Design and synthesis of novel hybrid sydnonimine and prodrug useful for glaucomatous optic neuropathy.

Synthesis and bioactivity of novel dual acting nitric oxide releasing and reactive oxygen scavenging hybrid compound SA-2 is described. The hybrid molecule SA-2 significantly increased the superoxide dismutase enzyme level and protected the photoreceptor cells from H2O2 induced oxidative stress. Synthesis of ocular esterase sensitive aceloxy alkyl carbamate prodrug SA-4 with improved aqueous half-life is achieved to aid topical ocular formulation. This class of hybrid molecule and prodrug may have dual potential of improved IOP lowering and neuroprotection in glaucomatous optic neuropathy.

[Metabolic effects of static physical load under the conditions of pharmakologicheskoi mobilization of physical endurance]. / Metabolicheskie éffekty staticheskoi fizicheskoi nagruzki v usloviiakh farmakologicheskoi vynoslivosti.

The model of static physical loading (SPL) was used to study the biochemical effects of graded static tension and potentiality for pharmacological mobilization of physical endurance with participation of male volunteers. A close pathogenetic linkage between the established metabolic effects of the model and their adaptive adequacy to the stressing factor show that there is every reason to arrange the observed shifts in a SPL syndrome. The SPL syndrome is primarily manifested by exaggerated tone of the adrenoactive structures, inhibition of insulin production by the pancreas, activation of the neuropeptide anti-stress mechanisms, predominant utilization of the lipid substrate in energy production, intensification of protein catabolism, and increase in myocyte membrane permeability due to energy deficit. The investigation demonstrated that improvement of static physical endurance can be attained with a mobilizing stimulator (sidnocarb) and a combination of sidnocarb with a nonmediatory preparation (bemytil). This pharmacological combination levels side-effects of exorbitant activation of the adrenal system. On the contrary, a metabolic vitamin-microelements complex ("cocktail C") perceivably enhances SPL endurance (sidnocarb dose was lowered in three times), possesses the stress-protective effect, the ability to moderate the intensity of free (uninvolved in phosphorylation) oxidation and to optimize energy-plastic processes with predominant utilization of the lipid substrate.

[Role of endothelin and nitric oxide in early gut ischemia].

OBJECTIVE: Inadequate perfusion in splanchnic organs and especially in the gut during acute burn period has been reported in many conventionally "successfully" resuscitated patients, but the mechanisms still remain unclear and its early preventive measures need to be further studied. The aim of this study is to evaluate the role of endothelin and nitric oxide in gut ischemia. METHODS: Eighteen male pigs were randomly assigned to one of the three groups: group C, a sham burn group that was subjected to all surgical procedures except burn; group B, sustained 30% TBSA cutaneous thermal burn; Group N, NO donor (C87-3754) was given intravenously (0.0125 mg.kg-1.min-1) at the beginning of resuscitation. RESULTS: In group B, PVF decreased rapidly after burn, and did not recover in the observation period (72 h), ET levels in portal blood and intestinal tissue elevated contrary to the changes in NO. In group N, PVF was higher than in group B. CONCLUSION: 1. Changes in ET and NO may influence the protal blood flow. 2. NO donor was proved to be beneficial in improving GI tissue perfusion by releasing NO.

The role of nitric oxide in modulating ischaemia-induced arrhythmias in rats.

The effect of a nitric oxide (NO) donor and the influence of endogenous NO in modulating ischaemia-induced arrhythmias was assessed in anaesthetised rats. The nitric oxide donor C87-3754 (1 mg/kg) caused a significant reduction in arterial blood pressure before coronary artery ligation but did not influence the incidence or severity of ventricular arrhythmias during a 30-min period of myocardial ischaemia [60 and 58% incidence of ventricular fibrillation (VF) in control and treated rats, respectively]. When the hearts were preconditioned by a short (3 min) coronary artery occlusion before the 30-min period of ischaemia, there was a marked reduction in both the number of ventricular ectopic beats (260 +/- 65 vs. 812 +/- 256 beats/min in controls; p < 0.05) and the incidence of ventricular fibrillation (9 vs. 67% in controls; p < 0.05). Neither NG-nitro-L-arginine methyl ester (L-NAME; 10-100 mg/kg) nor methylene blue (1-50 mg/kg) attenuated this marked antiarrhythmic effect of preconditioning. L-NAME caused a significant increase in blood pressure with all doses used, whereas methylene blue did not increase blood pressure. Both L-NAME and methylene blue attenuated ventricular arrhythmias in non-preconditioned hearts. L-NAME reduced the number of ventricular ectopic beats (from 812 +/- 256 to 318 +/- 81 beats/min at 10 mg/kg; p < 0.05), whereas methylene blue decreased the incidence of VF from 67 to 20% at a dose of 50 mg/kg (p < 0.05). These findings suggest that neither endogenous nor exogenously administered NO reduces ischaemic arrhythmias in anaesthetised rats. Furthermore, the antiarrhythmic effect of preconditioning in this species appears to be independent of NO. The antiarrhythmic effects seen with both methylene blue and L-NAME may be the result of actions other than inhibition of the production or actions of NO.

