Phenotype of Urine Sediment Cells in Patients with Bladder Cancer.

Phenotype of urine sediment cells were studied in patients with bladder cancer depending on the cancer stage and recurrence prognosis. In T1N0M0 stage, the number of lymphocytes decreased, in T2N0M0 stage, the most pronounced shift was an increase in the number of erythrocytes. Irrespectively of the disease stage, we observed increased number of innate immunity cells and cells that inhibit antitumor immunity in the composition of the leukocyte fraction of urine sediment cells. At T1N0M0 stage, the epithelial-endothelial fraction was characterized by increased content of cells expressing CD13 marker (responsible for tumor growth and metastasis) and reduced number of cells expressing CD15 marker (responsible for intercellular adhesion). In patients developing relapse of bladder cancer, the number of lymphocytes was decreased in urine sediment cells and the number of epithelial and endothelial cells expressing CD13 marker was increased.

[Density of lymphocyte beta-2 adrenoreceptors in the course of hypertension]. / Plotnost' limfotsitarnykh beta2-adrenoretseptorov v techenie gipertonicheskoi bolezni.

Baseline density of intact lymphocyte beta2 adrenoreceptors (B max., 3H-DHA) was compared to dynamics of left ventricular hypertrophy (LVH) and frequency of essential hypertension (EH) complications within 7-9-year follow-up in 27 patients with EH stage II. No significant correlation was noted between B max and LVH changes. In a subgroup of 9 patients with initially very high B max overall number of complications reached 77.8% against 27.5%) (p<0.05) in control. These patients also developed acute myocardial infarctions more frequently (33.3% versus 0%, p<0.05). Such complications as strokes, coronary failure occurred with the same frequency. More extended trials are needed to infer on prognostic value of lymphocytic beta2-adrenoreceptor density.

Combination ethacizin and ethmozin treatment of resistant ventricular ectopy: theoretical, experimental, and clinical study.

Ethmozin (Moricizine HCl) and ethacizin are two class I antiarrhythmic drugs with different rate constants of interaction with the sodium channel. Computer simulation using the "guarded-receptor" model predicted that the combination of ethacizin and ethmozin should exert a greater decrease in excitability and conduction at short coupling intervals, but little effect at normal heart rates (HR). To test this prediction, we measured intraventricular conduction delay in canine hearts in vivo. In agreement with the model, the combination more potently prolonged the delay only at intervals < 600 ms as compared with ethacizin alone. Combination therapy was tested in 6 patients with idiopathic ventricular ectopic depolarizations (VEDs). Three patients were resistant to either ethmozin or ethacizin monotherapy, and three could not tolerate effective doses because of side effects. Quantitative continuous ECG monitoring showed that total VEDs in the resistant group decreased 0 and 17 +/- 13% for 400 and 800 mg/day ethmozin and 18 +/- 12 and 55 +/- 12% for 100 and 200 mg/day ethacizin, respectively. Combined therapy with ethmozin (400 mg/day) and ethacizin (100 mg/day) reduced the number of VEDs by 78 +/- 2% in these patients without side effects. In the "nonresistant" but intolerant group of patients, use of the combination allowed relief of symptomatic ectopy without side effects. A theoretical model correctly predicted an effective combination of class I antiarrhythmic drugs, one with "fast-off" and one with "slow-off" kinetics, which may provide a general rationale for choosing drug combinations.

[The effect of obzidan monotherapy on the beta 2-adrenoreceptors of the lymphocyte adenylate cyclase system in hypertension patients]. / Vliianie monoterapii obzidanom na beta 2-adrenoretseptornuiu adenilattsiklaznuiu sistemu limfotsitov bol'nykh gipertonicheskoi bolezn'iu.

Obsidan (propranolol) monotherapy was investigated for the effect on the density of lymphocytic beta2-adrenoreceptors (B max), the activity of lymphocytic homogenates adenylate cyclase (AC), plasma renin activity (PRA), aldosterone concentration (A) and plasma catecholamines (CA). Obsidan treatment brought about a 40% increase in B max without a significant changes in AC activity. Contrary to a significant fall in PRA, A and norepinephrine in plasma reduced insignificantly. Changes in B max correlated with its baseline level (r = -0.56, p < 0.01), PRA (r = 0.57, p < 0.01) and A level in plasma (r = 0.62, p < 0.01). No significant correlations appeared between hypotensive effect of the drug and drug-related changes in B max and AC activity, while PRA and A concentrations showed such dependence. B max and before treatment mass of the left ventricular myocardium correlated significantly (r = = 0.595, p < 0.01). A small decrease in the myocardial mass followed obsidan administration, being related to B max (r = = 0.497, p < 0.05). It is concluded that obsidan-induced changes in lymphocytic beta 2-adrenoreceptors correlate with alterations in the activity of renin-angiotensin-aldosterone system and myocardial hypertrophy dynamics.

