, cytokine activation, hormonal and metabolic influences can play a role. The functional consequences of myocardial damage in nonischemic heart failure is a global instead of localized abnormality of ventricular contractility. There is epidemiological evidence that in general the prognosis of nonischemic heart failure is better than in ischemic heart failure. The mortality of patients with ischemic heart failure was usually higher in the placebo groups of recent heart failure trials than in patients with nonischemic etiology. Furthermore, therapeutic responses to angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, amlodipine and amiodarone were also different in some studies. The outcome of nonischemic heart failure is better even in transplant candidates with the most advanced stages of heart failure, they survive longer and respond better to intensified drug regimens than patients with similar clinical severity of ischemic heart failure. Thus, an early and precise diagnosis of the etiology of heart failure should be encouraged not only in clinical trials but also in every day patient management. As more therapeutic options are developed, individualized drug selection for patients with various etiologies of heart failure may become possible.

Animals↗

Oxygen uptake kinetics during low level exercise in patients with heart failure: relation to neurohormones, peak oxygen consumption, and clinical findings.

OBJECTIVE: To investigate whether oxygen uptake (VO2) kinetics during low intensity exercise are related to clinical signs, symptoms, and neurohumoral activation independently of peak oxygen consumption in chronic heart failure. DESIGN: Comparison of VO2 kinetics with peak VO2, neurohormones, and clinical signs of chronic heart failure. SETTING: Tertiary care centre. PATIENTS: 48 patients with mild to moderate chronic heart failure. INTERVENTIONS: Treadmill exercise testing with "breath by breath" gas exchange monitoring. Measurement of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and noradrenaline. Assessment of clinical findings by questionnaire. MAIN OUTCOME MEASURES: O2 kinetics were defined as O2 deficit (time [rest to steady state] x DeltaVO2 -sigmaVO2 [rest to steady state]; normalised to body weight) and mean response time of oxygen consumption (MRT; O2 deficit/DeltaVO2). RESULTS: VO2 kinetics were weakly to moderately correlated to the peak VO2 (O2 deficit, r = -0.37, p < 0.05; MRT, r = -0.49, p < 0.001). Natriuretic peptides were more closely correlated with MRT (ANF, r = 0.58; BNP, r = 0.53, p < 0.001) than with O2 deficit (ANF, r = 0.48, p = 0.001; BNP, r = 0.37, p < 0.01) or peak VO2 (ANF, r = -0.40; BNP, r = -0.31, p < 0.05). Noradrenaline was correlated with MRT (r = 0. 33, p < 0.05) and O2 deficit (r = 0.39, p < 0.01) but not with peak VO2 (r = -0.20, NS). Symptoms of chronic heart failure were correlated with all indices of oxygen consumption (MRT, r = 0.47, p < 0.01; O2 deficit, r = 0.39, p < 0.01; peak VO2, r = -0.48, p < 0. 01). Multivariate analysis showed that the correlation of VO2 kinetics with neurohormones and symptoms of chronic heart failure was independent of peak VO2 and other variables. CONCLUSIONS: Oxygen kinetics during low intensity exercise may provide additional information over peak VO2 in patients with chronic heart failure, given the better correlation with neurohormones which represent an index of homeostasis of the cardiovascular system.

Adult↗

Long term follow up of prosthetic valve endocarditis: what characteristics identify patients who were treated successfully with antibiotics alone?

