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It was the aim of this study to examine the compatibility and the pharmacokinetics of the angiotensin converting enzyme inhibitor enalapril after oral application in racing pigeons and Amazons, and to contribute to a safe dosage regime of this drug in birds.For the examination of drug compatibility, three groups of pigeons (n = 8 each) received enalapril into the crop at a dose of 5 or 10 mg/kg body weight, or placebo, respectively. Health status, and water and food consumption were monitored regularly, and clinical, hematological and blood-chemical parameters were determined. To determine a suitable starting dosage, birds were treated with enalapril at a dose of 2.5 mg/kg (first trial) and 1.25 mg/kg (second trial), and blood samples were collected at defined time points. Using high performance liquid chromatography (HPLC), the enalapril concentration in the plasma samples was determined.Drug application did not cause any significant drug-related difference between the groups. Nearly all measured parameters were found to be within normal physiological ranges. Only for hematocrit was a slight but significant increase found for the group treated with 5 mg/kg enalapril. In pigeons, after application of 2.5 mg/kg enalapril, the maximum plasma concentration was found in the first sample taken (388.2 ± 174.1 mg/kg). The application of 1.25 mg/kg resulted in a maximum concentration of 116.1 ± 70.2 ng/ml after 30 minutes in pigeons. In the Amazon birds, the maximum value was found after 1 hour (first sampling) of 43.3 ±6.0 ng/ml. In all examinations, the enalapril concentration was15 ng/ml after 8 hours. The terminal half-life was 2.68 hours for pigeons and 2.36 hours for Amazons.The results underline the good compatibility of enalapril after oral administration in healthy pigeons. A starting dosage of 1.25 mg/kg enalapril given twice daily can be recommended.The study provides basic data (compatibility and pharmacokinetics) for the application of enalapril in birds such as the racing pigeon.

Pancreatic cancer is a devastating and almost uniformly lethal malignancy that accounts for approximately 12,600 deaths in Germany every year (1), 3 Percent of all cancers. The reasons for the poor prognosis are too late to diagnose and the aggressive biology of the tumor cell. At the time of diagnosis, pancreatic cancer is usually at an advanced stage and has often metastasis. Only 10 to 20 percent of patients have a resectable tumor. But less than 2 percent of patients survive five years. For patients with the resectable primary tumor is the median survival 10 to 12 months. Patients with adjuvant chemotherapy may survive up to 20 months (51). An advanced tumour stage come only palliative measures. Survival without therapy is around 3 to 4 months (22). The results of chemotherapy, adjuvant radio and Intraoperative irradiation are not satisfactory. Notably, there is now strong evidence that invasive pancreatic adenocarcinoma proceeds through a morphological spectrum of non-invasive ductal lesions known as pancreatic intraepithelial neoplasia (PanIN), David A. Tuveson showed that the transgenic mice had the similar dysplasia-carcinoma sequence of pancreatic cancer, which corresponds to the human pancreatic carcinoma. After 3 and 5 months of treatment, enalapril was able to significantly delay progression of mPanINs in LSL-KrasG12D; Pdx1-Cre mice (p, In Deutschland erkranken jährlich etwa 12.600 Menschen am duktalen Adeno-karzinom des Pankreas, was 3 Prozent aller Krebserkrankungen entspricht (1). Die Gründe für die schlechte Prognose liegen in der späten Diagnosestellung und der aggressiven Tumorzellbiologie. Nur 10 bis 20 Prozent der Patienten haben bei Diagnosestellung einen resektablen Tumor; weniger als 2 Prozent überleben fünf Jahre. Beim resektablen Primärtumor beträgt die mediane Überlebenszeit 10 bis 12 Monate. Mithilfe einer adjuvanten Chemotherapie kann die Überlebenszeit auf bis zu 20 Monate verlängert werden (51). Bei acht von zehn Patienten liegt bei Diagnosestellung ein fortgeschrittenes Tumorstadium vor; in diesen Fällen kommen nur noch palliative Maßnahmen in Betracht. Die Überlebenszeit ohne Therapie liegt bei etwa 3 bis 4 Monaten (22). Die Resultate der adjuvanten Radio- und Chemotherapie sowie der intraoperativen Bestrahlung erwiesen sich als nicht zufriedenstellend. Die Transformationsprozesse der Dysplasie-Karzinom-Sequenz des Pankreaskarzinoms wurden auch festgestellt, die als sogenannte Pancreatic Intraepithelial Neoplasias (PanIN) bezeichnet wurde. Ein Tumormausmodell von der Arbeitsgruppe David A. Tuveson zeigte, dass die transgenen Mäuse die ähnliche Dysplasie-Karzinom-Sequenz des Pankreaskarzinoms hatten, die dem humanen Pankreaskarzinom entspricht. Bei Pdx-1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+-Mäusen wird die Progression von PanINs zum invasiven Pankreaskarzinom durch Chemoprävention mit Enalapril verlangsamt oder teilweise gestoppt. In der Behandlungsgruppe mit Eannapril nach 3 und 5 Monaten wird die Progression der PanINs in Pdx-1-Cre;LSL-KrasG12D/+-Mäusen signifikant verzögert(p

