[Thermoprotector properties of a combination of sydnocarb with ladasten].

Thermoprotector properties of a 1 : 1 combination of sydnocarb and ladasten (both in a dose of 10 or 20 mg/kg) along with its effect on the hemodynamics and respiration in experimental animals were studied. The combination of sydnocarb (20 mg/kg) and ladasten (20 mg/kg) produced a significant thermoprotector effect, enhanced the regional and local cerebral flow, and increased the respiration rate.

Effect of d-amphetamine and sydnocarb on the extracellular level of dopamine, 3,4-dihydroxyphenylacetic acid, and hydroxyl radicals generation in rat striatum.

d-AMPH and its congeners are able to produce several neurotoxic effects, including behavioral evidences of dopaminergic dysfunction, enhanced generation of reactive oxygen species, and depletion of endogenous DA. As has been shown, Sydnocarb produces a slow and gradual increase of the parameters of dopaminergic dysfunction. Present investigations report that Sydnocarb, the original Russian psychostimulant, at a dose of 23.8 mg/kg (equimolar to 5 mg/kg d-AMPH) elicited a moderate increase in the extracellular level of DA. We found that Sydnocarb increased OH generation in less degree than that by d-AMPH. Sydnocarb was also able to elicit stereotyped behavior, but to a less extent than d-AMPH. Differences between the mode of action of this drug were previously observed. In our study, the DOPAC extracellular level was significantly decreased after the fourth injection of Sydnocarb, unlike with d-AMPH treatment. Taken together, this finding probably reflects less neurotoxic potential of the novel, original psychostimulant Sydnocarb with good clinical efficaciousness in comparison to the amphetamine.

Behavioral, toxic, and neurochemical effects of sydnocarb, a novel psychomotor stimulant: comparisons with methamphetamine.

Sydnocarb (3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine) is a psychostimulant in clinical practice in Russia as a primary and adjunct therapy for a host of psychiatric disorders, including schizophrenia and depression. It has been described as a stimulant with an addiction liability and toxicity less than that of amphetamines. The present study undertook to evaluate the psychomotor stimulant effects of sydnocarb in comparison to those of methamphetamine. Sydnocarb increased locomotor activity of mice with reduced potency (approximately 10-fold) and efficacy compared with methamphetamine. Sydnocarb blocked the locomotor depressant effects of haloperidol at doses that were inactive when given alone. The locomotor stimulant effects of both methamphetamine and sydnocarb were dose-dependently blocked by the dopamine D1 and D2 antagonists SCH 39166 and spiperone, respectively; blockade generally occurred at doses of the antagonists that did not depress locomotor activity when given alone. In mice trained to discriminate methamphetamine from saline, sydnocarb fully substituted for methamphetamine with a 9-fold lower potency. When substituted for methamphetamine under self-administration experiments in rats, 10-fold higher concentrations of sydnocarb maintained responding by its i.v. presentation. Sydnocarb engendered stereotypy in high doses with approximately a 2-fold lower potency than methamphetamine. However, sydnocarb was much less efficacious than methamphetamine in inducing stereotyped behavior. Both sydnocarb and methamphetamine increased dialysate levels of dopamine in mouse striatum; however, the potency and efficacy of sydnocarb was less than methamphetamine. The convulsive effects of cocaine were significantly enhanced by the coadministration of nontoxic doses of methamphetamine but not of sydnocarb. Taken together, the present findings indicate that sydnocarb has psychomotor stimulant effects that are shared by methamphetamine while demonstrating a reduced behavioral toxicity.

Efficiency of aerosolized nitric oxide donor drugs to achieve sustained pulmonary vasodilation.

Inhalation of nitric oxide (NO) causes selective pulmonary vasodilation, but demands continuous supply of the gaseous agent. We investigated the suitability of aerosolization of NO-donor drugs for achieving sustained reduction of pulmonary vascular tone. In buffer-perfused rabbit lungs, stable pulmonary hypertension was achieved by continuous infusion of the thromboxane-analogue U46619. The NO-donor drugs molsidomine, 3-morpholinosydnone-imine (SIN-1), sodium nitroprusside (SNP) and glyceryl-trinitrate reduced the pulmonary hypertension in a dose-dependent fashion, whether admixed to the perfusate or inhaled as alveolar-accessible aerosol particles (aerosolization time 3-6 min), with an efficiency ranking of SNP > SIN-1 >> molsidomine and glyceryl-trinitrate. Notably, nearly identical dose-response curves were obtained when corresponding molar quantities of the most potent agents, SNP and SIN-1, were applied either via transbronchial or via intravascular routes, with respect to rapidity of onset, extent (pressure reduction to near baseline) and duration (>90 min) of vasorelaxation. Appearance of sydnonimines in the perfusate after aerosolization and reduction of SIN-1 efficacy when nebulized in nonrecirculatingly perfused lungs demonstrated substantial entry of this prodrug into the vascular space after alveolar deposition. In contrast, undiminished vasodilatory efficacy of aerosolized SNP under conditions of non-recirculating perfusion suggested predominant efficacy via local NO release for this agent. We conclude that short aerosolization maneuvers of NO-donor drugs are suitable to achieve dose-dependent, extensive and sustained vasodilation in the pulmonary circulation, thus offering a new therapeutic approach in pulmonary hypertension.