[Regulation of the adenylate cyclase system of lymphocytes in patients with therapy-resistant arterial hypertension and during PGE2 administration]. / Reguliatsiia adenilattsiklaznoi sistemy limfotsitov u bol'nykh arterial'noi gipertoniei, refrakternoi k terapii, pri vvedenii pge2.

The effects of prostaglandin E2 (PGE2) infusions on lymphocyte beta 2-adrenoceptor-dependent adenylate cyclase (beta 2ARAC) system were studied in 26 patients with resistant hypertension (RH). The density of beta 2-adrenoceptors and their affinity for 1-isoproterenol were measured with 125ICYP and adenylate cyclase activity was determined by alpha-[32P]AMP generation in mononuclear lymphocytes of RH patients before and 1, 7, and 14 days after the last PGE2 infusion. Plasma epinephrine and norepinephrine concentrations were analyzed by using HPLC. The resistance to the four-component drug therapy was overcome with PGE2 infusions in patients, leading to a decrease in lymphocyte beta 2-adrenoceptor density and an increase in beta 2-receptor affinity for catecholamines and in adenylate cyclase activation by stimulating agents. PGE2 infusions unchanged the sensitivity to antihypertensive drugs in patients resulting in an increase in lymphocyte beta 2-adrenoceptor density, a decrease in beta 2-receptor affinity for catecholamines and in adenylate cyclase activation.

[Antioxidants, lipid peroxidation, and receptor-dependent increase in Ca2+ concentration in human platelets]. / Antioksidanty, perekisnoe okislenie lipidov i retseptorzavisimoe uvelichenie kontsentratsii Ca2+ v trombotsitakh cheloveka.

Content of tocopherol and total antiradical activity of hydrophobic antioxidants were estimated in human blood platelets. Two hydrophobic antioxidants--tocopherol and ubiquinone were detected in hexane extracts of thrombocytes using thin-layer chromatography. After incubation of thrombocytes with N-ethyl maleimide content of malonyl dialdehyde was increased and of tocopherol--decreased, receptor-dependent increase of Ca2+ concentration in cytoplasm was potentiated, while the Ca(2+)-blocking effect of nitroglycerol was decreased. Nitroglycerol did not inhibit the N-ethyl maleimide effect on content of malonyl dialdehyde in blood platelets. Addition of exogenous vitamin E to thrombocytes did not affect the receptor-dependent increase of Ca2+ concentration. Ascorbic acid inhibited the receptor-dependent increase of Ca2+ concentration. The data obtained suggest that nitrates may be used more rationally in combination with antioxidants and/or inhibitors of cyclooxygenase.

[Pharmacodynamics of allapinine during long-term infusion in patients with chronic ischemic heart disease and frequent ventricular extrasystole]. / Farmakodinamika allapinina dlitel'noi infuzii u bol'nykh khronicheskoi ishemicheskoi bolezn'iu serdtsa s chastoi zheludochkovoi ékstrasistoliei.

During a prolonged (24-hour) intravenous administration in a dose of 126 mg, allapinine produced a stable pronounced antiarrhythmic effect in 90% of the patients with frequent premature ventricular contraction and adverse reactions in the central nervous system in 65% of the cases. However, the latter effect of allapinine is short-term and ceased independently without altering the infusion rate. More serious adverse effects (hypotensive reactions, proarhythmic effects) occurred in 4% of the cases.

Modulating intraventricular conduction through competition of two class 1 antiarrhythmic agents: experience with ethacizin and lidocaine in canine heart.

The frequency-dependent effects on the intraventricular conduction through the dog heart in situ produced by two class 1 antiarrhythmic drugs, ethacizin and lidocaine, with different kinetic properties were investigated. Conduction delay was measured using stimulation of the His-bundle after pharmacologically induced atrioventricular (AV) block. Electrical events were derived from local epicardial bipolar electrograms at the base of the right ventricle. The stimulation program consisted of several 50-pulse trains with progressively shorter interstimulus intervals (ISI) separated by a l-s pause. Ethacizin (1.5 mg/kg) increased conduction delay by 30% at ISI of 1000 ms, and the effect was enhanced when ISI was shortened to 200 ms; l-s pauses did not significantly increase conduction velocity. Addition of lidocaine (12 mg/kg) strongly potentiated the ethacizin effect at ISI shorter than 300 ms without any noticeable increase in conduction delay at longer intervals. The major result was dramatic acceleration of conduction during the l-s pauses while both drugs were infused. With this combination, conduction delay after pause was shorter than with ethacizin alone, which is consistent with the competition of the drugs for the same binding site inside the sodium channel. Combination of two class 1 compounds in clinical practice may enhance their antiarrhythmic effects without adversely inhibiting normal impulse conduction in the heart. Computer-predicted data were in reasonable agreement with experimental results. The "guarded receptor" model, thus, can provide a simple method for predicting local anesthetic drug interactions in man.