Ziel dieser Studie war es, die Verträglichkeit sowie die Pharmakokinetik des Angiotensin-Converting-Enzyme-Hemmers Enalapril nach oraler Applikation bei Brieftauben zu untersuchen. Hierdurch sollte eine effektive und sichere Dosierung für den Einsatz bei Vögeln am Beispiel der Taube bestimmt werden. Im ersten Teil der Studie wurde zur Überprüfung der Verträglichkeit drei Gruppen mit je acht Tauben über 21 Tage Enalapril in einer Dosierung von 5 mg/kg Körpermasse (KM), 10 mg/kg KM beziehungsweise ein Placebo in jeweils identischer Flüssigkeitsmenge in den Kropf appliziert. Während der Versuchsdauer wurden der Gesundheitsstatus sowie die Wasser- und Futteraufnahme regelmäßig kontrolliert und es wurden klinische, hämatologische, blutchemische und elektrokardiographische Kontrolluntersuchungen durchgeführt. Zwischen den Gruppen ergab sich an wenigen Tagen ein signifikanter Unterschied in der Wasseraufnahme. An zwei Untersuchungstagen waren die Kaliumwerte in allen Gruppen signifikant gegenüber den anderen Untersuchungstagen erhöht. Beide Veränderungen konnten aber nicht mit der Applikation bzw. der Dosierung von Enalapril in Zusammenhang gebracht werden. Weitere signifikante Unterschiede zwischen den Gruppen wurden zu keinem Zeitpunkt und bei keiner Untersuchung festgestellt. Die Ergebnisse dieser Studie belegen die gute Verträglichkeit von Enalapril nach oraler Verabreichung auch in höheren Dosierungen und über einen längeren Zeitraum. Der zweite Teil der Studie diente der Festlegung einer geeigneten Dosierung von Enalapril bei Vögeln. Hierzu wurde zunächst 12 Tauben eine Dosis von je 2,5 mg/kg KM Enalapril in den Kropf appliziert und es wurden nach 2, 4, 6, 8, 12, 24 und 36 Stunden Blutproben entnommen. Mittels High Performance Liquid Chromatography (HPLC) wurde eine Verlaufskurve zur Enalaprilat-Konzentration im Blutplasma erstellt. Die maximale Konzentration (Cmax) wurde hierbei bereits bei der ersten Blutentnahme gemessen und erwies sich mit im Mittelwert 388,2 ±174,1 ng/ml als im Vergleich zu Werten beim Säuger sehr hoch. Im Anschluss wurde 12 Tauben eine Dosis von je 1,25 mg/kg KM Enalapril in den Kropf appliziert und es wurden Blutproben nach ½, 1, 1½, 2, 4, 6 und 8 Stunden entnommen. Der mittlere Cmax-Wert lag bei 116,1± 70,2 ng/ml und stellte sich ebenfalls bei der ersten Blutentnahme ein. Die Halbwertszeit lag im Mittel bei 2,68 Stunden, die Area under the Curve (AUC0-8) betrug 396,25 ng*h/ml. Bei beiden Versuchen lag die Wirkstoffkonzentration nach 8 Stunden unter 15 ng/ml. Die nach Applikation von 1,25 mg/kg Enalapril berechnete AUC entspricht weitgehend der für Hunde nach oraler Applikation von 0,5 mg/kg Enalapril angegebenen AUC. Dieser Parameter wie auch die kurze Halbwertszeit und die bereits bei den ersten Messungen erreichte Maximalkonzentration belegen die rasche Absorption, Metabolisierung und Elimination des Wirkstoffes und rechtfertigen die Empfehlung einer Dosierung von 1,25 mg/kg KM Enalapril zweimal täglich.

