Influence of imatinib at a low dose and sildenafil on pulmonary hypertension in rats.

The study investigates whether combination therapy of sildenafil with imatinib at a low dose (20 mg/kg) further ameliorates pulmonary hypertension (PH) in rats. The effects on right ventricle pressure (RVP), and right ventricle hypertrophy (RVH) were assessed in experimental monocrotaline (MCT)-induced pulmonary hypertension. Combined therapy reversed the MCT-induced increase in RVP more than each drug alone and decreased RV hypertrophy (RV/LV+ S ratio), significantly. Such additive effects toward improvement of PH may result from both pharmacodynamic and pharmacokinetic drug-drug interactions, however, further studies are required to assess its mechanistic background.

Adipohormones as prognostric markers in patients with nonalcoholic steatohepatitis (NASH).

Nonalcoholic steatohepatitis (NASH) represents one of the most common liver diseases. It is strongly associated with obesity and insulin resistance and is thought to be part of the metabolic syndrome. NASH can progress to cirrhosis and liver failure. Adipohormones, synthesized in adipose tissue, are involved in the pathophysiology of many acute and chronic liver diseases. The aim of this study was to evaluate the plasma concentrations of adiponectin, resistin, leptin, TNF-alpha and Il-6 in patients with NASH, as well as their correlation with the pathologic parameters. Serum concentration of leptin, adiponectin, resistin, insulin, TNF-alpha, IL-6 were measured with ELISA method. Liver biopsies were obtained from 18 (age 42.55+/-21 years) patients. NASH has been classified according to Dixon score. The control group was represented by 16 non-obese subjects. Mean serum concentration of adiponectin in patients with NASH was significantly lower than in healthy subjects (4.87+/-1.96 vs. 8.33+/-4.56 ng/ml; p<0.05). Mean serum levels of TNF-alpha in patients with NASH were significantly higher than in controls (34.2+/-19.7 vs. 20.7+/-15.5 ng/ml; p<0.05). In patients with more advanced inflammation (grade 2-3) and fibrosis (stage 2) in pathology, serum concentration of leptin was significantly higher than in patients with steatosis and less advanced inflammation (grade 1) and fibrosis (stage 1) (median 8.94 vs. 16.2 ng/ml; p<0.05). No significant differences of serum concentration of others adipohormones between these two groups of patients were stated. Moreover, we observed the correlation in serum levels (examined group vs controls) between: resistin and TNF-alpha (r = 0.62; p<0.05), adiponectin and IL-6 (r = -0.60; p<0.05) and leptin and insulin (r = -0.51; p<0.05). In conclusion, based on our study we speculate that changes of adipohormones levels may be markers of NASH and the serum level of leptin can be associated with more advanced form of NASH.

Elevated plasma gastrin, CEA, and CA 19-9 levels decrease after colorectal cancer resection.

BACKGROUND AND AIMS: Gastrin stimulates mucosal growth of much of the gastrointestinal tract and has also been implicated in promoting growth of colonic tumors, but its role in colorectal carcinogenesis remains controversial. This study determined fasting serum gastrin levels before and after surgery for colorectal cancer (CRC) and the relationship to the clinical stage of the disease to investigate it possible prognostic role. PATIENTS AND METHODS: Fasting radioimmunoassay gastrin, CA 19-9, and CEA levels were measured before and after surgery for CRC. Helicobacter pylori status was also assessed since it causes significant hypergastrinemia. RESULTS: Mean fasting plasma gastrin level was significantly higher in CRC patients than in controls before surgery but not 59 days after surgery. Mean CEA and CA 19-9 levels were significantly higher in patients with CRC before surgery than after tumor resection. There was a significant positive correlation between the plasma gastrin, CEA, and CA 19-9 levels and the CRC stage (Dukes' classification). CONCLUSION: The significance of gastrin as a marker for diagnosis or prognostic purposes in colorectal cancer needs to be further examined.

The influence of midazolam on plasma concentrations and pharmacokinetic parameters of lidocaine in rabbits.

The object of this study was to investigate the influence of midazolam on the plasma concentrations and pharmacokinetic parameters of lidocaine in rabbits. Lidocaine levels were determined by the immunofluorescence polarization method, using Abbott reagents. After intravenous administration of a combined dose of midazolam (0.2 mg kg(-1)i.v.) with lidocaine (1 mg kg(-1)i.v.) a statistically perceivable decrease of lidocaine concentration, together with an increase of the constant rate of its elimination and reduction of the biological half-life with average time of lidocaine remaining in the system were observed. Midazolam administered intravenously together with lidocaine shortens the residence time of the drug.