OBJECTIVE: To identify predictors for the safe use of antibiotic treatment without reoperation in patients with prosthetic valve endocarditis. SETTING: Retrospective study in a tertiary care centre. SUBJECTS AND DESIGN: All 49 episodes of definite prosthetic valve endocarditis (Duke criteria) diagnosed at one institution between 1980 to 1997 were analysed. Ten episodes (20%) were treated with antibiotics only (antibiotic group) and 39 episodes (80%) with combined antibiotic and surgical treatment (surgery group). The analysis included detailed study of hospital records and data on long term follow up which were obtained in all patients by a questionnaire or telephone contact with physician or patient. The length of follow up (mean (SD)) was 41 (32) months in the antibiotic group and 45 (24) months in the surgery group (NS). Long term survival was estimated by the Kaplan-Meier method and compared by the log-rank test. RESULTS: There was no significant difference in age, history of previous endocarditis, number of previous heart operations, vegetations, emboli, type of prosthesis, or percentage of early prosthetic valve endocarditis and positive blood cultures between the two groups. In the antibiotic group, there were more enterococcal (50%; p = 0.005) and in the surgery group more staphylococcal infections (55%; p = 0.048). Annular abscesses (p < 0. 0001) and aortoventricular dehiscence (p = 0.02) were more common in the surgery group. No patient in the antibiotic group had heart failure. Long term follow up showed no significant difference between the surgery and antibiotic groups regarding late mortality (14% v 18%) and five year rates of recurrent endocarditis (14% v 16%), event related mortality (14% v 3%, log-rank test), and the need for reoperation (14% v 19%; log-rank test). The only patient with conservatively treated staphylococcal prosthetic valve endocarditis died after reoperation for recurrence. CONCLUSIONS: Haemodynamically stable patients with non-staphylococcal prosthetic valve endocarditis who are carefully supervised can be treated with antibiotics alone without an increased rate of reinfection, reoperation, or death.

Adolescent↗

Is blood pressure response to the Valsalva maneuver related to neurohormones, exercise capacity, and clinical findings in heart failure?

OBJECTIVES: To investigate the relationship of the BP response to the Valsalva maneuver (VM) to parameters of congestive heart failure (CHF) other than hemodynamic measures. DESIGN: Comparison of neurohormones (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], norepinephrine [NE]), parameters of spiroergometry, and clinical parameters with BP response to the VM. SETTING: Tertiary care center. PATIENTS: Forty-five patients with stable CHF (ejection fraction, 28 +/- 7%). MEASUREMENTS: Pulse amplitude ratio (PAR) calculated between the end and the beginning of the VM using the last two and the first three beats of the straining phase. Failure of the systolic BP to fall below the resting level during the VM. RESULTS: Patients in the New York Heart Association class III (n = 15) had a higher PAR than those in class II (0.82 +/- 0.21 vs 0.63 +/- 0.20; p < 0.01). There was a close correlation between PAR and ANP (r = 0.76) and BNP (r = 0.62), whereas other parameters were less well correlated (eg, for peak f1.gif" BORDER="0">O(2), r = -0.35; p < 0.05). Patients with failure of the systolic BP to fall below the resting level (n = 24) had higher neurohormones (mean ANP, 246 +/- 158 vs 84 +/- 43 pg/mL; mean BNP, 282 +/- 289 vs 81 +/- 85 pg/mL; p < 0.001; mean NE, 3.9 +/- 1.7 vs 3.4 +/- 1.5 nmol/L; nanosecond), lower exercise capacity (19.8 +/- 5.2 vs 23.0 +/- 3.7 mL/kg/min; p < 0.05), and their quality of life (Minnesota questionnaire) was more compromised (31 +/- 19 vs 18 +/- 15; p < 0. 05). CONCLUSIONS: The BP response to the VM is related to a broad range of clinical and neurohumoral parameters of CHF. Whether or not it is also related to prognosis remains to be determined. Nevertheless, this easily applicable test should be part of the assessment of patients with CHF.

Adult↗

Plasma levels of enalaprilat in chronic therapy of heart failure: relationship to adverse events.