The angiotensin-converting enzyme inhibitor (ACE-I) enalapril has been shown to lower elevated levels of circulating adhesion molecules (cAM) in critically ill patients. To delineate the mechanisms of this possibly beneficial effect of enalapril, we studied the acute effects of enalapril in a well-defined model of endotoxin-triggered, cytokine-mediated cAM up-regulation. In a randomized, controlled trial, 30 healthy male volunteers received 2 ng/kg lipopolysaccharide (LPS)after pretreatment with placebo or 20 mg/day enalapril for 5 days or with a single dose of 20 mg of enalapril 2 h before LPS infusion. LPS infusion increased TNF levels 300-fold above normal, circulating (c) E-selectin levels by 425% (CI,359%–492%), VCAM-1 and ICAM-1. LPS infusion also enhanced ICAM-1 and CD11b expression 2- to 3-fold on monocytes. However, no differences were seen between treatment groups (P > 0.05), despite 95% inhibition of ACE activity by enalapril. Inhibition of ACE activity by enalapril does not influence plasma indices of endothelial activation after endotoxin infusion in healthy individuals. Our results do not support the concept of a beneficial clinical effect of enalaprilat in septicemia., In dieser Studie untersuchte man die Auswirkungen eines ACE-Inhibitors Enalapril in einer LPS induzierten, TNF-Alpha vermittelten systemischen Entzündung und betrachtete, ob eine Verminderung der erhöhten Adhäsionsmoleküle während einer Sepsis durch Enalapril gesenkt werden könnte. 30 männliche Probanden, die ein Alter von durchschnittlich 31 plus/minus 5 (SD) und einen Body Maß Index von 22 plus/minus 2 (SD) hatten, wurden in einer randomisierten, doppelblind placebo-kontrollierten Studie per Zufall in drei parallele Gruppen (A, B, C) unterteilt. Die Probanden waren einschließlich normaler Laborwerte gesund und dies wurde durch eine Voruntersuchung gesichert. Gruppe A erhielt sechs Tage ein Placebo, Gruppe B fünf Tage ein Placebo und am 6. Tag (Studientag) 20 mg Enalapril und Gruppe C sechs Tage 20 mg Enalapril. Man konnte anhand von gemessenen Parametern, wie zum Beispiel cE-Selektin, cICAM-1, cVCAM-1, TNF- und zelluläre Parameter, keine signifikante Veränderung durch Enalapril feststellen. Dies bedeutet, dass eine kurzfristige Hemmung der ACE-Aktivität durch Enalapril in dieser Dosierung keinen positiven Einfluss auf die LPS induzierte, TNF-Alpha vermittelte Aktivierung von Endothel, Leukozyten und der Adhäsionsmoleküle während einer Endotoxinämie hat.

While ACE-inhibitors have proven their prognostic benefit in many hypertension studies, a new approach has been proposed by inhibiting neutral endopeptidase, which degrades natriuretic peptides. The combined inhibition of ACE and endopeptidase was named "vasopeptidase-inhibition" and tested in several trial. Though effective in lowering blood pressure, a superiority to ACE-inhibitors alone could not be shown. A potentially serious side effect was the increased incidence of angioneurotic edema, which led to a complete stop in the development of this pharmaceutical strategy.