[Cellular beta-adrenergic receptor complex in patients with heart failure and its changes during digoxin therapy]. / Beta-adrenoretseptornyi kompleks kletok u bol'nykh s serdechnoi nedostatochnost'iu i ego izmeneniia pri terapii digoksinom.

Twenty eight males with dilated cardiomyopathy, 5 males with coronary heart disease concurrent with postinfarction cardiosclerosis, 4 males and 2 females with rheumatic heart disease were examined. The findings suggest desensitization of the cellular beta-adrenoreceptor complex in patients with circulatory failure, which appeared as lower beta-adrenoreceptor density with cardiac decompensation progression and impaired transmission of a hormonal signal in the cell, particularly in patients with dilated cardiomyopathy. Digoxin therapy let to an increase in beta-adrenoreceptor density with its initial decrease and to adenylate cyclase activity enhancement. The absence of a positive ++clinico-hemodynamic effect and time course of plasma catecholamine levels in some patients with severe circulatory failure during digoxin use, as well as no changes in the values of the beta-adrenoreceptor adenylate cyclase complex indicate that the abnormalities in beta-adrenergic regulation play an important role in the pathogenesis of refractoriness at the cellular level. Retention of forskolin's stimulant effect allows one to expect a significant positive therapeutic response to be shown with the usage of drugs whose load point is a catalytic subunit of adenylate cyclase.

[The combined effect of 2 first-line anti-arrhythmia drugs on the conduction velocity of myocardial stimulation]. / Deistvie kombinatsii dvukh antiaritmicheskikh preparatov I klassa na skorost' provedeniia vozbuzhdeniia po miokardu.

Experiments with recording the time of intraventricular reentry of the canine heart by a special protocol of stimulation showed that the first-line antiarrhythmic agents having various kinetics, ethacizine and lidocaine, compete for their binding to the Na+ channels of cardiac fibers. As a result of this competition, additivity was not found in the effects of ethacizine, 1.5 mg/kg, and lidocaine, 12 mg/kg, on the rate of intraventricular conduction at heart rate under 180/min. At higher cardiac rhythm values, the total effects of the two agents on the conduction were observed. The experimental evidence confirm the results of mathematical modelling of the combined effects of ethacizine and lidocaine on the intraventricular conduction velocity, which were calculated on the basis of kinetic constants for binding and dissociation of the agents to Na+ channels. The findings show that when the two first-line antiarrhythmics having a substantially different kinetics were used in combination, their antiarrhythmic effect may be enhanced without their total effects on the rate of normal intraventricular conduction velocity reentry.

Relationship between the inhibition of receptor-induced increase in cytosolic free calcium concentration and the vasodilator effects of nitrates in patients with congestive heart failure.

Nitroglycerin, isosorbide dinitrate and sodium nitroprusside, like nifedipine, were found to inhibit the receptor-provoked increase of cytosolic free calcium concentration in human platelets loaded with 2-[(2-amino-5-methylphenoxy)methyl]-6-methoxy-8-aminoquinoline-N,N,N',N' - tetraacetate. Sodium nitroprusside and nitroglycerin induced elevation of cyclic guanosine 3',5'-monophosphate content in platelets which correlated with their calcium-blocking activity. Methylene blue and epinephrine decreased the calcium-blocking effect and the influence of nitroglycerin on cyclic guanosine 3'-5'-monophosphate content, but failed to suppress the inhibitory effect of sodium nitroprusside. Ascorbic acid increased the calcium blocking effect of sodium nitroprusside and its influence on cyclic guanosine 3'-5'-monophosphate content, but did not alter the inhibitory effect of nitroglycerin. In order to evaluate the relationship between the mode of action of nitrates at cellular level and their vasodilatory effectiveness, we studied the circulatory response of the forearm to isosorbide dinitrate and the influence of nitroglycerin on free calcium concentration in the platelets in 10 patients with chronic heart failure. We established a significant positive correlation between the basal values for venous tone and its peak decrease after administration of the 10-mg dose of isosorbide dinitrate. A correlation was also found between the deviation of maximal decrease of venous tone by this dose of isosorbide dinitrate from the regression line (the relationship between the basal venous tone and its lowering by the drug) and mean inhibitory concentration values for nitroglycerin in blocking that proportion of the rise of calcium ion concentration in platelets due to blocking of the platelet-activating factor. Thus, nitrates, like calcium antagonists, inhibit the receptor-provoked calcium supply to the contractile system of the cells so neutralizing the effects of increased concentrations of vasoconstrictors. This suggests that the effectiveness of nitrates appears to be positively related to the contribution of receptor-induced increase of cytosolic free calcium concentration in vasoconstriction together with their capacity to raise cyclic guanosine 3',5'-monophosphate.