Cytochrome P4503A is the major source of N-vinylprotoporphyrin IX formation after administration of 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone to untreated and dexamethasone-pretreated rats.

The sydnone, 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS), which has previously been shown to cause mechanism-based inactivation of rat hepatic cytochrome P450 (P450) 1A and 3A, was shown to cause in vitro mechanism-based inactivation of rat P450s 2B1, 2C6, and 2C11, but not of P4502A1/2. Administration of TTMS to rats is known to cause degradation of rat hepatic P450 by heme N-alkylation yielding N-vinylprotoporphyrin IX (N-vinylPP). Pretreatment of rats with beta-naphthoflavone (beta NF) failed to increase hepatic N-vinylPP after TTMS administration. Because beta NF causes a marked increase in hepatic levels of P4501A, we conclude that P4501A of rat liver is not a quantitatively important source of N-vinylPP from TTMS. The increased formation of N-vinylPP in phenobarbital (PB)- and dexamethasone (DEX)-pretreated rats suggested that an inducible P450 isozyme (e.g. P4502B1/2, P4503A, or both) is/are an important contributor to N-vinylPP formation from TTMS. When troleandomycin (TAO) (a selective inhibitor of P4503A) was coadministered with TTMS, N-vinylPP formation was reduced to 25% of control in DEX-pretreated rats and to 34% of control in untreated (UT) rats, showing that P4503A was quantitatively the major source of N-vinylPP formation in UT- and DEX-pretreated rats. No significant differences were found in the formation of the ring A-substituted (NA), ring B-substituted (NB), ring C-substituted (NC), and ring D-substituted (ND) regioisomers of N-vinylPP among UT, beta NF-, PB-, or DEX-pretreated rats. Regioisomer data, in addition to data obtained with TAO, indicate that a single inducible form of P450, namely P4503A, is responsible for the bulk of N-vinylPP formation in UT and DEX-pretreated rat liver after TTMS administration.

Differential hemodynamic effects of the nitric oxide donor pirsidomine in comparison to SIN-1, nitroprusside and nitroglycerin.

The systemic and coronary hemodynamic effects of the nitrovasodilator, pirsidomine, were compared with SIN-1, nitroprusside, and nitroglycerin. Four groups consisting of 32 experiments were performed in 17 conscious dogs chronically instrumented for measurement of aortic and left ventricular pressure, left ventricular dP/dtmax, diastolic coronary blood flow velocity, cardiac output, and subendocardial segment length. On separate experimental days, systemic and coronary hemodynamics were recorded during control conditions and after intravenous administration of pirsidomine (1.0, 2.0, and 4.0 mg.kg-1), SIN-1, (50, 100, and 200 micrograms.kg-1), nitroprusside (0.5, 1.0, and 2.0 micrograms.kg-1.min-1), or nitroglycerin (1.0, 2.0, and 4.0 micrograms.kg-1.min-1). Pirsidomine decreased mean arterial, left ventricular systolic and end-diastolic pressures, stroke volume and systemic vascular resistance. Diastolic coronary blood flow velocity and heart rate were increased and coronary vascular resistance decreased by pirsidomine. SIN-1, nitroprusside and nitroglycerin caused similar decreases in preload (evaluated by left ventricular end-diastolic pressure) and afterload (indirectly assessed by mean arterial pressure and systemic vascular resistance) as compared to pirsidomine. However, equihypotensive doses of SIN-1, nitroprusside, and nitroglycerin improved ventricular performance as assessed by increases in left ventricular dP/dtmax, cardiac output and segment shortening, in contrast to those findings during comparable doses of pirsidomine (4 mg.kg-1). Despite similar loading conditions, high doses of pirsidomine did not enhance left ventricular function, suggesting that pirsidomine may have direct negative inotropic effects.

Potentiation of retinoic acid-induced U-937 differentiation into respiratory burst-competent cells by nitric oxide donors.