A 34-year-old previously healthy woman was admitted to another hospital because of abdominal pain, cough and dyspnea. Peripheral eosinophilia was present. Two months later she was admitted to the cardiology department with signs of mitral regurgitation. Dyspnea, fatigue, skin rashes with pruritus and a systolic murmur were noted.Laboratory tests showed 11.4/nl leukocytes (normal range 4.8-10.8/nl) with an eosinophilia of 19% (normal range4%) corresponding to 2.2/nl. Cardiac magnetic resonance imaging revealed endomyocardial fibrosis involving the posterior mitral leaflet with resulting valvular regurgitation. Doppler ultrasound showed restrictive heart failure. DIAGNOSIS, THERAPY AND FURTHER COURSE: The diagnosis of idiopathic hypereosinophilia most likely as part of hypereosinophilic syndrome with cardiac involvement was made. The patient was treated with digitalis, diuretics and peptidyl dipeptidase (PDP) inhibitor. The treatment with glucocorticoids and cytotoxic agent to achieve a reduction of eosinophil count was ended by the patient a few weeks later.The hypereosinophilic syndrome with endomyocardial fibrosis is rare, and its prognosis is grave. The pathophysiological mechanisms are not entirely clear, nearly 70 years after Löffler first described fibrous endocarditis with eosinophilia. Patients receive symptomatic medical therapies. Additional surgical treatment has been reported,. Antihypereosinophilic therapy is used to control the disease.

Drug therapy of coronary heart disease (CHD) is a life-long treatment. With every change from in-patient to out-patient care and back, changes in medication may occur. If a drug is chosen which provides no proven long-term benefit in terms of reduced morbidity and mortality, the expected therapeutic benefit may be missed. We investigated in 224 patients admitted to the medical departments of two hospitals (one with a specialized Cardiology Unit, one with a General Internal Medicine Unit) the prescriptions for CHD by the general practitioner before admittance into the hospital, the prescriptions recommended at the time of discharge, and the prescriptions made by the general practitioner three months after discharge. Of the drug classes with proven effects on morbidity and mortality (acetylsalicylic acid, beta-blockers, statins, ACE inhibitors), none had sufficiently high prescription rates. Prescription rates at discharge were 30% for beta-blockers and statins, 70% for acetylsalicylic acid, and 60% for ACE inhibitors. Only in patients with acute myocardial infarction were the prescription rates for these drug classes higher at this time point. The presence of contraindications was not of prime importance for the low prescription rates, as even in patients without contraindications prescription rates were not significantly higher than in the total patient cohort. Out of the patients with hypercholesterolemia, one third of those treated in the Cardiology Department and two thirds of those treated in the General Internal Medicine Department were not given any lipid-lowering medication. Prescription rates for those drug classes that provide symptomatic relief but have little impact on mortality rates (calcium channel blockers, nitrates) were high in both hospitals. The present study shows that evidence-based guidelines for the drug treatment of coronary heart disease are not adequately put into practice.

Increasing drug costs are an economic burden for the health insurance system.The regional drug prescription pattern for ACE inhibitors in the Austrian county Burgenland was compared for patients discharged from hospital and those in primary care. Furthermore, the potential cost reduction by voluntary prescription of cheaper generic drugs was estimated in the project "Bessere Therapie zum besseren Preis".Following consensual analysis of the regional cross-sectional study, a cheaper generic of the most cost-intensive class of ACE-inhibitor drugs should be prescribed at internal medicine wards and in primary care. The number of prescriptions for patients from the largest health insurance company BGKK was studied and the costs were calculated.Of the 1347 patients discharged during October 1999 from internal medicine departments of four different hospitals 879 patients received a total of 1440 cardiovascular drugs. The regional prescription pattern at hospitals matched that of physicians in primary care. Between the second quarter of 2000 and 2001, the prescription of ACE inhibitor drugs increased by project advertising from 23,627 packages by 13.1%, and drug costs in this group were reduced by [symbol: see text] 29,778 in this quarter (7.3% of costs). The number of Enalapril prescriptions increased by 33.4% with a percentual portion of generic Enalapril of 57.3%, and in the rest of Austria by 16.9% with 45.0% generics.Consensus based projects are appropriate pharmacoeconomic interventions to change prescription patterns, increase the use of drugs and reduce the increasing cost requirements.