Attempts at formulation of syrup with theophylline.

The aim of this study was attempt to formulate syrup with theophylline. This form of drug would enable easy adjustment of individual doses of drug for therapeutic purposes in children. Due to poor solubility of theophylline in water, attempts at increasing of its solubility by adding special adjuvant substances, which could increase solubility and stabilise the obtained solution, were of particular importance.

Effect of propranolol and midazolam therapy on hemodynamic parameters in rabbits.

Some of anesthetic drugs cause cardiac arrhythmia, myocardial depression, blood pressure as well as hepatic and renal blood flow decrease. The aim of the following research study was the evaluation of midazolam effect on hemodynamic parameters in propranolol-treated rabbits. The following parameters: cardiac output and stroke volume, peripheral blood resistance, heart rate and blood pressure were estimated in the hemodynamics study. Blood pressure was significantly higher in case of propranolol and midazolam therapy as compared with midazolam alone. Blood pressure inconstancy did not exceed 20% of the initial value. Midazolam did not improve the depressive effect of propranolol on heart rate. The peripheral vascular resistance in coherent propranolol and midazolam therapy oscillated at the values observed after sole midazolam administration. After midazolam administration with propranolol, insignificant increase of cardiac output and stroke volume during the first minutes of experimental protocol correlated with marked decrease of peripheral blood resistance at the same time.

The influence of lidocaine and verapamil on haemodynamic parameters after intravenous administration of midazolam in rabbits.

Cardiac arrhythmia can be a serious complication during general anaesthesia of patients suffering from cardiac arrhythmias and using antiarrhythmic drugs. The aim of the present experiments was to establish the way in which lidocaine and verapamil influence haemodynamic parameters of rabbits after midazolam anaesthesia. The experiments were performed on rabbits. Heart rate was counted according to ECG. Blood pressure was measured directly in the carotid artery. Cardiac output, stroke volume, and total peripheral resistance were estimated using the method of human 125J albumin dilution. Midazolam caused a gradual fall of arterial blood pressure till 30 min of the experiment. The decrease of blood pressure in the first 45 min of the experiment might be a result of decreasing peripheral resistance, and after 60 min should be rather attributed to a decrease of cardiac output and stroke volume. Lidocaine did not change the influence of midazolam on the blood pressure and heart rate. The consequence was a decrease of blood pressure after midazolam and lidocaine administration. Combined administration of midazolam and lidocaine decreased the influence of both midazolam and lidocaine on the total peripheral resistance. An injection of midazolam with verapamil resulted in a significant decrease of blood pressure. Combined administration of midazolam and verapamil caused a significant decrease of heart rate as compared with the initial value and administration of midazolam alone.

[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.

Influence of lidocaine on the hemodynamic parameters in rabbits during general anesthesia.

The aim of the study was to investigate the combined influence of lidocaine and selected general anesthetics on the hemodynamic parameters in rabbits: arterial blood pressure, heart rate, cardiac output, stroke volume, peripheral vascular resistance, renal and hepatic blood flows. Lidocaine given during ketamine general anesthesia decreased markedly renal blood flow. Lidocaine administration intensified the disadvantageous influence of propofol, thiopental and pentobarbital on hepatic blood flow and during ketamine anesthesia lidocaine caused the decrease of hepatic blood flow, not observed after ketamine alone. During thiopental or pentobarbital anesthesia lidocaine may lead to a marked deceleration of heart rate. Lidocaine in thiopental, pentobarbital or propofol anesthesia appeased the hypotensive activities of these anesthetics.

The presence of histamine and tele-methylhistamine in the pineal gland of chick.

The levels of histamine (HA) and tele-methylhistamine (t-MeHA) in chick pineal gland were measured by RIA at two time points, i.e. at the end of the light (L) phase and in the middle of the dark (D) phase of 12 h: 12 h L:D cycle. The chick pineal gland showed high HA levels (12.19 and 13.09 ng/pineal at L and D, respectively). The t-MeHA content of chick pineal gland was about 20-times lower than HA level (650.2 and 536.4 pg/pineal at L and D, respectively). An aminoacid precursor of HA, L-histidine (1 g/kg, ip), given to chicks during L or D significantly increased both HA and t-MeHA content of the pineal gland. The L-histidine-evoked elevations in HA level were 2-4-times higher than changes in t-MeHA content. Enzymatic study showed the presence in chick pineal of a moderate activity of L-histidine decarboxylase (HDC), and well expressed activity of HA-methyltransferase (HMT), HA synthesizing and inactivating enzyme, respectively, which suggests that both HA and t-MeHA may be produced within the gland. It is suggested that the metabolic dynamics of the pineal HA may be higher during lighthours than darkhours of the daily light:dark illumination cycle.

