Evaluation of antiarrhythmic activity of captopril and enalaprilat in experimental cardiac arrhythmias in rabbits. Part II.

The influence of 21-day administration of captopril and enalaprilat on barium chloride and adrenaline-induced experimental arrhythmias was assessed. The experiments were performed on rabbits. Arrhythmias were evoked by two alternative arrhythmogen doses. The patterns of disturbances, their frequency and duration were evaluated on the basis of ECG examination. Antiarrhythmic properties of angiotensin converting enzyme inhibitors administered for 21 days were also compared with their effects after single administration. The results were subjected to statistic analysis. On the basis of the obtained results we were able to establish that repeated administration of enalaprilat decreases the frequency of barium chloride- and adrenaline-induced arrhythmias. Repeated administration of captopril and enalaprilat shortened the duration of adrenaline- and barium chloride-induced arrhythmias. Long-term enalaprilat administration was much more effective in preventing arrhythmias than its single dose, it also proved to be more efficient than either single or repeated administration of captopril.

Evaluation of antiarrhythmic activity of captopril and enalaprilat in experimental cardiac arrhythmias in rabbits. Part I.

The present study was undertaken to investigate the influence of captopril and enalaprilat--two different angiotensin converting enzyme (ACE) inhibitors--on experimental cardiac arrhythmias induced by barium chloride, ouabain or adrenaline. The research was carried out on rabbits. Captopril and enalaprilat were administered only once. Arrhythmias were evoked by three different doses of arrhythmogens: ED50 and two higher ones causing rhythm disturbances in 80-100% rabbits. The patterns of arrhythmias as well as their frequency and duration were evaluated on the basis of ECG examination. The results were subjected to statistic analysis. As a result of our research, we were able to establish that ACE inhibitors, when administered at a single dose, did not influence the patterns but changed the frequency and duration of barium chloride-, adrenaline- or ouabain-induced arrhythmias. Captopril and enalaprilat administered at a single dose decreased the frequency of barium chloride- or ouabain- but not adrenaline-induced arrhythmia. A single administration of captopril and enalaprilat limit the duration of arrhythmias caused by barium chloride, ouabain or adrenaline.

[Mean values of blood pressure and endothelin plasma concentration in patients with chronic renal failure]. / Srednie wartosci cisnienia tetniczego krwi a stezenie proendoteliny w osoczu chorych na przewlekla niewydolnosc nerek.

The aim of the present study was evaluation of correlation between big-endothelin concentration of the precursor substance of endothelin and mean values of blood pressure in 13 patients with compensates chronic renal failure. Their age ranged from 29 years to 55 years the mean age was 42.9 +/- 8.2 years. The patients were from the Consultational Nephrologic Outpatient Clinic. These patients were sent to the clinic after a hospital observation with recognised chronic renal failure (CRF), caused by chronic glomerulonephritis (without pathomorphological differentiation). The control group consistent of 10 healthy volunteers, an age ranged from 22 years to 49 years, a mean was 32.6 +/- 10.8 years. The following mean blood pressure values were found: in patient group a systolic pressure was 139.1 +/- 17.3 mm Hg and a diastolic pressure was 88.4 +/- 12.5 mm Hg and similar values in healthy control group were respectively: 118.6 +/- 4.0 and 72.4 +/- 5.9 mm Hg. Analogously the proendothelin concentration was 18.48 +/- 22.04 fmol/ml in patients with CRF and it was 4.67 +/- 0.27 fmol/ml in the control group. A positive correlation between mean blood systolic pressure values and the proendothelin concentration (r = 0.666, Y = 0.52X + 129.5; p < 0.05) in the was found patients group.

Metoclopramide and nitrendipine are unable to enhance cytotoxicity of mitoxantrone in sensitive and resistant murine leukemias in vivo.

The influence of metoclopramide and nitrendipine on the antitumor action of mitoxantrone (MX) in murine leukemias L1210 and P388 was investigated. These agents were administered in combination with MX to mice bearing sensitive or resistant leukemias. Mitoxantrone resistant P388 was developed in vivo by repeated passages of the tumor to animals treated with suboptimal dose of the drug. Survival time of mice receiving combined therapy were not prolonged as compared with animals treated with MX alone. Both metoclopramide and nitrendipine were unable to overcome MX resistance even partially.