[Effect of anti-arrhythmia drugs on the beta2 receptor-dependent adenyl cyclase system of lymphocytes in patients with cardiac rhythm disorders]. / Vliianie antiaritmicheskikh preparatov na beta2-retseptorzavisi- muiu adeniultsiklaznuiu sistemu limfotsitov bo'lnykh s narushe- niiami ritma serdtsa.

The authors analyzed the density of beta 2-adrenoreceptors, their affinity for catecholamines and activity of peripheral lymphocyte adenylate cyclase in healthy donors and patients with frequent ventricular premature contraction (VPC) in their pretreatment state and during short-term ethmosine or allapinine therapy. The density of beta 2-adrenoreceptors was increased by 43%, whereas guanylimidodiphosphate- or forskolin-induced stimulation of adenylate cyclase was decreased in the lymphocytes of VPC patients as compared to those of healthy donors. Ethmosine therapy failed to produce any changes in the density and affinity of the receptors for catecholamines. Allapinine caused a 47% reduction in beta 2-adrenoreceptor density and a 10(2)-10(3)-fold decrease in receptor affinity for 1-isoproterenol. After discontinuation of allapinine, the changes in beta 2-adrenoreceptor density and affinity for catecholamines remained on days 3 and 7, respectively. The clinical effect of both ethmosine and allapinine was accompanied by an increase in lymphocyte adenylate cyclase activity.

[Biochemical features of platelet alpha2-adrenergic receptors and their connection with an increase in concentration of intracellular Ca2+]. / Biokhimicheskie osobennosti alpha2-adrenoretseptorov trombotsitov i ikh sviaz' s povysheniem kontsentratsii vnutrikletochnogo Ca2+.

Epinephrine (E) and norepinephrine (NE) alone did not increase free intracellular Ca2+ ([Ca2+]i) in human platelets loaded with Quin-2 or Fura-2; however, they did potentiate the effects of vasopressin (VP), serotonin (S) and platelet activating factor (PAF). The synergism in [Ca2+]i increase was also obtained in the presence of VP together with PAF, S with PAF as well as VP with S. The effect of E or NE was blocked by yohimbine and phentolamine. Prazosin was less effective, while propranolol had no effect at all. Clonidine did not potentiate the effects of VP, S or PAF on [Ca2+]i; however, it did block the potentiation induced by E or NE. E potentiated the VP-induced 45Ca2+ uptake as well as VP-stimulated inositol 1,4,5-trisphosphate (IP3) formation. E alone did not change significantly the level of IP3 in platelets, nor did it influence the cyclic AMP level. The experimental results suggest that both Ca2+ influx and polyphosphoinositide breakdown underlie the mechanism of potentiation.

[Calcium metabolism and transmembrane potential of thrombocytes in patients with frequent ventricular extrasystole treated with anti-arrhythmia drugs]. / Obmen ca'ltsiia i transmembrannyi potentsial trombotsitov u bo'lnykh s chastoi zheludochkovoi ekstrasistoliei na fone lecheniia antiaritmicheskimi preparatami.

The effect of antiarrhythmic drugs on platelet calcium metabolism in peripheral blood has been examined. Anti-arrhythmic agents (ethmozine, ethacizine, quinidine, disopyramide, amiodarone), used extensively for the control of various heart rhythm disorders, as well as calcium antagonists (verapamil were shown to have a calcium-blocking property. It is demonstrated that the rate of reduction in the total number of extrasystoles in the presence of antiarrhythmic drugs is correlated to the magnitude of their in vitro calcium-blocking effect. It can be assumed that the action of antiarrhythmic drugs is in part mediated by their effect on calcium currents; at the same time, disorders of Ca2+ transport in myocardial cells are a cause of developing arrhythmias. The ability of antiarrhythmic drugs to affect platelet calcium ion currents may be used for preliminary assessment of the efficiency of antiarrhythmic drugs, used clinically to control heart rhythm disorders.

[Allapinin pharmacokinetics after its single intravenous administration]. / Allapinin. Farmakokinetika pri razovom vnutrivennom vvedenii.

Allapinin after i.v. bolus infusion in a dose of 30 mg is relatively quickly eliminated from blood (in patients without congestive heart failure half-elimination period is 2.4 +/- 0.5 h and clearance is 79.0 +/- 8.9 l/h) which makes a good reason for its intravenous infusion according to the scheme "load dose + drop infusion". Marked heart failure in patients with acute myocardial infarction compared to patients without heart failure results in reduced elimination rate, decreased clearance, significantly increased plasma allapinin concentration which should be taken in account when choosing the regime of drug infusion. The elimination of allapinin is mainly metabolic and not renal (only about 17% of the drug is excreted with urine).