High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril.

OBJECTIVES: To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril. BACKGROUND: The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect. METHODS: In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II-III: +/-80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones. RESULTS: At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p < 0.05). Exercise time increased 45 s in the 10-mg group (p = 0.02 vs. placebo), but it did not significantly change in the 5-mg (+16 s), and 2.5-mg (+11 s) imidapril group, compared to placebo (+3 s). Physical working capacity also increased in a dose-related manner. Plasma brain and atrial natriuretic peptide decreased (p < 0.05 for linear trend), while (nor)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was suppressed similarly (+/-60%) on all three doses. CONCLUSIONS: Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.

Changes of neurohumoral parameters and endothelin-1 in response to exercise in patients with mild to moderate congestive heart failure.

UNLABELLED: Plasma endothelin levels are increased in patients with moderate and severe CHF. Conflicting data exist about the endothelin-1 (ET) level in patients with mild to moderate CHF and the effect of maximal exercise on plasma ET levels. METHODS AND RESULTS: We determined the plasma levels of ET and various neurohumoral parameters in 93 patients with CHF in functional class II and III of the NYHA classification at rest and after maximal bicycle exercise. Baseline ET level was increased compared to an age-matched healthy volunteer group (6.95+/-0.31 vs 3.29+/-0.17 pg/ml, mean+/-S.E.M., P<0.05), without significant differences between NYHA class II and III patients. Maximal exercise did not increase the ET level. In contrast, the neurohumoral parameters were significantly increased with maximal exercise. In conclusion, plasma levels of ET are increased in patients with mild to moderate CHF. However, no further increase in response to exercise was observed. Thus, it is highly unlikely that exercise capacity may be limited by ET-mediated peripheral vasoconstriction.

Pathologists' attitudes to implementing telepathology.

If pathologists will benefit so much from using telepathology, why is it taking so long to be introduced? This question has been discussed between experts, but the potential users are rarely asked for their opinions. A questionnaire was sent to the 256 members of the Austrian Society of Pathology; this addressed general aspects of telemedicine, telepathology in frozen-section services and expert consultation, videoconferencing technologies, teleteaching and teletraining. The response rate was 46%. In general, the pathologists thought that telemedicine could become valuable in their daily routine. However, pathologists were most afraid of sampling errors in remote diagnosis and would not readily accept an alternative to the conventional method of looking at a sample. This is only possible using realtime, remotely controlled microscopes. Telepathology systems providing only still images would not be acceptable to most respondents. There was interest in the use of videoconferencing for clinicopathological conferences. Teleteaching and teletraining were seen as welcome additional techniques, but were nevertheless judged unable to replace classical methods of teaching and training.

The legal situation of telemedicine in Austria.

Searches were conducted of two legal databases dealing with civil law in Austria. The searches produced 12 references relevant to telemedicine, which were obtained from a university legal library. From the literature, it can be concluded that Austrian civil regulations are sufficient to clarify the questions of liability arising in connection with the practice of telemedicine. Although no specific legislation has been enacted as yet, we would not expect such legislation to produce different results in the legal assessment of the case patterns discussed in this paper.

What do students think about telemedicine?

A questionnaire was distributed to 300 medical students attending a conference in 1996. The return rate was 32%. The majority of students believed that telemedicine will become very important in future. About a quarter of students had had practical experience of telemedicine in a hospital. More than 75% of the respondents said that they would attend telemedicine lectures if they were offered by their university. There were no major concerns among medical students about telematics and its applications in medicine. There was a clear need for more information, which suggests that universities should offer special lectures and practical courses in telemedicine. The interest of students in tele-learning was very high. This interest would justify more attempts to introduce tele-learning by the universities.

[The legal status of telemedicine in Austria]. / Die rechtliche Lage der Telemedizin in Osterreich.