The influence of selected general anesthetics on pharmacokinetic parameters of some antiarrhythmic drugs in rabbits. Part V. Verapamil.

The influence of general anesthesia with thiopental (10 mg/kg), ketamine (4 mg/kg) or propofol (10 mg/k) on the verapamil (0.2 mg/kg) pharmacokinetic parameters was studied in rabbits. It was established that during thiopental or ketamine anesthesia the levels of verapamil may be higher than therapeutic ones. The increase of area under drug level curves and the decrease of volume of distribution of verapamil during thiopental or propofol anesthesia were found.

Influence of selected antiarrhythmic drugs on the hemodynamic parameters in rabbits during anesthesia. Part III. Ketamine anesthesia.

The influence of procainamide, N-acetylprocainamide, verapamil or propranolol on hemodynamic parameters in rabbits was studied during ketamine anesthesia. Using radioisotopic methods the following parameters were estimated: cardiac output, stroke volume, total peripheral resistance, renal and hepatic blood flows, arterial pressure and heart rate. During ketamine anesthesia the inhibitory effect of verapamil on peripheral resistance was intensified; after administration of the rest of antiarrhythmic drugs the decrease of peripheral resistance was not observed in the animals without general anesthesia. During ketamine anesthesia the negative chronotropic effect of N-acetylprocainamide was decreased, but the negative chronotropic effect of procainamide was intensified. Procainamide administration during ketamine anesthesia markedly decreased renal blood flow. Propranolol given without anesthetic, as well as given together with ketamine markedly decreased hepatic blood flow.

The influence of selected general anesthetics on pharmacokinetic parameters of some antiarrhythmic drugs in rabbits. Part IV. Lidocaine.

The influence of selected general anesthetics: thiopental, propofol, ketamine and pentobarbital on the lidocaine pharmacokinetic parameters was studied in rabbits. Thiopental, ketamine and propofol caused a decrease of lidocaine blood level, but pentobarbital caused its increase. Pentobarbital, thiopental and ketamine caused an increase of lidocaine distribution rate constant, a decrease of its elimination rate constant, and prolongation of biological half-life. These anesthetics caused also an increase of volume of distribution and mean residence time of lidocaine. The anesthesia with propofol resulted in the increase of lidocaine volume of distribution and clearance.

The influence of selected general anesthetics on pharmacokinetic parameters of some antiarrhythmic drugs in rabbits. Part III. Propranolol.

The influence of general anesthesia with thiopental (10 mg/kg), ketamine (4 mg/kg), or propofol (10 mg/kg) on the propranolol (0.3 mg/kg) pharmacokinetic parameters was studied in rabbits. It was established that during thiopental or propofol anesthesia the levels of propranolol were significantly higher than in control animals. The following main changes in propranolol pharmacokinetic parameters were found: 1) increase of the distribution rate constant during propofol anesthesia 2) prolonged biological half-life and mean residence time during thiopental or propofol anesthesia 3) increase of the area under drug level curve during thiopental or propofol anesthesia 4) decrease of systemic clearance and volume of distribution during thiopental or propofol anesthesia. The slightest influence on propranolol pharmacokinetics was exerted by ketamine anesthesia.

The influence of selected general anesthetics on pharmacokinetic parameters of some antiarrhythmic drugs in rabbits. Part II. N-acetylprocainamide.

The influence of general anesthesia with thiopental (10 mg/kg), ketamine (4 mg/kg), propofol (10 mg/kg) or pentobarbital (20 mg/kg) on the N-acetylprocainamide (15 mg/kg) pharmacokinetic parameters was studied in rabbits. It was established that during thiopental or pentobarbital anesthesia the levels of N-acetylprocainamide may be temporary higher than therapeutic levels. The following main changes in N-acetylprocainamide pharmacokinetic parameters were found: 1) increase of the elimination rate and shortening of biological half-life during thiopental or ketamine anesthesia 2) decrease of mean residence time during thiopental anesthesia 3) increase of the elimination rate from the central compartment constant (but not the mean residence time) during pentobarbital anesthesia 4) decrease of distribution rate and penetration rates (k12, k21) during propofol anesthesia.