In view of the prevalence of left ventricular hypertrophy (LVH) in patients with essential hypertension, (15-30%), with an increased risk (2-4 x) of developing myocardial infarction, heart failure or malignant arrhythmia, possibly even leading to sudden cardiac death, effective reversal of LVH is a major aim of treatment. For this purpose, angiotensin-converting enzyme (ACE) inhibitors have proved to be most suitable.In an open bicentric study involving 37 hypertensive patients with LVH confirmed by echocardiography, the effect of spirapril in reversing the left ventricular mass index (LVMI) and diastolic left ventricular wall thickness was investigated after 3 and 6 months.The LVMI decreased by 14.7% after 3, and by 27.3% after 6 months, irrespective of whether spirapril was given alone or in addition to other antihypertensive pre-medication. The results may be due to the proven 24-hour effect of spirapril in conjunction with the very long half-life.

A 61-year-old male patient complained about diffuse upper abdominal pain and a progressive dyspnoe on exertion. Of clinical relevance were signs of congestive heart failure and a distinct kyphoscoliosis.A cardiac catheter examination proved a pulmonary hypertension without cardiac genesis. Both, pulmonary function test and computed tomography of the thorax rule out obstructive bronchial asthma and embolism of the lung. As the sole cause of pulmonary hypertension, kyphoscoliosis was diagnosed. Since the patient refused noninvasive positive pressure ventilation, a medication with calcium entry blocker and ACE blocker was induced, followed by oxygen breathing. This successfully helped to reduce pulmonary resistance (746 vs. 332 dyn*s*cm(-5)).Kyphoscoliosis can create a considerable increase of pulmonary resistance. Medical treatment and oxygen breathing have proven to be an efficient method to lower that significantly.

Angio-oedema are often massive but temporary swellings of the soft tissue of the face or the throat, which can also affect other regions of the human body (e.g. the skin or internal organs). An oedema of the face and throat represents a life-threatening situation. Apart from the clinical condition of the patient and detailed knowledge of the medical history (incl. medical applications), the treatment should depend on the different pathogenesis. In this reported case, we describe the severe clinical development of an angio-oedema under a long-term treatment with an ACE-inhibitor, which in the end was only successfully treated with the application of a C1 inhibitor concentrate.

Several reports indicate the benefit of ACE inhibitors for patients with left ventricular systolic dysfunction after acute myocardial infarction (MI). We sought to determine the implementation of the treatment guidelines in patient samples from the general population. Furthermore we aimed to identify patient characteristics associated with the use of ACE inhibitors. Screening of two MI-registries allowed the identification of 226 MI patients with left ventricular dysfunction. Patients were considered to be eligible for ACE inhibitor therapy when a EFor = 40% was documented in the patient records of cardiac rehabilitation clinics (REG-MI, n = 147) or detected by standardised echocardiography (KORA, n = 78). On average 5.5 years following MI, a standardised questionnaire and a detailed medical history was obtained. Specifically, information was collected regarding current medication and potential contraindications for ACE inhibitors. MI patients with LV dysfunction received ACE inhibitors in 62% (REG-MI) and 45% (KORA). The doses prescribed were substantially smaller than target doses used in the large-scale studies (REG-MI: 40 +/- 4%, KORA: 23 +/- 3%, % of target doses). Only 13% (REG-MI) and 3% (KORA) received more than 50% of the target dosage. Additionally, actual doses of the most frequently used ACE inhibitors were significantly different (captopril: 23 +/- 2%, enalapril: 42 +/- 5% of target doses). The likelihood of receiving ACE inhibitors was significantly higher in patients with written recommendation for such medication (odds ratio 6.02, confidence interval 1.93-20.16) and in patients visiting cardiologists (odds ratio 3.69, confidence interval 1.26-11.07) as revealed by multivariate analysis of the REG-MI database. Despite national and international guidance, a large proportion of MI patients with left ventricular dysfunction is not receiving ACE inhibitors, and when used, the doses prescribed are markedly smaller than target doses used in clinical trials that established the utility of these drugs. Medical care by cardiologists and written recommendation of ACE inhibition in patient records were independent predictors of a more appropriate prescription of ACE inhibitors.