Effects of S-ethylisothiourea, a potent inhibitor of nitric oxide synthase, alone or in combination with a nitric oxide donor in splanchnic artery occlusion shock.

1. The aim of this study was to compare the effects of an intravenous infusion of a potent and non selective nitric oxide synthase inhibitor S-ethylisothiourea (Ethyl-TU) with that of a nitric oxide (NO) donor on the pathological sequelae associated with splanchnic artery occlusion (SAO) shock. In addition the effects of the combination of these two treatments were also investigated. 2. SAO shock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min. Sham operated animals were used as controls. Survival time, white blood cell (WBC) count, mean arterial blood pressure, myeloperoxidase activity (MPO; studied as a quantitative means to evaluate neutrophil accumulation) and the responsiveness of aortic rings to acetylcholine (ACh, 10 nM-10 microM) and to phenylephrine (PE, 1 nM-10 microM) were studied. 3. SAO shocked rats had a decreased survival rate (0% survival 2 h after the release of occlusion) and survival time (76 +/- 10 min), increased MPO activity in the ileum (3.39 +/- 0.8 u x 10(-3) g-1 tissue), a marked leukopenia and a profound hypotension. In addition aortic rings from shocked rats showed a marked hyporeactivity to PE and reduced responsiveness to ACh. Endothelium denuded aortic rings had also a marked hyporeactivity to PE. 4. In vivo administration of Ethyl-TU (0.1 mg kg-1 h-1, beginning 1 min after the onset of reperfusion) significantly increased survival time and rate, improved mean arterial blood pressure, restored the responsiveness to PE, but did not change MPO activity, leukopenia or the impairment in the responsiveness of aortic rings to ACh. Addition of Ethyl-TU (2 microM) to endothelium denuded aortic rings in vitro, restored the marked hyporeactivity to PE. Administration of the NO donor C87-3754 (0.75 mg kg-1 h-1, beginning 1 min after the onset of reperfusion) slightly increased survival time and reduced MPO activity and leukopenia, but did not change survival rate and mean arterial blood pressure. In addition C87-3754 restored the responsiveness of aortic rings to ACh to control values, but did not modify the hyporeactivity to PE. The combination of these two interventions produced a higher degree of protection than either Ethyl-TU or C87-3754 alone. In fact, co-administration of Ethyl-TU plus C87-3754 completely prevented mortality, reduced MPO activity, attenuated leukopenia and the profound hypotension and restored the impaired responsiveness of aortic rings to PE and ACh. 5. Our study suggests that treatment with a nitric oxide synthase inhibitor combined with an NO donor may be a new therapeutic approach to the treatment of splanchnic artery occlusion shock.

Short-term hemodynamic, anti-ischemic, and antianginal effects of pirsidomine, a new sydnonimine.

Pirsidomine is a new sydnonimine compound in clinical development. As a prodrug, it is transformed into a nitric oxide-releasing metabolite in vivo. In animal tests there were no signs of tolerance with repeated administration. The short-term effects of 10, 20, and 40 mg of the drug on pulmonary hemodynamics and ischemic parameters were examined at rest and during exercise in a double-blind, randomized, placebo-controlled study. The study included 48 patients with documented coronary artery disease and exercise-induced ST-segment depression. Compared with the baseline test, there was a reduction of diastolic pulmonary artery pressure with pirsidomine at rest (placebo: -0.4 +/- 0.5 mm Hg; 10 mg: - 1.5 +/- 2.4 mm Hg; 20 mg: - 1.4 +/- 1.1 mm Hg; 40 mg: - 2.3 +/- 1.3 mm Hg [p < 0.05 ]) and at the highest comparable workload (placebo: -2.8 +/- 1.9 mm Hg; 10 mg: -7.3 +/- 6.8 mm Hg; 20 mg: -8.4 +/- 7.9 mm Hg [p <0.05]; 40 mg: -13.8 +/- 7.1 mm Hg [p <0.05]). ST-segment depression decreased at the highest comparable workload (placebo: -0.33 +/- 0.49 mm; 10 mg: -1.33 +/- 1.37 mm [p <0.05]; 20 mg: -1.33 +/- 0.83 mm [p <0.05]; 40 mg: -1.96 +/- 0.86 mm [p <0.05]) and total exercise time increased (placebo: 15 +/- 48 s; 10 mg: 98 +/- 126 s; 20 mg: 165 +/- 251 s [p <0.05]; 40 mg: 155 +/- 174 s [p <0.05]). Of 40 patients who complained of angina pectoris symptoms in the baseline test, 15 became free of angina pectoris with pirsidomine. Compared with placebo, blood pressure, heart rate during exercise, and cardiac output during exercise showed no significant change. Plasma concentration response relations of the metabolite revealed concentrations that caused a half-maximum effect of 6 ng/ml, 13 ng/ml, 20 ng/ml, and 28 ng/ml in reduction of ST-segment depression, reduction of diastolic pulmonary artery pressure, relief of angina pectoris symptoms, and an increase in exercise duration, respectively. Thus, pirsidomine is an effective anti-ischemic and antianginal agent. A significant preload reduction was obtained with plasma metabolite concentrations lower than those necessary to achieve a satisfactory antianginal effect.