All-trans retinoic acid (tretinoin) is a known inducer of differentiation of the human monoblastic cell line, U-937. We now report that the ability of retinoic acid (RA) to induce differentiation of U-937 cells into cells possessing respiratory burst activity is enhanced by the known nitric oxide-donating drugs glyceryl trinitrate, molsidomine and CAS 936, and by tetranitromethane in combination with cysteine. RA alone was a strong inducer of U-937 differentiation as indicated by the following responses to 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation: (1) increase in the percentage of cells staining with nitroblue tetrazolium (NBT); (2) increase in the total amount of formazan (the product of NBT reduction by O2-.) as determined spectrophotometrically; (3) increase in hexose monophosphate shunt (HMPS) activity as assessed by [14C]CO2 released from D-[1-14C]glucose. RA was also able to increase mRNA levels for two respiratory burst-related genes and for glucose-6-phosphate dehydrogenase (G6PD), an HMPS enzyme. Other indications of differentiation were reduced cell proliferation, increased adherence and altered nuclear morphology. The observed increase in formazan production and HMPS activity and the reduction of cell proliferation due to RA were augmented by co-treatment with either glyceryl trinitrate, molsidomine, CAS 936 or tetranitromethane plus cysteine. Glyceryl trinitrate alone increased HMPS activity and G6PD mRNA levels and also reduced cell proliferation. Glyceryl trinitrate, molsidomine and CAS 936 are presumed to release nitric oxide and increase intracellular cGMP levels by stimulation of soluble guanylate cyclase. The mechanism of action of tetranitromethane is less certain, although it may also generate reactive nitrogen intermediates. These data suggest that a NO./cGMP pathway may augment a retinoic acid-mediated pathway to enhance maturation of U-937 cells with respect to the respiratory burst. Glyceryl trinitrate may act additionally by another pathway.

Inactivation of chick embryo hepatic cytochrome P450 1A, 2H and 3A following in ovo administration of 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine and 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone.

Rat hepatic cytochrome P450 (P450) isozymes 1A1, 2C6, 2C11, 3A1 and 3A2 are targets for mechanism-based inactivation by the porphyrinogenic compound 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DDC). It is of interest to determine whether similar P450 isozymes are targets of porphyrinogenic drugs in the chick embryo liver. The chick embryo expresses P450 2H1/2 isozymes, which are similar to the rat P450 2B1/2 isozymes, a polycyclic aromatic hydrocarbon-inducible P450 1A isozyme, and a pregnenolone 16 alpha-carbonitrile-inducible P450 3A isozyme. We have found previously that chick embryo hepatic P450 1A and 3A isozymes are targeted for in vitro mechanism-based inactivation by 4-ethyl DDC and by the sydnone 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS). Marked differences have been observed between the in vitro and in vivo effects of porphyrinogenic drugs on P450 isozymes. Thus, the first objective of this study was to determine whether chick embryo hepatic P450 1A and 3A isozymes are subject to in ovo inactivation by these porphyrinogenic compounds. Our second objective was to determine whether the chick embryo hepatic P450 2H isozyme(s) was subject to in ovo and in vitro inactivation by 4-ethyl DDC and TTMS. Using hepatic microsomes prepared from beta-naphthoflavone-, dexamethasone-, phenobarbital-, and glutethimide-induced 19-day-old chick embryos, we found that total P450 content was decreased significantly in microsomes prepared from all treatment groups following in ovo administration of 4-ethyl DDC and TTMS. Moreover, in ovo administration of both 4-ethyl DDC and TTMS caused a significant decrease of 7-ethoxyresorufin O-deethylase, erythromycin N-demethylase, and benzphetamine N-demethylase activities, which are selective catalytic markers for chick embryo hepatic P450 1A, 3A and 2H isozymes, respectively. In addition, in vitro administration of 4-ethyl DDC and TTMS caused mechanism-based inactivation of benzphetamine N-demethylase activity in microsomes from phenobarbital- and glutethimide-treated chick embryos, showing that the chick embryo hepatic P450 2H isozyme is a target for mechanism-based inactivation. Therefore, it was concluded that the chick embryo hepatic P450 1A, 2H and 3A isozymes serve as targets for both in ovo and in vitro mechanism-based inactivation by 4-ethyl DDC and TTMS.

Effectiveness of an NO-releasing pirsidomine derivative on coronary conductance during long-term administration.

