Veselin Mitrovic

Hemodynamic and neurohumoral effects of moxonidine in patients with essential hypertension

SummaryThe hemodynamic and neurohumoral effects of a single oral dose (0.4 mg) of the novel centrally acting antihypertensive agent moxonidine were investigated over 4 hours in ten patients with essential hypertension (WHO I-II). Pulmonary pressure indices and cardiac output were determined both at rest and during ergometric exercise by means of Swan-Ganz catheterization. Blood pressure was measured by sphygmomanometry and in the brachial artery. Moxonidine induced a significant fall in blood pressure over the 4-hour observation period from 176/105 mmHg to 158/95 mmHg (p<0.01), accompanied by a decrease in systemic vascular resistance from 1695 to 1427 dyn.sec/cm5 (p<0.01). Cardiac output remained unchanged, while heart rate increased slightly from 69 to 75 beats/min (p<0.01). No significant changes were recorded for either pulmonary artery pressure or pulmonary vascular resistance. Plasma levels of noradrenaline (337 vs. 224 pg/ml) and renin (2.6 vs 2.0 ng/ml/hr) activity fell significantly after moxonidine (p<0.05), both at rest and during exercise. Although aldosterone plasma levels fell slightly, levels of angiotensin II and ANF remained unchanged.Moxonidine has favorable effects on hemodynamics and the neurohumoral system in patients with essential hypertension and is well tolerated at the dose administered.

Thrombotic complications with pacemakers

To analyze thrombotic complications, we performed brachial phlebographies in 100 consecutive patients (group 1), about 44 months after permanent pacemakers had been installed. Thirty-nine patients showed thrombotic lesions in the veins used to pass the stimulation electrode into the right ventricle. In 10 patients the medical history and in 12 patients clinical symptoms and signs indicated an impairment of venous flow. Fifteen of the 39 patients showed complete occlusion of one venous segment; collateral vessel formation was found dependent on the site and the extent of the occlusion. In the remaining 24 patients only partial occlusion without collateralization was demonstrated. Group 2 comprised 12 patients in whom the pacing lead originally inserted via right-sided veins had been severed and the free distal end left unsecured intraluminally when the second electrode was inserted via the left-sided cephalic vein. In all these patients phlebography about 19 months later revealed thrombotic complications, while 11 presented with clinical symptoms and signs. The incidence of thrombotic complications including segmental occlusion after the application of permanent pacer leads is only one-third of patients with segmental occlusion symptoms. However, since severed leads produce severe symptomatic complications in almost all cases their removal is mandatory.

The use of intravenous milrinone in chronic symptomatic ischemic heart disease

To evaluate the antiischemic effects of intravenous milrinone, 20 patients with angiographically proved coronary artery disease and stable angina were studied at rest and during exercise under control conditions and after an intravenous loading injection of milrinone (50 micrograms/kg/10 min) followed by an infusion with 0.5 micrograms/kg/min. Hemodynamic parameters, epinephrine, norepinephrine, and atrial natriuretic factor were assessed. Control ergometry revealed ischemia; however, during exercise with intravenous milrinone, ischemia was eliminated. Because of unloading effects, there was also a significant decrease in ST segment depression (p less than 0.001). Heart rate increased significantly (p less than 0.001) at rest but increased significantly less after exercise testing (p less than 0.001). The changes in mean arterial pressure, cardiac output, and myocardial oxygen consumption during exercise were not significantly different between the milrinone and control phase. Intravenous milrinone delayed the onset of angina (p less than 0.001) and significantly shortened the duration of anginal attacks (p less than 0.05); exercise duration in the milrinone phase was longer than in the control phase (p = 0.051). Because of vasodilatation, a mild secondary increase in norepinephrine was observed during the milrinone phase, and there was a significantly smaller increase in atrial natriuretic factor during exercise while receiving milrinone as a result of preload reduction (p less than 0.05). Intravenous milrinone produced beneficial hemodynamic and antiischemic effects in patients with coronary artery disease, stable angina, and reproducible ST segment depression probably by enhancing myocardial contractility and reducing preload and afterload.

Dose-ranging and safety with intravenous levosimendan in low-output heart failure: experience in three pilot studies and outline of the levosimendan infusion versus dobutamine (LIDO) trial

Abstract A series of dose-ranging and tolerability studies of intravenous levosimendan (bolus then infusion) were conducted in 40 patients with low-output heart failure (cardiac index 2 per minute). These trials were conducted as preparation for the Levosimendan Infusion versus Dobutamine (LIDO) study, an international, randomized, comparative phase III trial of intravenous levosimendan versus dobutamine in heart failure. Response rates to levosimendan therapy (defined as ≥30% increase in cardiac index during levosimendan administration) were 73–100% (compared with 60% with dobutamine 8–16 μg/kg per minute). Dose dependence was apparent in several hemodynamic responses to levosimendan. From experience in these studies it was concluded that the preferred bolus dose for initiating levosimendan therapy was 12–24 μg/kg, followed by infusion at rates up to 0.4 μg/kg per minute. It was also concluded that, in the dose range identified, levosimendan offered a valid alternative to dobutamine in heart failure patients who require intravenous inotropic support.

