Concept of and preliminary trial protocol for adjuvant treatment of mediastinitis with immunoglobulins after cardiac surgery (ATMI): response to comments and criticism.

During the consensus-based process of protocol development external experts were invited to comment on a proposal for a trial protocol on adjuvant immunotreatment of patients with wound infection after median sternotomy (ATMI). Controversies and arguments can be divided into five main areas: 1) rationale and objectives; 2) criteria for patient selection; 3) adjuvant treatment; 4) measures of efficacy; and 5) course and timetable of the study. We present and summarise the experts comments and criticism as well as the result of the final discussion of the study group with respect to these areas.

Analysis of adverse effects among patients with essential hypertension receiving an ACE inhibitor or a beta-blocker.

Evaluation of safety and efficacy of new drugs is based largely on data from clinical trials involving a limited number of patients. This approach does not necessarily detect the rare adverse events that may only be observed when very large numbers of patients are studied. Consequently, we designed a double-blind 12-week trial comparing the new angiotensin-converting enzyme (ACE) inhibitor, quinapril (n = 5,053), with a well-established beta-adrenergic receptor blocker, metoprolol (n = 506). Essentially hypertensive patients (diastolic blood pressure 95-114 mm Hg) received either 10 mg quinapril or 50 mg metoprolol once daily, and the doses were doubled at 4-week intervals to a maximum of 40 and 200 mg, respectively, in nonresponders. Responder rates were similar under both regimens. Adverse events were assessed by interview as well as by a standard questionnaire. The overall prevalence of adverse events reported by standard questionnaire was higher than that reported spontaneously during interviews. With respect to typical ACE inhibitor adverse reactions (e.g. cough and taste disturbances), there was no difference between quinapril and metoprolol independent of the mode of reporting. In summary, both drugs showed comparable overall tolerance and safety. The discrepancy between spontaneously reported and questionnaire-reported adverse events was noteworthy, and this finding prevailed in a volunteer group of 327 patients who were treated with quinapril for 52 weeks. Thus, a questionnaire is of great significance in addition to the patient history/interview in a large-scale, double-blind study designed to learn about details of drug safety.

[Plasma level and action of sotalol-HCL on the ECG interval after parenteral administration in healthy subjects]. / Plasmaspiegel und Wirkung von Sotalol-HCl auf EKG-Zeitintervalle nach parenteraler Applikation an gesunde Probanden.

Sotalol (Sotalex; Sotacor) is a beta-blocker with additional class III antiarrhythmic activity. In this study two intravenous doses of 1.5 mg/kg and 2 mg/kg body weight were administered in 8 healthy volunteers in order to determine the pharmacokinetics and ECG intervals. After a short-term infusion (5 min) plasma levels and the relevant pharmacokinetic parameters were determined. The ECG parameters (QRS, PQ, QT, QTc), blood pressure, heart rate and tolerability were also evaluated. A correlation between the plasma concentration of sotalol, the decrease in heart rate and a prolongation of the real QT interval was found for both dose levels and for a period of 2 h after administration. A prolongation of the QTc-time could only be statistically confirmed for the higher dose. No differences in pharmacokinetic parameters were observed between the two doses.

Dynamics of beta-adrenoceptor blockade with cetamolol.

Cetamolol is a new beta-adrenoceptor blocking agent shown in animals to have moderate beta 1-adrenoceptor selectivity and partial agonist activity. In healthy normal volunteers, beta 1-adrenoceptor blockade was measured as the reduction of exercise-induced tachycardia, systolic blood pressure, and double product at 2, 8, and 24 h after a single oral dose of 10, 25, and 50 mg cetamolol. beta 1-adrenoceptor blockade was significantly linearly related to log serum cetamolol level, was maximal at 2 h, and was still clinically significant at 24 h. A crossover study of single 0, 10, and 25 mg doses confirmed these findings.

An early phase I study to determine the tolerance, safety and pharmacokinetics of idebenone following multiple oral doses.