Nitrovasodilators have long been used in the treatment of myocardial ischemia. One of the limitations of their chronic administration is loss of drug action over time. Nitrovasodilator-induced drug tolerance results from either the loss of cyclic guanosine monophosphate-dependent dilator effects, or from biological counterregulatory processes, usually neurohormonal adaptations. C87-3754, a derivative of pirsidomine, is a new nitric oxide-releasing sydnonimine. Continuous 5-day infusion of C87-3754 in dogs did not result in a substantial loss of drug action. There was long-lasting dilation evident in the large coronary arteries and venous bed, resulting in improved coronary conductance. Administration of C87-3754 was associated with reduction in cardiac preload, wall stress, and subendocardial tissue pressure.

Cardiovascular effects of the new nitric oxide donor, pirsidomine. Hemodynamic profile and tolerance studies in anesthetized and conscious dogs.

The hemodynamic profile of pirsidomine, a new donor of NO (nitric oxide), was evaluated in dogs. In anesthetized dogs, the intravenous or intraduodenal administration of pirsidomine (0.3-10 mg/kg) decreased dose relatedly the preload and afterload of the heart, total peripheral resistance, cardiac output, left ventricular work and myocardial oxygen consumption. In conscious renal-hypertensive dogs, oral administration of pirsidomine (1.0-10 mg/kg) caused a marked and sustained decrease in systolic blood pressure and left ventricular end-diastolic pressure, which was accompanied by a slight and transient increase in heart rate and contractility. The diastolic blood pressure was affected less than in anesthetized dogs. Similar hemodynamic effects were obtained with M1 (3-(1-(2,6-dimethylpiperidino))-sydnonimine; 0.3-1 mg/kg), the main metabolite of pirsidomine, and with the known NO donor, isosorbide-5-mononitrate (IS-5-MN; 2-10 mg/kg). Tolerance development after repeated administration of pirsidomine and IS-5-MN was also investigated. In anesthetized dogs, repeated intraduodenal administrations of pirsidomine did not attenuate the response whereas tolerance occurred with hemodynamically equieffective doses of IS-5-MN. In conscious dogs, long term oral treatment, three times daily every 8th h for 5 days, revealed tolerance to IS-5-MN, slight or no tolerance to pirsidomine, and no cross-tolerance between the two agents. The results indicate that pirsidomine possesses an antianginal hemodynamic profile similar to that of its main metabolite, M1, and of IS-5-MN. This suggests a common mode of action via the release of NO.(ABSTRACT TRUNCATED AT 250 WORDS)

[Narrow-band changes in the the EEG spectral composition under the influence of an agonist and an antagonist of noradrenergic neuromediation]. / Uzkopolosnye izmeneniia spektral'nogo sostava EEG pod vliianiem agonista i antagonista noradrenergicheskoi neiromediatsii.

At pharmaco-electroencephalographic examination of patients with neuroses narrow-band components was carried out of the EEG spectrum, which oppositively changed under the influence of sidnocarb and obsidan--agonist and antagonist of noradrenergic system, the initial hypothesis on the perspectivity of search of the EEG markers of the level of activation of the brain neurotransmitter systems thus being confirmed. Comparison of the obtained EEG-data with pharmacological properties of the applied drugs allows to project the aspects of further EEG studies of neurotransmission.

[The convulsive activity of white rats after immunization with a conjugate of sidnofen and serum albumin]. / Sudorozhnaia aktivnost' belykh krys posle immunizatsii kon''iugatom sidnofena s serumal'buminom.

The influence of white rats immunization by a covalent conjugate of serum albumin with sydnophen on the seizure activity in the single and repeated injections of pentylenetetrazole was investigated. The immunization lowered the seizure activity in single injections of threshold doses, (60 mg/kg) of pentylenetetrazole. The repeated daily injections of the drug in subthreshold doses (30 mg/kg) inhibited the process of "kindling" effects formation.

[Randomized ergometric study of vasodilators combined with betablockaders]. / Etude ergométrique randomisée des vasodilatateurs associés aux bêtabloqueurs.

The ergometric effects of different vasodilator drugs in 5 series of 10 patients with stable angina and persistent effort ischaemia despite beta-offckade, were compared two by two in a random, single blind cross-over study under basal conditions on betablocker therapy and at the peak of their action, the second measurement being performed after a 2 to 7 day interval. The principal criteria of assessment were the work required to induce 1 mm ST depression (WST1), and the maximum ST depression (ST max) at comparable work loads. Molsidomine (2 mg), Risordan 20 mg) and Nifedipine (10 mg) significantly improved both parameters (p less than 0.001). Lenitral (7.5 mg), Langoran (40 mg), Trinitrin skin patch (10 mg) did not produce a significant improvement. Corditrine improved WST1 (p less than 0.05) and slow release Trinitrin (2.5 and 5 mg) improved WST1 at 3 hours (p less than 0.05) and ST max at 15 minutes (p less than 0.001) and 3 hours (p less than 0.05). The fall in resting blood pressure was parallel to the ergometric changes. These results suggest that Molsidomine, Nifedipine, Risordan and slow release Trinitrin (2.5 mg) are the most effective vasodilators when used in association with betablockers.