Angiotensin-converting enzyme (ACE) inhibitors are established as first-line therapy in chronic heart failure (CHF). However, little is known about the dosage-plasma-level relationship of ACE inhibitors in CHF and its relation to drug-induced adverse effects. We investigated 45 patients (age 55 +/- 10 years) with stable CHF who presented with a maintenance dosage of enalapril of either 5 mg b.i.d. (E10, n = 16), 10 mg b.i.d. (E20, n = 18), or 20 mg b.i.d. (E40, n = 11). This dosage was changed three times to treat all patients with lower, higher, and, finally, the initial dosage for 4 weeks each. Patients were examined clinically, by questionnaire, and by spiroergometry. In addition, neurohormones (atrial and brain natriuretic peptide and norepinephrine), enalaprilat trough levels, and serum potassium and creatinine were measured. Enalaprilat trough levels differed significantly between the three groups at study entry but also varied markedly within each group. In addition to the dose of enalapril, serum creatinine, severity of CHF, basal metabolic rate, and body weight significantly influenced enalaprilat trough levels (R2 =.84, p <.001). Within-patient comparisons revealed that serum creatinine (107 +/- 26 versus 102 +/- 20 micromol/liter) and potassium (3.8 +/- 0.4 versus 3.7 +/- 0. 3mmol/liter) were higher, cough was more common (scored on a scale of 0-8: 1.7 +/- 2.1 versus 1.4 +/- 1.8), and blood pressure was lower (systolic, 112 +/- 14 versus 117 +/- 13 mm Hg; diastolic, 66 +/- 9 versus 69 +/- 11 mm Hg) on the highest than on the lowest enalaprilat trough level (all p <.05). Highly variable enalaprilat trough levels and the fact that adverse effects were more common on high enalaprilat trough levels provide a rationale for individually adjusting ACE-inhibitor dose in case of adverse effects.

Adult↗

Myocardial amiodarone concentrations after short- and long-term treatment in patients with end-stage heart failure.

BACKGROUND: Pharmacokinetics and tissue concentrations of amiodarone may vary considerably in end-stage heart failure, but may be crucial for treatment efficiency and antiarrhythmic drug therapy. OBJECTIVE: This study was undertaken to determine plasma amiodarone and desethylamiodarone concentrations and to determine whether they correlate with myocardial concentrations in explanted hearts from patients with end-stage heart failure. PATIENTS AND METHODS: Eight patients with idiopathic dilated cardiomyopathy and normal coronary arteries were included in the present study. Myocardial tissue samples (seven sites) and epicardial fat were taken from each explanted heart, and drug concentrations of amiodarone and desethylamiodarone were determined. In addition, plasma drug levels were measured and compared with the myocardial amiodarone/desethylamiodarone concentrations. RESULTS: The mean cumulative amiodarone dose was 91 g and the mean plasma concentrations of amiodarone and desethylamiodarone were 0.68 and 0.84 microg.ml(-1), respectively. The tissue concentrations of amiodarone amounted to 13.2 and 28.3 microg.g(-1), respectively, in the atria and to 13.0 and 40.8 microg.g(-1), respectively, in the ventricles. The distribution of the drug and its metabolite were similar in the right and left ventricles. There was a good correlation between myocardial concentration of amiodarone and desethylamiodarone and the cumulative ingested dose of amiodarone. Tissue drug concentrations correlated only poorly with plasma amiodarone or desethylamiodarone levels. The highest drug levels were measured in the epicardial fat tissue, where the ratio of amiodarone 105 microg.g(-1) to desethylamiodarone 32 microg.g(-1) was reversed (3.3 compared with 0.29 in the ventricles). Thus, amiodarone concentrations in epicardial fat were approximately 10 times higher than myocardial and 150 times higher than plasma levels. CONCLUSIONS: Our data confirm the slow equilibrium of amiodarone and desethylamiodarone concentrations between plasma and myocardium. Myocardial tissue concentrations of desethylamiodarone and, to a lesser degree, amiodarone correlate with the cumulative ingested dose of amiodarone. Monitoring of the total cumulative dose may be more relevant clinically than monitoring plasma levels. These results support the clinical practice of reducing the maintenance dose of amiodarone in patients who are on long-term treatment.

Amiodarone↗

Etiology and response to drug treatment in heart failure.

Clinical trials in heart failure (HF) tend to randomize patients according to demographic characteristics and severity of left ventricular dysfunction, without taking account of the precise diagnosis. This article reviews results from recent trials suggesting that the etiology of HF, and particularly whether it is ischemic or nonischemic, may influence the long-term prognosis and the response to treatment. Some studies, but not all, suggest that nonischemic HF has a better prognosis than ischemic HF. The data on the benefits of angiotensin-converting enzyme inhibitors in ischemic versus nonischemic HF are conflicting. Carvedilol, and recently, bisoprolol have been shown to reduce mortality in ischemic and nonischemic HF, whereas metoprolol has, to date, improved prognosis only in dilated cardiomyopathy. Better responses to digoxin, amlodipine and amiodarone have been reported in non-ischemic HF. There is at present no clear explanation for the apparent therapeutic differences between ischemic and nonischemic HF. Absence of a rigorous definition of "nonischemic HF" in many studies makes interpretation of the results difficult. Further studies to clarify the effects of etiology of HF on the response to treatment could be particularly important for preventing progression to more advanced stages, in which any type of drug therapy may have limited value in prolonging survival. An individualized therapeutic approach, based on etiology of HF and possibly other factors such as plasma drug levels or the levels of neurohormones, could result in major progress in treating HF patients.