Ten healthy male volunteers participated in this Phase I multiple dose study with CV-2619 (6-[10-hydroxydecyl]-2,3- dimethoxy-5-methyl-1,4-benzoquinone, idebenone). Each volunteer received single oral doses of 100 mg CV-2619 on study days 1 and 35, and during days 2 to 34, 300 mg daily in three divided doses. Blood and urine samples were collected for pharmacokinetic analysis of CV-2619 and its two major metabolites. CV-2619 was well tolerated with regard to the subjective and objective assessments made during the study. There were no changes in clinical laboratory values which could be directly attributed to the administration of CV-2619. The elimination of CV-2619 appeared to be biphasic with a mean terminal elimination half-life of 18 h. Levels of metabolites in serum were too low to provide adequate description of their elimination kinetics. CV-2619 and its metabolites showed no tendency to accumulate over the 35-day period.

Plasma levels of isosorbide dinitrate and its main metabolites following oral administration of two sustained release formulations in normal man.

The plasma levels of isosorbide dinitrate (ISDN) and the two pharmacologically active metabolites were measured following administration of two oral sustained release formulations containing 40 mg ISDN in nine healthy male volunteers. The new galenic formulation (pellets in a hard gelatin capsule) resulted in generally higher plasma levels for all three assayed substances over the time period of 24 h. The pharmacokinetic interpretation of the plasma levels following administration of the sustained release capsule assuming a one-compartment body model with zero-order invasion and first-order elimination showed a constant liberation over approximately 5 h. The elimination of all three substances was not altered by the new formulation. The plasma levels after administration of the tablet formulaation showed great variations within and between individuals. These data could therefore not be interpreted by the same model.

Finger pulse plethysmographic effects of two oral sustained-release formulations of isosorbide dinitrate in normal man.

Two sustained release formulations of 40 mg isosorbide dinitrate, encapsulated pellets and a tablet, were compared double blind following oral administration of single doses in terms of response on finger pulse plethysmography in nine healthy male volunteers. Following both formulations there was a distinct effect on the depth of b-wave in the first derivative of the finger pulse up to 9 h after administration. This change of the parameter of nitrate action was significantly different from placebo for both formulations. The onset of action was more rapid and the peak response greater for the capsule than for the tablet. The overall effects in terms of area under the effect-time curves was also greater for the capsule than for the tablet, however, not statistically significant. Furthermore, the results show that the method of finger pulse plethysmography can be used to determine onset and duration of action nitrate compounds, after single dose administrations.

Relationship between the pharmacodynamics and pharmacokinetics of two oral sustained-release formulations of isosorbide dinitrate in normal man.

The relationship between the pharmacodynamics and pharmacokinetics of isosorbide dinitrate (ISDN) following oral administration of 40 mg of two different models. A model assuming an additive contribution of all active drug-related substances in plasma to pharmacological effect, i.e., finger pulse plethysmograph, resulted in estimates of relative potencies of ISDN:2-MN:5-MN (2-MN:2-isosorbide mononitrate; 5-MN:5-isosorbide mononitrate) as being 1:0.1:0.025. The data analysis using a receptor model (plasma concentration-effect curves) yielded sigmoid curves yielded sigmoid curves for 2-MN and 5-MN with similar relative potencies in the range of 20-80% of maximum response providing an upper limit for the pharmacodynamic effect due to ISDN, 2-MN or 5-MN in healthy volunteers.

Effects of the beta-adrenoceptor blocking agent sotalol on CNS: sleep, EEG, and psychophysiological parameters.

Sotalol (Sotalex), 320 or 960 mg, was administered to 12 healthy subjects daily for a period of four days in a double-blind trial over 11 days. The effects of sotalol on heart rate, blood pressure, EEG, subjective quality of sleep, polygraphically determined sleep pattern, and psychophysiological parameters such as psychomotor performance, memory, perception, vigilance, and general condition were studied and were related to dosage and plasma levels. Steady-state plasma levels of sotalol were reached within 24 hours after a single dose; 960 mg resulted in plasma levels three times higher than those reached with 320 mg, which indicates first-order linear absorption. The effects of sotalol on EEG, sleep, and performance in psychological tests were equivocal and do not yield evidence for CNS activity of sotalol.

Studies on the pharmacokinetics and pharmacodynamics of the beta-adrenergic blocking agent sotalol in normal man.