Effect of some anticancer drugs and combined chemotherapy on renal toxicity.

The nephrotoxic action of anticancer drugs such as nitrogranulogen (NG), methotrexate (MTX), 5-fluorouracil (5-FU) and cyclophosphamide (CY) administered alone or in combination [MTX + 5-FU + CY (CMF)] was evaluated in experiments on Wistar rats. After drug administration, creatinine concentrations in the plasma and in the urine of the rats were determined, as well as creatinine clearance. Histopathologic evaluation of the kidneys was also performed. After MTX administration a significant increase (p = 0.0228) in the plasma creatinine concentration and a significant (p = 0.0001) decrease in creatinine clearance was noted compared to controls. After the administration of NG, 5-FU and CY neither a statistically significant increase in creatinine concentration nor an increase in creatinine clearance was observed compared to the group receiving no cytostatics. Following polytherapy according to the CMF regimen, a statistically significant decrease (p = 0.0343) in creatinine clearance was found, but creatinine concentration did not increase significantly compared to controls. CY caused hemorrhagic cystitis in 40% of rats, but it did not cause this complication when combined with 5-FU and MTX. Histologic changes were found in rat kidneys after administration of MTX, CY and NG, while no such change was observed after 5-FU and joint administration of MTX + 5-FU + CY compared to controls. Our studies indicate that nephrotoxicity of MTX + 5-FU + CY administered jointly is lower than in monotherapy.

Comparative studies of doxorubicin and 4'-epidoxorubicin effects on cardiovascular system in rabbits.

4'-epidoxorubicin (4'-epiDXR) was compared with doxorubicin (DXR) for myocardial effects in rabbits. Histologically, both drugs when given for six weeks induced a high incidence of diffused myocardial damage. The myocardial damage was less evident in rabbits treated with 4'-epiDXR than DXR for 3 weeks. Functionally 4'-epiDXR like DXR significantly reduced cardiac index (CI), stroke index (SI) and mean arterial blood pressure (MAP).

The effect of ethanol on arterial blood pressure, central venous pressure and ECG in rabbits treated with the single or multiple dose of amitriptyline or imipramine.

Amitriptyline and imipramine given in the single dose insignificantly depressed the arterial blood pressure but significantly elevated the central venous pressure, prolonged the PQ interval and widened the QRS complex. After a prolonged daily treatment, the subsequent 21st dose of either antidepressant significantly depressed the arterial blood pressure; amitriptyline also depressed the central venous pressure. When given chronically, amitriptyline induced rhythm disturbances and the flattening of T-wave, while imipramine caused the widening of the QRS complex, block of the left bundle branch, changes in the T-wave amplitude, elevation in the ST interval. An intravenous infusion of ethanol potentiated those changes. The impairment of atrioventricular conduction occurred more frequently after administration of ethanol jointly with amitriptyline than with imipramine. Physostigmine salicylate elevated the depressed arterial blood pressure, aggravated the impairment of conduction and potentiated rhythm disturbances caused by the interaction of ethanol with antidepressants. In the above interactions with ethanol imipramine was less toxic than amitriptyline.

[New anti-arrhythmia drug. III. Comparative studies of the effects of N-propionylprocainamide, procainamide and N-acetylprocainamide on hemodynamics and cardiac blood flow]. / Nowy lek antyarytmiczny. III. Porównawcze badania wplywu N-propionyloprokainamidu, prokainamidu i N-acetyloprokainamidu na hemodynamike krazenia i ukrwienie serca królików.

Procainamide (PA) often applied in cases of ventricular arrhythmias causes numerous cardiac and extracardiac undesirable symptoms. Its active metabolite, N-acetylprocainamide (NAPA; Acecainide) is known to affect less noxiously the ventriculo-atrial conduction and the intraventricular++ conduction, and it does not impair contractility of the heart muscle. Many drugs with proven antiarrhythmic activity cannot be used in clinical practice because of disadvantageous effects on the function of the left ventricle and on the coronary blood flow, particularly in patients with the recent myocardial infraction. It seems that another acyl derivative of procainamide with potential antiarrhythmic activity, N-propionylprocainamide (NPPA) may be less harmful than PA, and NAPA. Effects of milimolarly equivalent doses of NPPA, NAPA and PA on the cardiac output and the stroke volume index, as well as on the coronary blood flow were investigated in rabbits by the radioisotope method. The obtained results were subjected to statistical analysis. NPPA was found to display no depressive action on the function of the left ventricle. Moreover, it was found to improve the coronary blood flow in rabbits.