Haemodynamic effects of molsidomine in patients with severe chronic coronary disease.

The haemodynamic effects of a single dose of intravenous molsidomine were assessed in 12 patients with severe coronary disease. The investigation was carried out at rest during angina induced by pacing and after molsidomine during pacing at the rate at which angina had been produced. During angina, left ventricular systolic and end-diastolic pressure rose, left ventricular stroke work fell and coronary flow and myocardial oxygen consumption increased by 58.3% above the control levels. After the administration of molsidomine, atrial stimulation was not followed by angina and there were no significant changes in systolic blood pressure. Left ventricular end-diastolic pressure fell sharply and coronary flow and myocardial oxygen consumption were only 38% and 33% higher, respectively, than the control levels. The beneficial effects of molsidomine in ischaemic heart disease, therefore, are the result of peripheral vasodilation which, by reducing the preload and afterload, lowers the oxygen requirements of the myocardium and thus increase the threshold for angina. A direct action on the coronary network can not be excluded but if such an action does exist it must be very small in the light of the marked systemic effect.

The influence of molsidomine and its active metabolite SIN-1 on fibrinolysis and platelet aggregation.

Molsidomine and its active metabolite SIN-1 were examined in humans and animals for platelet suppressant and fibrinolytic activities. Following oral administration of molsidomine at doses of 6 or 15 mg/kg to rabbits, their blood platelets in PRP ex vivo required higher threshold concentrations of ADP, AA and thrombin to be aggregated. Unlike molsidomine, SIN-1 when infused (10 and 20 micrograms/kg i.v.) into anaesthetized cats caused a release of a substance disaggregating platelet clumps which had adhered to blood superfused collagen strip. The appearance of this unstable disaggregating substance was prevented by the pretreatment of cats with aspirin (50 mg/kg i.v.). It is suggested that SIN-1 may promote formation of a PGI2-like substance. In humans shortening of euglobulin clot lysis time was observed 60 min after a single ingestion of 2 mg of molsidomine. This fibrinolytic effect of molsidomine was not abolished by the pretreatment of patients with aspirin. Neither molsidomine nor SIN-1 activated fibrinolysis in preformed euglobulin clots in vitro.

[Intravenous administration of molsidomin in the acute period of myocardial infarct]. / Vnutrivennoe primenenie molsidomina v ostrom periode infarkta miokarda.

A study of central hemodynamic parameters, ECG charting and the activity of serum CPK and its MB fraction in 58 patients with acute myocardial infarction demonstrated that intravenous administration of 20 mg Corvaton, at the rate of 3 micrograms/kg/min, was effective for both controlling an acute left-ventricular failure, and limiting the infarcted area. A three-day treatment normalized systemic and central hemodynamic parameters in cases of medium-size infarction, and considerably reduced manifestations of acute left-ventricular failure in patients with a large area of necrosis.

Effectiveness of molsidomine in the long-term treatment of exertional angina pectoris and chronic congestive heart failure.

Molsidomine, similar to nitrates, improves myocardial blood flow in hypoperfused, poststenotic myocardial regions, reduces left ventricular pressure and volumes, and leads to improvement in impaired regional wall motion. In patients with chronic, stable anginal pectoris who underwent long-term treatment with 2 mg of molsidomine three times daily there were reductions in ST segment depression of 45% and 9% at 1 and 3 hours after administration, respectively, and slight but statistically significant reductions in the rates of anginal attacks and nitrate consumption of 16% and 18%. Administration of 3 mg three times daily did not render more significant effects. Doubling the frequency of administration--that is, 2 mg six times daily--led to reductions in the rates of anginal attacks and nitrate consumption of 38% and 36%, respectively, and 4 mg led to a more marked reduction in ST segment depression of 57%. With administration of 8 mg of sustained-release molsidomine, a prolonged antiischemic effect was documented with reductions in ST segment depression of 74% at 1 hour and 31% at 8 hours after medication. In patients with congestive heart failure, 1 hour after administration of 4 mg of molsidomine there were significant reductions in systolic and diastolic pulmonary artery pressures of 25% and 30%, respectively. After 7 days of continuous treatment with 4 mg of molsidomine four times daily, comparable reductions in pulmonary artery pressure were observed. Thus molsidomine, in adequate dosages, elicits an unequivocal anti-ischemic and antianginal effect as well as a salutary reduction in left ventricular filling pressure.