The rapid development of modern communication technologies offers new opportunities for medical diagnosis and treatment. In spite of the obvious theoretical benefits of telemedicine, which have been proven by many projects in practice, telemedicine has not become generally established in Europe. Besides lack of technical standardisation and high purchase costs, one of the reasons might be the as yet unclarified legal situation. Taking the present legal situation in Austria we tried to explore questions of liability concerning telemedicine. The outstanding point seems to lie in the contract between the participating physicians on the one hand and between the physicians and the patient on the other hand. If the consulting physician is self-employed he has to take responsibility for any error on the part of the consulted physician. However, if he is working in a hospital, then he is legally considered an "Erfüllungsgehilfe" (person employed by the debtor in the performance of his obligation) an any further doctor consulted is automatically also an "Erfüllungsgehilfe" of the hospital and therefore the hospital takes responsibility for any mistakes made by the consulted physician. Although there has not been any specific jurisdiction concerning telemedicine in Austria, the present legal provisions are adequate for reaching decisions on questions of liability, so that there are no objections from the legal point of view to the general implementation of telemedicine.

Dose-finding study of imidapril, a novel angiotensin converting enzyme inhibitor, in patients with stable chronic heart failure.

OBJECTIVE: To study the haemodynamic profile and tolerability of imidapril, a new long-acting ACE inhibitor, and to investigate the effect of inhibition of circulating ACE on blood pressure in patients with stable chronic heart failure. METHODS: Twenty-four patients with stable, chronic heart failure (New York Heart Association (NYHA) functional Class II-III) were randomised to receive either 2.5 mg or 5 mg imidapril. Other vasodilators were withheld for > or = 5 half-lives. Blood pressure and ACE activity were carefully monitored for 24 h after dosing. RESULTS: Both 2.5 mg and 5 mg imidapril decreased systolic blood pressure, while diastolic blood pressure fell only after 5 mg imidapril. The two doses produced a significant and similar inhibition of circulating (serum) ACE. No serious adverse effects were observed, although symptomatic hypotension occured in 1 patient (5 mg). The decrease in blood pressure was not related to baseline ACE activity, serum sodium or serum creatinine concentration. CONCLUSIONS: Imidapril significantly lowered systolic blood pressure and was well tolerated. The difference in the first dose response to the two doses with respect to diastolic blood pressure suggests that this haemodynamic effect of ACE-inhibition is not related to inhibition of circulating ACE.

Investigations on the acute toxicity of acidic and basic triamterene derivatives.

Acidic and basic triamterene derivatives were evaluated with respect to their acute toxicity. After single intravenous application in mice, derivatives with a basic side-chain were much more toxic than compounds with an acidic side-chain. There is a significant correlation between the potassium retaining properties (measured as ED50) and the acute toxicity (measured as LD50) of the substances. The low acute toxicity after oral application of the compounds can be explained by their low oral bioavailability.

Modulation of electrolyte excretion by potassium retaining diuretics.

Triamterene and amiloride belong to the potassium retaining diuretics of the cycloamidine type. These agents exert natriuretic as well as antikaliuretic effects. After administration of high doses an additional magnesium-sparing property also becomes evident. Whereas amiloride is only metabolized to a minor extent, triamterene is rapidly bio-transformed to the phase-I metabolite, hydroxytriamterene, and the phase-II metabolite, hydroxytriamterene sulphuric acid ester. This acidic phase-II metabolite is still diuretically active, but its electrolyte excretion profile is different from the parent compound: although the natriuretic properties are not altered, the potassium retention is very weak. Further studies in rats with cycloamidine derivatives of the triamterene type containing neutral, acidic or basic side chains at the phenyl moiety as well as with basic pteridine derivatives, revealed further evidence that the natriuretic, antikaliuretic and antimagnesiuretic effects can be influenced almost independently by structural variations of the parent drug. Thus, it was possible to obtain compounds predominantly increasing sodium excretion without affecting potassium or magnesium excretion. On the other hand, substances could be developed with mainly antikaliuretic effects, or compounds, which enhanced sodium and reduced magnesium excretion and did not interfere with the potassium elimination. Based on these findings, it can be concluded that distal tubular transport of sodium, potassium and magnesium may be influenced independently from each other. These renal effects of triamterene and its derivatives seem to be independent of their antiarrhythmic actions, as suggested by recent studies.

Synthesis, natriuretic, antikaliuretic and antimagnesiuretic properties of an acidic triamterene derivative.