The influence of ethanol on pharmacokinetic parameters of procainamide in rabbits.

The effect of ethanol on procainamide pharmacokinetics was investigated in rabbits. Procainamide was injected iv in a dose of 13 mg.kg-1 together with ethanol in doses of 0.1, 0.5 or 1.0 g.kg-1.h-1. In another experiment procainamide was given in a dose of 40 mg.kg-1 together with ethanol in a dose of 1.0 g.kg-1 p.o. The third group of rabbits received procainamide in the form of 1 tablet 0.25 g together with ethanol in a dose of 1.0 g.kg-1 p.o. Ethanol shortened biological half-life of procainamide elimination, increased the value of the rate constant of elimination and procainamide clearance. Concomitant oral administration of ethanol and procainamide decreased the peak plasma concentration and decreased the area under the drug level curve.

The acute effect of doxorubicin and its analogue--4'-epidoxorubicin on circulatory system in rabbits.

The acute influence of doxorubicin (DXR) and its analogue - 4'-epidoxorubicin (4'-epiDXR) on cardiovascular system in rabbits was compared. A single intravenous dose of DXR (1 and 3 mg/kg) did not affect the cardiac index, stroke index and heart rate, but reduced the mean arterial blood pressure and total peripheral resistance. In contrast, 4-epiDXR, in the same doses, did not affect any of the hemodynamic parameters.

[Acetylation phenotype in patients with cancer of the bladder. Preliminary report]. / Fenotyp acetylacji u chorych na raka pecherza moczowego. Doniesienie wstepne.

In 23 patients affected by urinary bladder cancer and 22 healthy volunteers, acetylation phenotype was determined in urine, using the Eidus technique involving isoniazid. In the healthy group 10 (45.4%) slow acetylators and 9 (40.9%) fast acetylators were found. Of 23 patients with the bladder cancer 14 (60.9%) were slow acetylators, whereas 5 (21.7%) exhibited fast acetylation phenotype. The studies demonstrate that among the bladder-cancer-affected patients those with slow acetylation phenotype predominates. In those of the affected patients who had been exposed to chemical substances in the past, the percentage of slow acetylators was still higher (62.5%).

Synthesis of asymmetric 1,4-disubstituted piperazines and their psychotropic and cardiovascular actions. Part I.

New asymmetric piperazines 1-6 were obtained by condensation of 1-acylpiperazines with 1,2-epoxy-3-chloropropane, 1,2-epoxypropane, arylacid chlorides and secondary amines. The compounds displayed a biological activity: they depressed the central nervous system, altered the blood pressure, and one of them increased the coronary flow.

The use of radioisotope methods in pharmacologic and toxicologic studies.

By the use of radioisotopes, some pharmacologic studies can be carried out with less perturbation of physiologic processes than with other methods. Some isotope methods used at the Chair of Pharmacology of the Medical Academy in Lódz include determination of capillary circulation in the heart and skeletal muscle, minute output and stroke volume of the heart, renal clearance of 125J hippurate, and levels of some hormones and enzymes.

Evaluation of the action of some drugs on the blood supply of the myocardium in rabbits by means of the test of 125J absorption.

In experiments with rabbits, the influence of nitroglycerine, sorbonite and aminophylline on blood flow through the myocardium was compared by the radioisotope method. Adrenaline, noradrenaline and isoprenaline diminished capillary blood flow in the heart of rabbits. Persantine had no effect on capillary circulation in the heart of the experimental animals.

The influence of glucagon on the blood supply of the heart and kidneys in rabbits.

In experiments with rabbits, glucagon prolonged the half-period of absorption of sodium iodide 125J in the left ventricular myocardium. Regitine prevented acceleration of the heart rate and impairment of capillary flow after glucagon. In healthy rabbits hippurate 125J clearance was unaffected by glucagon. After injury of the heart muscle by injection of silver nitrate solution into the left ventricular wall and depression of blood pressure, glucagon partly normalized renal clearance of hippurate 125J.