The influence of selected general anesthetics on pharmacokinetic parameters of some antiarrhythmic drugs in rabbits. Part I. Procainamide and its active metabolite-N-acetylprocainamide.

The influence of general anesthesia with thiopental (10 mg/kg), ketamine (4 mg/kg), propofol (10 mg/kg) or pentobarbital (20 mg/kg) on the pharmacokinetics of procainamide (13 mg/kg) and its active metabolite-N-acetylprocainamide was studied in rabbits. The general anesthesia with those drugs caused only the slight changes in procainamide pharmacokinetics, namely changing volume of distribution, penetration rate constants between central and peripheral compartments. However, the following main changes in N-acetylprocainamide (metabolite) pharmacokinetic parameters were found: 1) increase of the penetration rate constants between the compartments and mean residence time during propofol anesthesia 2) prolongation of the mean residence time during thiopental anesthesia 3) increase of mean residence time of N-acetylprocainamide during anesthesia with ketamine, pentobarbital or propofol.

The influence of selected antiarrhythmic drugs on the hemodynamic parameters in rabbits during anesthesia. Part I. Propofol anesthesia.

Cardiac arrhythmia can be a serious complication during general anesthesia. On the other hand, there is a need for general anesthesia of patients suffering from cardiac arrhythmias and using antiarrhythmic drugs. The aim of the present experiments was to establish the way in which procainamide, N-acetyl-procainamide, verapamil and propranolol influence hemodynamic parameters of rabbits during propofol anesthesia. The experiments were performed on rabbits. Heart rate was counted from ECG. Blood pressure was measured directly in the carotid artery. Cardiac output, stroke volume, and total peripheral resistance were estimated using the method of human Cr51 albumin dilution. Hepatic blood flow was estimated after single injection of 99mTc/Sn Hepida. Renal blood flow was estimated after a single injection of 125J-hippurate. Propofol decreases renal and hepatic blood flows, decreases blood pressure and peripheral vascular resistance. Propranolol given alone or in combination with propofol decreases hepatic blood flow. The administration of antiarrhythmic drugs during propofol anesthesia decreases renal blood flow. Propofol decreases blood pressure in rabbits as a result of decreased peripheral vascular resistance. It also decreased RBF and HBF. Disadvantages of interactions of propofol and antiarrhythmic drugs concern mainly with RBF and HBF. Propranolol (given alone or in combination with propofol) strongly decreases HBF. NAPA given during P anesthesia exerts a weaker effect on HBF. The administration of antiarrhythmic drugs during propofol anesthesia decreases RBF. The strongest disadvantageous action is exerted by propranolol, the slightest one--by verapamil.

The influence of selected antiarrhythmic drugs on the hemodynamic parameters in rabbits during anesthesia. Part II. Thiopental anesthesia.

The aim of the study was to investigate the combined influence of thiopental and antiarrhythmic drugs: procainamide, N-acetylprocainamide, verapamil or propranolol on hemodynamic parameters in rabbits: arterial blood pressure, heart rate, cardiac output, stroke volume, peripheral vascular resistance, renal and hepatic blood flows. Propranolol used during thiopental anesthesia deepened the decrease of hepatic and renal blood flow resulting from the action of the anesthetic drug. Verapamil in a dose that did not change hepatic blood flow caused significant decrease of that parameter during thiopental anesthesia. Other hemodynamic changes observed after administration of antiarrhythmic drugs during thiopental anesthesia are essentially similar to those resulting from the action of antiarrhythmic drugs alone. The administration of procainamide or N-acetylprocainamide during thiopental anaesthesia in rabbits had no significant influence on hemodynamic changes evoked by thiopental alone. Verapamil injected to rabbits together with thiopental caused a significant decrease of blood flow in the liver, which was not observed after thiopental alone or verapamil alone. Propranolol injection together with thiopental caused a decrease of blood pressure, heart rate, cardiac output but an increase of vascular peripheral resistance, which was similar to the action of propranolol alone. Propranolol administered during thiopental anesthesia caused a significant decrease of the renal and hepatic blood flow, more marked than after the injection of that beta-blocker alone.

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.