2,4,7-Triamino-6-(4-methanesulfonamidophenyl) pteridine (RPH 3048) is a new acidic triamterene derivative. Relevant physico-chemical constants were determined (solubility at pH 7.4 = 3.7 mg/l; logP at pH 7.4 = 0.2) and pharmacokinetic as well as pharmacodynamic properties were investigated, using male Wistar rats. After intravenous application of the test substances urine was collected, its volume and electrolyte composition determined, and the urine recovery of the drugs was analysed. The comparison of RPH 3048 with triamterene (CAS 396-01-0) revealed almost equipotent natriuretic and potassium-retaining effects for both drugs and an additional relative magnesium-sparing activity of RPH 3048. The urine recovery of RPH 3048 after 6 h was higher (20.6%) than that of triamterene (12.9%). No metabolite of RPH 3048 could be detected in the urine whereas a triamterene metabolite was found. Due to its good solubility in alkaline medium RPH 3048 could be dissolved (at pH 11-12) and then administered intravenously together with a loop diuretic (furosemide). Urinary electrolyte excretion following administration of two different combinations of RPH 3048 and furosemide (combination A: 12.5 mumol/kg RPH 3048 and 25 mumol/kg furosemide; combination B: 25 mumol/kg RPH 3048 and 25 mumol/kg furosemide) was compared to urinary electrolyte excretion of a control group and a group only treated with furosemide (25 mumol/kg). The additional application of RPH 3048 reduced in both groups potassium and magnesium excretion to control level but did not compromise furosemide induced natriuresis. In contrast to earlier investigations these results suggest that it is possible to develop acidic triamterene derivatives with potent antikaliuretic effects.

Effects of a new pteridine derivative on urinary sodium, potassium and magnesium excretion in conscious saline-loaded rats.

1. Two recently synthesized pteridine derivatives (RPH 3036; RPH 3038) were tested in conscious saline-loaded rats and showed natriuretic and antimagnesiuretic properties but hardly reduced potassium excretion. 2. In the same model a dose-response curve was performed for RPH 3036. ED50 and Emax values were calculated for the natriuretic (ED50 = 13.4 mumol kg-1; Emax = 1.08 mmol kg-1) and antimagnesiuretic (ED50 = 11.3 mumol kg-1; Emax = -0.099 mmol kg-1) properties of RPH 3036. There were no significant changes of potassium and calcium excretion. 3. After a single dose of RPH 3036 (100 mumol kg-1) the time course of electrolyte excretion was analysed over 6 h. RPH 3036 did not show any significant effects on renal potassium and calcium excretion whereas a pronounced decrease (P less than 0.01) in renal magnesium excretion was evident during the 6 h. A moderate increase of sodium excretion was observed only after 3, 5 and 6 h. 4. A selective reduction of magnesium secretion in the late distal tubule and collecting duct was proposed as a possible mechanism of action of RPH 3036. This would explain the fast onset of action as well as the lack of antikaliuretic and anticalciuretic effects. The high selectivity of RPH 3036 makes it potentially valuable for the future investigation of renal magnesium transport.

Antiarrhythmic properties of benzyl-triamterene derivatives in the coronary artery ligated and reperfused rat.

Triamterene (CAS 396-01-0) and a series of benzyl-triamterene derivatives were evaluated for their antiarrhythmic properties in the coronary artery ligated and reperfused (CAL-R) rat. The effects were compared with the antiarrhythmic activity of the potassium sparing diuretic amiloride and drugs out of the class-I (lidocaine) and class-III (amiodarone and sotalol). Triamterene and sotalol revealed at high doses antifibrillator activity, while the benzyl-triamterenes 2, 3, 5 and 6 could also depress ventricular extrasystoles (VES) and ventricular tachycardia (VT). At low doses the most benzyltriamterenes protected significantly against ventricular fibrillation (VF) and so they were equieffective or more effective than amiodarone or lidocaine. Amiloride showed in the CAL-R rat no antiarrhythmic activity, so that we conclude different mechanisms responsible for antikaliuretic and antiarrhythmic properties of amiloride and triamterenes. Taking into account the results of recently reported in vitro studies, where we could demonstrate antiarrhythmic activity combined with positive inotropic properties for triamterenes, the antiarrhythmic profile of these compounds may offer new possibilities for the treatment of ventricular arrhythmias.