A Dose-response Study of Intravenous Enoximone in Congestive-heart-failure

Previous clinical studies with intravenous enoximone have used cumulative dosing to quantify enoximones hemodynamic effects. The magnitude and duration of the hemodynamic effects of single intravenous doses of enoximone were evaluated in patients with congestive heart failure. Sixty patients, who were in New York Heart Association functional classes III and IV, received single intravenous doses of enoximone, either 0.25 (12 patients), 0.5 (13 patients), 1 (14 patients), 1.5 (10 patients) or 2 mg/kg (11 patients). Cardiac index was increased by 20% with the 0.25 mg/kg dose and by 48% and 42% with the 1.5 and 2 mg/kg doses, respectively. These increases were statistically significant (Students paired t test with Bonferronis correction, p less than 0.007) for 1 hour after 0.25 and 0.5 mg/kg, for 2 hours after 1 mg/kg and for 4 hours after 1.5 and 2 mg/kg. Enoximone also reduced pulmonary artery diastolic pressure by 19% with 0.25 mg/kg and by 29% with 2 mg/kg. The duration of effect varied from 1 hour with 0.25 mg/kg to 4 hours with 2 mg/kg. Enoximone produced no consistent or dose-related effects on heart rate or blood pressure. Eighteen adverse reactions were reported by 15 patients, of which 11 were minor and transient (vein pain, flushes, nausea). In 5 patients ventricular or supraventricular arrhythmias were observed, including nonsustained ventricular tachycardia and extrasystoles; 3 of these patients had evidence of arrhythmias before enoximone. Laboratory studies before and after treatment showed no drug-related effects. Dose-related effects on the magnitude and duration of hemodynamic responses to intravenous enoximone were evident within the dose range of 0.25 to 2 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Tedisamil (KC 8857) is a new specific bradycardic drug: does it also influence myocardial contractility? Analysis by the conductance (volume) technique in coronary artery disease.

To determine whether inotropism influences the bradycardic action of tedisamil, hemodynamic assessment was performed in 13 patients with ischemic coronary artery disease including analysis of end-systolic pressure-volume relationships after an infusion of tedisamil, 0.3 mg/kg, at rest, and during paced tachycardia stress. Slope Emax fell by 14% at rest (13 patients) and by 10% during tachycardia (6/13 patients), whereas loops of end-systolic pressure-volume relationships moved rightward; all parameter changes indicated a lack of significant inotropism loss with tedisamil (p > 0.05). Although the mean heart rate decreased from 77.5 to 64.7 beats/min and QTc duration increased by 14% (p < 0.05), filling pressure and dp/dtmin remained unchanged and vascular resistance increased by 30%. Parameters of left ventricular pump function (ejection fraction, stroke volume, left ventricular efficiency) decreased slightly (between 3% and 13%), whereas left ventricular volumes increased (end-diastolic volume by 6%, end-systolic volume by 23%). The respective parameter changes during tachycardia were comparable in tendency, and angina could no longer be induced during postdrug pacing stress. We concluded that the bradycardic effects of tedisamil are selectively generated without impairing either ventricular pump function or contractility in a clinically relevant fashion, whereas the postdrug anginal threshold appears elevated. Thus tedisamil can be used safely in ischemic coronary artery disease.

Hemodynamic, antiischemic, and neurohumoral effects of enoximone in patients with coronary artery disease.

To evaluate the risk of ischemia in 17 patients with significant coronary artery disease, the influence of enoximone was analyzed under the following conditions: (1) at rest (RC) and during exercise (ExC) under control conditions and (2) at rest (RE) and during exercise (ExE) after administration of enoximone (0.75 mg/kg, intravenously). During ExC all patients had ischemia (angina, and ST segment alterations); metabolic markers of ischemia (MMI) increased, as did the mean pulmonary artery pressure, from 19 to 41 mm Hg. However, during ExE ischemia was abolished (no angina, decrease in mean pulmonary artery pressure to 24 mm Hg, and improvement in MMI) and there was some improvement in left ventricular pump function, whereas pre- and afterload decreased (pulmonary artery pressure by 40%, systemic vascular resistance by 10%), and heart rate, arterial pressure, and myocardial oxygen consumption (MVO2) were all unchanged (p greater than 0.05). Comparative hemodynamics at RE vs RC showed a decrease in pulmonary artery pressure (by 25%) and pulmonary vascular resistance (by 19%) and an increase in heart rate (by 11%), whereas arterial pressure and MVO2 were unchanged (p greater than 0.05). Enoximone did not induce changes in plasma catecholamine, prostaglandin, or thromboxane levels (p greater than 0.05), whereas the atrial natriuretic factor decreased (by 15%), probably because of unloading of the atria during exercise. We concluded that enoximone induces beneficial hemodynamic effects in coronary artery disease without causing ischemia, probably by enhancing myocardial contractility, vasodilation, and improved diastolic properties.