After intravenous injection, sotalol follows a two-compartment distribution pattern. The processes of distribution and elimination are of first order; the intravenous biological half-life is 6 to 8 hours. The drug is mainly excreted by glomerular filtration via the kidney, and metabolites are not found. Of the pharmacodynamic parameters measured, the isoproterenol-induced changes in heart rate, diastolic blood pressure, and free fatty acid return to baseline values immediately during the injection of the beta blocker. Peripheral arterial circulation, lactate, glucose, and pyruvate respond to the beta blocker after a delay. Besides the compartmental distribution of sotalol, other mechanisms of sotalol such as varying responses of the receptors to sotalol or more sluggish intrinsic kinetics of the decrease of parameters measured have to be considered. The effects of various beta blockers may be qualitatively and quantitatively differentiated on the basis of experiments with our test model using steady-state isoproterenol infusion in humans.

Hemodynamic effects of cutaneously administered isosorbide dinitrate ointment.

With a view to testing the hemodynamic effects of a 10% isosorbide dinitrate ointment, about 40 mg of the drug was applied to the skin of nine cardiologically healthy volunteers. The ensuing hemodynamic changes were followed up for six hours by means of noninvasive techniques including echocardiography. As early as 30 min after drug application, significant decreases in heart rate, cardiac output, systolic blood pressure and intracardiac diameters were recorded. Only systolic blood pressure had returned to initial values by the end of the observation period. Isosorbide dinitrate ointment diminished myocardial oxygen consumption for a duration beyond six hr, by reducing pressure and heart-rate work of the left ventricle.

[Mode of action of cardiovascular drugs. Echocardiographic studies (author's transl)]. / Wirkungsmechanismus herz- und kreislaufwirksamer Medikamente. Untersuchungen mit Hilfe der Echokardiographie.

Echocardiography--combined with additional non-invasive methods--has proved a sensitive tool for measuring hemodynamic and left ventricular function parameters. This study was undertaken to measure by these methods the effect of digoxin, isoproterenol, of the beta-receptorblocker sotalol, sodium nitroprusside and isosorbide dinitrate on the hemodynamics and left ventricular contractility in various patients and normal volunteers. Besides the good reproducibility of results of recent invasive investigations, partly in animal experiments, new aspects about the mode of action of the individual substances were obtained.

[Treatment of acute myocardial infarction with sodium nitroprusside (author's transl)]. / Die Behandlung des akuten Myokardinfarktes mit Nitroprussid-Natrium.

In 12 patients with acute myocardial infarction, seven of whom had high and five low blood pressure measurements, sodium nitroprusside infusions were given to reduce the myocardial oxygen consumption. The dosage was between 20 and 300 mug/min. Sodium nitroprusside led to a considerable reduction of the systemic arterial pressure, while the left ventricular filling pressure was less influenced. In normotensive patients the filling pressure could often not be sufficiently lowered as a too severe reduction of arterial pressure occurred beforehand. In hypertensive patients the relationship between left ventricular filling pressure and arterial pressure was better: in all patients the arterial pressure could be lowered to normal values and the filling pressure also became normal in most cases. Angina pectoris improved markedly in all patients. These results show that sodium nitroprusside has a satisfactory effect on the haemodynamics in hypertensive infarct patients, whereas it is less suitable for the treatment of normo- or hypotensive patients.

[Treatment of arterial hypertension with sotalol, a beta-blocker (author's transl)]. / Behandlung der arteriellen Hypertonie mit dem Beta-Rezeptorenblocker Sotalol. Klinisch-pharmakologische Befunde

Plasma concentrations and the effect of sotalol, a beta blocker, on arterial blood pressure and other haemodynamic variables (determined by echocardiography) were measured in 15 patients with arterial hypertension of different severity, after acute administration and during long-term treatment for 3 to 16 months. Sotalol absorption was relatively constant, the correlation coefficient between plasma concentrations and administered dose being r=0.67. The biological half-life was about eight hours, The effects of the drug on blood pressure, heart rate and other haemodynamic variables were small after acute administration. But in ten patients blood pressure returned to normal during chronic treatment with sotalol alone, while in five others it was necessary to combine sotalol with a diuretic and dihydralazine. These results show that sotalol is suitable for long-term treatment of arterial hypertension.

Time sequence of direct vascular and inotropic effects following intravenous administration of digoxin in normal man.

The effects of a bolus injection of digoxin upon hemodynamics and left ventricular function were studied in 5 normal volunteers using cardiac ultrasound, ECG, carotid pulse pressure, and arterial blood pressure recording. Whereas the injection was followed by an immediate rise of the systemic vascular resistance, the inotropic action upon the myocardium followed with a delay of 10 to 30 minutes after injection.