Two women, both aged 54 years, were admitted because of supraventricular arrhythmias of recent onset. Patient 2 was also in heart failure. Male family members of both patients were known to have Duchenne's muscular dystrophy, of which one had died.The electrocardiogram of patient 1 demonstrated atrial fibrillation. Patient 2 had a raised serum creatine kinase concentration and increased pulmonary marking in the chest radiogram. Patient 1 had normal findings on left heart catheterization, but immunohistochemical analysis of a myocardial biopsy revealed dystrophin mosaic with 20% dystrophin-negative fibres. Patient 2 had a reduced ejection fraction and 80% dystrophin-negative fibres.Myocardial involvement in the carrier state for Duchenne's muscular dystrophy having been demonstrated in both women, patient 1 received antihypertensive treatment while patient 2, who was in cardiac failure, was given diuretics, ACE-inhibitor and beta-receptor blockers.Cardiomyopathy in carriers of Duchenne's muscular dystrophy is a rare cause of supraventricular arrhythmias. The cause can be confirmed by immunochemical analysis of an endomyocardial biopsy.

The efficacy and safety of the angiotensin converting enzyme inhibitor enalapril in dogs with naturally acquired class III or class IV heart failure was evaluated in this study. Eighteen small-breed dogs with insufficiency of their mitral valves, but without other diseases were included in this study over a period of six months. When necessary due to massive pulmonary edema or high serum potassium concentrations, furosemide was added to the therapy with enalapril. No other drugs, including digitalis, were used in this study. The treatment was followed by anamnesis, clinical examinations, electrocardiography, radiography, echocardiography and laboratory diagnosis. Examinations were performed before treatment and after one week, after six weeks and after six months of treatment. 72% of the dogs improved in NYHA classification until the end of the study (p0.05). The incidence of seizures due to syncopes or severe respiratory distress decreased during this study (p0.01). For 28% of the dogs this treatment was not successful. In the electrocardiographic, radiographic and laboratory examinations statistically significant changes could not be recorded. The decrease in heart rate did not reach statistical significance. The echocardiographic investigation evaluated a significant decrease in fractional shortening and in the diastolic diameter of the left ventricular wall (p0.05 respectively p0.01), but no significant change in the diastolic or systolic diameter of the interventricular septum. The average oral dose of enalapril was 0.38 mg/kg body weight b.i.d., the average dose of furosemide was 0.37 mg/kg body weight b.i.d. in the first week of the study and was raised to 0.74 mg/kg body weight b.i.d. until the end of the study. Side effects like diarrhea, vomiting or reduced appetite did not increase during the course of the study. However one dog was excluded from the study because of repeated vomiting after six weeks of treatment. This study shows the beneficial clinical and hemodynamic effects and the security of the therapy with enalapril for dogs with heart failure due to mitral insufficiency.