Present use of positive inotropic drugs in heart failure.

Cardiac failure is treated with increasing success by phosphodicsterase-III (PDE-III) inhibitors such as amrinone. milrinone. and enoximone. While relatively pure positive inotropic substances (e.g., dopamine and dobutamine) are limited by tolerance development and MVO2 increase, the efficacy of PDE inhibitors is maintained by avoiding catecholamine and β-reeeptors. They have positive inotropic, positive lusitropie. and vasodilatatory properties: myoeardial oxygen consumption remains unaltered. PDE-III inhibitors act by selectively inhibiting PDE-III. leading to an increased cAMP concentration in myoeardial and smooth muscle cells. In contrast, forskolin increases intracellular cAMP by activation of adenylate cyclase. It could be shown that parenteral administration of the PDE inhibitors sulmazole. amrinone. and enoximone resulted in preload and after-load reduction due to vasodilation with concomitant decrease of peripheral and pulmonary vascular resistance: they also led to elevated cardiac output and ejection fraction as well as a significant increase in dp/dtmav. while left ventricular filling pressures were markedly lowered. Pulmonary pressure values fell significantly, whereas heart rate and myoeardial oxygen consumption showed no clinically relevant alterations. In patients with angiographi-cally documented coronary artery disease, the anti-is-chemic efficacy of enoximone could be proven both during exercise and stress pacing. The decrease of the pathologically elevated pulmonary pressures during ischemia was accompanied by reduced ST-segment depression following enoximone without changing MVO2 significantly. First tests after intracoronary application of enoximone confirmed its direct myoeardial efficacy, indicating its positive inotropic and lusitropie properties. Thus, patients in cardiac failure have useful therapeutic alternatives at their disposal when taking PDF. inhibitors. The anti-isehemic properties of these drugs need further evaluation

Rapid and sensitive assay of dobutamine in plasma by high-performance liquid chromatography and electrochemical detection.

A sensitive and specific high-performance liquid chromatographic method with electrochemical detection was developed for measuring dobutamine in human plasma samples. Following an external standard method, 0.1 ml of EDTA-glutathione plasma was diluted on ice with 0.2 ml of a 5% trichloracetic acid solution. The mixture was centrifuged, filtered, and 30 microliters were injected. Assessment was done by electrochemical detection. The assay was linear from 1 to 400 ng/ml plasma. For determination of dobutamine we also used a liquid-liquid extraction method routinely applied for plasma catecholamines. Liquid-liquid extraction requires application of 100-1000 microliters of plasma. The standard curve was linear from 0.1 to 600 ng/ml. Absolute recovery of dobutamine was 90 +/- 3% with the liquid-liquid extraction procedure and 91 +/- 3% with the protein precipitation method. For both methods dobutamine was separated on Nova-Pak C18 columns. The mobile phase used was 0.1 molar phosphate buffer-acetonitrile (80:20, v/v) with 1-octanesulfonic acid and triethylamine as ion-pair reagents. The pH was adjusted to 2.7.

Hemodynamic and antiischemic effects of tedisamil in humans

SummaryTwenty-four patients with angiographically documented coronary artery disease, chronic stable angina, and reproducible ST-segment depression took part in this openlabel, baseline-controlled study on the hemodynamic, antiischemic, metabolic, and neurohumoral effects of tedisamil following IV doses of 0.1, 0.2, and 0.3 mg/kg (eight patients in each dose group). Tedisamil produced a dose-dependent decrease in both heart rate [rest: 2.4, 7.5 (p<.01), and 9.2 beats/min (p<.001); exercise: 6, 4.6, and 8.9 beats/min (p<.01), respectively] and the index of myocardial oxygen consumption (exercise: 6–9% in each group) associated with an improvement of ST-segment depression [−12.1%, −10.7%, −41.9% (p>.01), resp.]. While cardiac output was found decreased due to the heart-rate reduction both at rest [−8.5%, −5.7%, and −10.2% (p<.05), respectively] and during exercise (2–8%), being significant only at rest in the highest dose group, stroke volume remained unaltered. Pulmonary artery pressure, pulmonary capillary wedge pressure, right-ventricular ejection fraction, and pulmonary vascular resistance were without significant changes. Blood pressure and systemic vascular resistance tended to increase, associated with a decrease in plasma catecholamines (20–40%). Tedisamil produced a dose-dependent prolongation of QTc duration [+2%, +6%, +12% (p<.05), respectively] with PQ and QRS unaltered. The elimination half-life of tedisamil IV ranges between 6.8 and 7.8 hours. In conclusion, tedisamil, at a dose of 0.3 mg/kg IV, was well tolerated and was found to have favorable hemodynamic and antiischemic effects in patients with ischemic heart disease.