Adrenergic beta-Antagonists↗

Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man.

AIMS: Saquinavir is a potent HIV protease inhibitor whose effectiveness is limited in vivo by its low bioavailability. Since saquinavir is metabolized by CYP3A4, the effect of grapefruit juice, an inhibitor of CYP3A4, was investigated on its bioavailability. METHODS: After an overnight fast, eight healthy volunteers were treated with either 400 ml grapefruit juice or water before intravenous (12 mg) or oral saquinavir (600 mg) was administered. Serial blood samples were obtained over the following 24 h and standardized meals were served 5 and 10 h after the administration of saquinavir. The plasma concentrations of saquinavir were determined by high-performance liquid chromatography and pharmacokinetic parameters were calculated by routine methods. RESULTS: The AUC was not affected by grapefruit juice after intravenous administration, but it increased significantly from 76+/-96 (water, mean (s.d.) to 114+/-70 (microg l[-1] h) (grapefruit juice) after oral saquinavir. Similarly, the oral bioavailability of saquinavir increased by a factor of 2 with grapefruit juice (from 0.7% to 1.4%). In contrast, clearance, volume of distribution and elimination half-life of saquinavir were not affected by grapefruit juice. After oral, but not after intravenous administration, the plasma concentration-time curve showed a second peak after lunch irrespective of pretreatment, suggesting enhancement of absorption by food. CONCLUSIONS: The studies demonstrate that grapefruit juice increases the bioavailability of saquinavir without affecting its clearance, suggesting that inhibition of intestinal CYP3A4 may contribute. Since the antiretroviral effect of saquinavir is dose-dependent, inhibition of CYP3A4 may represent a way to enhance its effectiveness without increasing the dose.

Adult↗

Acute cardiovascular effects of insulin-like growth factor I in patients with chronic heart failure.

Insulin-like growth factor I (IGF-I) enhances myofibrillar development in cardiomyocytes of rats in culture and in vivo. In addition, IGF-I has vasodilatory effects and improves cardiac function in healthy volunteers. This study was conducted to evaluate the acute hemodynamic effects of IGF-I in patients with chronic heart failure Eight patients with chronic heart failure were randomized to receive recombinant human IGF-I (60 micrograms/kg) or placebo, i.v., over 4 h in a cross-over, double blind study on 2 consecutive days. Electrocardiogram as well as systemic hemodynamics were continuously monitored over 7 h by flow-guided thermodilution and radial artery catheters. IGF-I was well tolerated by all patients, and no pathological changes on electrocardiogram were recorded. Compared with placebo, IGF-I increased the cardiac index by 27 +/- 3.7% (+/- SE; P < 0.0005) and the stroke volume index by 21 +/- 5.6% (P < 0.05), and decreased systemic vascular resistance by 28 +/- 4.4% (P < 0.0002), right atrial pressure by 33 +/- 9.0% (P < 0.003), and pulmonary artery wedge pressure by 25 +/- 6.1% (P < 0.03). Mean systemic and pulmonary artery pressure as well as heart rate and pulmonary vascular resistance were not significantly influenced by IGF-I treatment. Insulin and C peptide levels were decreased by IGF-I, whereas glucose and electrolyte levels remained unchanged. Urinary levels of norepinephrine decreased significantly (P < 0.05) during IGF-I infusion. Thus, acute administration of IGF-I in patients with chronic heart failure is safe and improves cardiac performance by afterload reduction and possibly by positive inotropic effects. Further investigations to establish whether the observed acute effects of IGF-I are maintained during chronic therapy appear to be warranted.

Adult↗