Morbidity and mortality data in Switzerland underline the socioeconomic importance of heart failure. In the SOLVD study (Study on Left Ventricular Dysfunction), cardiovascular morbidity and mortality were reduced with the ACE inhibitor enalapril in patients with heart failure. The economic implications of this treatment were analyzed in a retrospective economic analysis from the perspective of Swiss third party payers.Source of the economic analysis was the SOLVD study data. This prospective study was placebo-controlled, double-blind and had a mean follow-up of 3.45 years (41.4 months), involving 2569 patients with heart failure, mainly in NYHA classes II and III. Costing data for treatment with enalapril, the per diem charges for hospitalization and the average length of hospital stay were retrieved from published national sources. The costs of in- and output were calculated and compared for the two treatment groups in a cost-efficacy analysis.Additional treatment with enalapril resulted in an additional cost of 2.5 million Swiss francs. These incremental costs were, however, offset by reduced hospital costs (CHF 6.45 million savings) in the enalapril group. For the complete treatment cohort of the SOLVD study, the net savings were approximately 4.26 million Swiss francs.From the clinical point of view, treatment with ACE inhibitors leads to a reduction in the progression of heart failure and reduced cardiovascular morbidity and mortality. With respect to health economics, it can be demonstrated that treatment with enalapril does not only offer clinical benefits, but that these also translate into impressive economic savings of CHF 3315 per patient.

Inhibitors of angiotensin converting enzyme may rarely cause an angioneurotic oedema of the upper aerodigestive tract. The pathomechanism of this side effect depends on an interaction of the drug with hormones regulating the vascular resistance such as the kallikrein kinin system and the prostaglandin system. Anglo-oedema is characterised by subcutaneous or submucosal swelling, which preferably affects the lips, the soft palate, the tongue and the larynx. Pathomechanisms, differential diagnosis and treatment of ACE-inhibitor induced oedema of the upper aerodigestive tract are described by means of 3 case reports.

In a subgroup of 301 hypertensive patients out of the user--observation study ("Anwendungsbeobachtung") with Renitec und CO-Renitec we studied which compliance-improving methods are effective. We tested the effects of blood pressure self-measurement and of an exclusive conversation with the patients. It could be shown, at least in our approach, that the conversation with the patient resulted in a lighter efficacy than blood pressure self-measurement:80% compliance was found in 80% of the patients, compared with only 40% of the patients with standard care.

Alteration of pancreatic secretion could be a pathogenetic factor for generation of an acute pancreatitis after administration of angiotensin-converting-enzyme (ACE) inhibitors. Therefore in 6 conscious dogs (weight 10-12 kg) with chronic gastric and duodenal fistulas according to Thomas, we studied single-blind, placebo-controlled and randomized the effect of a long-term (74 d) daily oral administration of 5 mg of the ACE inhibitor enalapril and of additionally daily oral administration of the diuretic furosemide from the 60th day on the secretin- (20.5 pmol/kg/h) and caerulein- (7.4, 14.8, 29.6, 59, and 118 pmol/kg/h) stimulated pancreatic bicarbonate and protein secretion at day 1, 29, 57, 60, and 74 after beginning of enalapril administration. Heart rate was measured daily and during the experiments. Neither enalapril nor enalapril plus furosemide significantly altered heart rate. The hormonally stimulated pancreatic bicarbonate secretion was significantly (p0.05) increased at day 57, 60, and 74 by 353%, 397%, and 79%. The hormonally stimulated pancreatic protein secretion was also distinctly increased, although not reaching statistical significance. The present study shows, that a long-term administration of therapeutic doses of enalapril +/-furosemide is capable to enhance the pancreatic bicarbonate secretion. Whether this altered pancreatic secretion can be taken for a primary origin of the observed cases of acute pancreatitis after therapeutic administration of enalapril is uncertain but not refutable.

We report the case of a patient with an angioedema during therapy with enalapril and tramadol. The most likely cause of the adverse effect if the ACE-inhibitor enalapril. A rechallenge with the ACE-inhibitor is dangerous and should not be performed. Because of its potential risks, further treatment with ACE-inhibitors should be avoided in all patients with ACE-inhibitor-induced angioedema. Possible therapeutic alternatives include diuretics, beta-blocking agents, calcium antagonists and also angiotensin II receptor antagonists.

In a user-observation study ("Anwendungsbeobachtung") it could be demonstrated that Renitec and Co-Renitec lowered elevated blood pressure but not sufficiently according to the WHO-criteria. It seems that the necessary dose titrations are not carried out in a daily routine. Furthermore it has to be stated that even widespread observation studies are not able to differentiate the properties of a drug. It remains to be considered whether more requirements on observation studies are necessary (regarding exact criteria for their design and increased monitoring) and should be implemented to improve the quality of data, although this would mean more time for the physician. Only under such conditions statements about rare side effects, influences of concomitant diseases and their treatments will be possible.

A 50-year-old very obese man had suffered from hypertension for more than 20 years and had undergone various treatment regimens, the last being with an ACE inhibitor. Since his hypertension had nevertheless increased, and he developed dizziness and headaches, a combination of ACE-inhibitor and calcium antagonist was now tried, followed--when this treatment proved unsuccessful--by the fixed-combination preparation containing enalapril plus hydrochlorothiazide. This at last led to a reduction in his blood pressure to approaching normal values, and his subjective symptoms cleared up.

Inhibitors of angiotensin converting enzyme (ACE) are suspected of inducing angioedemas in up to 0.2% of all patients. These angioedemas are mainly localized in the upper airways and therefore can cause severe airway obstruction and even death due to suffocation. We report the case of a 64-year-old man, who underwent emergency tracheotomy because of severe angioedema of the larynx, which was refractory to pharmacological treatment. We conclude that patients with ACE inhibitor-induced angioedemas should be observed by monitoring in an intensive care unit to ensure the possibility of early intubation, because conventional antiallergic-antiedematous therapy by histamine-receptor antagonists and corticosteroids is an insufficient, unreliable form of therapy in severe cases. Especially otolaryngologists should know about this uncommon potentially life-threatening side-effect of ACE inhibitors.

Spirapril is a recent ACE inhibitor with a both renal and hepatic elimination pathway. In order to determine its tolerability, primarily the impact on renal function, Spirapril was tested in a single-blind trial with a 2-week placebo run-in phase and a 4-week active treatment period. Forty-nine patients (34 males and 15 females) with varying degrees of renal impairment were included. Their pretreatment diastolic blood pressure (DBP) ranged from 95 to 115 mm Hg. Spirapril was administered in oral doses of 6 mg once daily.Forty-four patients completed the study. Four patients dropped out due to side effects, 1 patient was withdrawn from the study due to lack of antihypertensive efficacy. 48% of the completers with renal failure achieved a normalized diastolic blood pressure (DBPor = 90 mm Hg) or a reduction in DBP ofor = 10 mm Hg; the corresponding figure for patients with normal renal function was 31%. Renal function was assessed in the beginning and at the end of the active Spirapril treatment period using Tc-99m-DTPA-clearance (representing glomerular filtration rate), J-131-hippuran-clearance (representing renal plasma flow) and creatinine clearance. Particularly in patients with renal impairment, Spirapril did not deteriorate renal function as given by these parameters. Regression analysis revealed a linear correlation between total plasma clearance of the active metabolite Spiraprilate and creatinine clearance. There was no evidence for drug accumulation.In patients with renal impairment the pharmacokinetic results indicate a non-renal elimination of the drug. Spirapril 6 mg once daily is concluded to be a well tolerated antihypertensive therapy for patients with mild to moderate hypertension and varying degrees of chronic renal failure.

A 52-year-old female was hospitalized with malaise, pruritus, jaundice, abdominal discomfort and vomiting. For 20 weeks she had been taking enalapril (Reniten) for hypertension. Serum aminotransferases and bilirubin were highly elevated with prolonged thromboplastin time. There was no evidence for extrahepatic cholestasis in ultrasonography. Serological investigations for a viral etiology of the liver failure were negative and the patient had no risk factors for viral hepatitis or exposure to hepatotoxic substances. Liver puncture revealed hepatitis of the fulminant viral hepatitis type, a picture that can be seen in a drug-induced hepatitis. The complete recovery of liver function after cessation of enalapril administration suggests acute toxic hepatitis due to enalapril. A metabolically mediated idiosyncratic reaction is the most plausible. Potential mechanisms of enalapril-induced hepatotoxicity are discussed and the current literature is surveyed.