Antiischemic effects of pirsidomine, a new nitric oxide donor.

The antiischemic effect of pirsidomine (CAS 936 (3-(cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl))-sydnon imine), a new nitric oxide donor, was investigated in a model of myocardial infarction in the dog. Dogs were anaesthetised, thoracotomized, and the left descending coronary artery was occluded for 6 h. Pirsidomine was given intraduodenally (i.d.) at the dose of 1.0 mg/kg to 11 dogs 30 min prior to coronary occlusion. Eleven dogs received the solvent i.d. and served as controls. Pirsidomine administration completely prevented the increase in left ventricular end-diastolic pressure and pulmonary artery pressure induced by the coronary occlusion and resulted in a marked decrease in systolic and diastolic blood pressure, cardiac output, left ventricular contractility, left ventricular work and left ventricular oxygen consumption. Additionally, pirsidomine completely prevented the occlusion-induced increase in flow in the non-occluded circumflex coronary artery. Regional blood flow measurements (with radioactive microspheres) revealed that pirsidomine induced a significant reduction in blood flow in the non-ischemic areas (both epi- and endocardial) but in the course of the ischemia, significantly increased flow in the ischemic epicardial areas. Infarct-size (triphenyltetrazolium chloride technique) in control dogs was 45% of the area at risk, but only 26% (P < 0.05) in pirsidomine-treated dogs. Thus, pirsidomine had a marked antiischemic effect in this model. This was probably due to the hemodynamic unloading of the heart as well as to redistribution of blood from the non-ischemic to the ischemic areas of the myocardium.

[The effect of fenazepam and sidnocarb in the phantom pain syndrome]. / Effekty fenazepama i sidnokarba pri fantomno-bolevom sindrome.

The phantom-pain syndrome model was used to examine the effects of phenazepam, sydnocarb and their combination in chronic oral administration. Phenazepam was shown to have no effects on the development of the phantom-pain syndrome. Sydnocarb arrested the progression of the pain syndrome, reduced its symptoms, alleviated inflammatory manifestations and extremity edema. The agent increased animals' excitability. When their combination was used, the clinical signs of the pain syndrome developed in the same way as with sydnocarb alone. At the same time phenazepam decreased the animals' aggression and excitability caused by sydnocarb. It is suggested that enhancing the efficiency of inhibitory GABAergic processes may result in lower clinical signs of the phantom-pain syndrome in case of involvement of brain catecholaminergic systems whose activation increases the inhibitory functions of its related GABA. The sympathomimetic action of sydnocarb induces an elevation of norepinephrine concentrations in the nerve endings and postsynaptic receptors, resulting in trophic improvement and restoration of tissue viability.

[Anti-ulcer effect of the drug OF-743 in an acid model of ulcer formation by the Okabe method]. / Protivoiazvennyi éffekt preparata OF-743 na kislotnoi modeli iazvoobrazovaniia po metody Okabe.

The application of acetic acid (100%) on gastric serosa produces hemorrhagic lesions, erosions and ulcers in the gastric mucosa of rats. Intraperitoneal injections of OF-743, a derivative of sydnonimine during 3 days after the acid application have revealed lesser expressed mucosal lesions: only hemorrhagic lesions and rather small erosions. The lesions degree in rats subjected to the action of OF-743 was 2.7 as compared with 4.4 in control rats without OF-743. Our findings indicate that OF-743 shows not only protective antiulcer action, as it was discovered earlier, but has also curative antiulcer effect.

Protection of ischemia-reperfusion injury by sydnonimine NO donors via inhibition of neutrophil-endothelium interaction.

Ischemia of a vascular bed followed by reestablishment of blood flow results in an accelerated and severe form of tissue injury known as "reperfusion injury." We have investigated reperfusion injury in cats subjected to either myocardial ischemia-reperfusion or splanchnic ischemia-reperfusion. In both cases, a critical early event after reperfusion is endothelial dysfunction characterized by reduced release of endothelium-derived relaxing factor now known to be nitric oxide (NO). Endothelial dysfunction leads to adherence of polymorphonuclear (PMN) leukocytes to the dysfunctional endothelium. Infusion of a sydnonimine NO donor (C87-3754), but not a similar compound lacking the NO moiety (C88-3934), just before reperfusion protected in both forms of ischemia-reperfusion. In the first case, C87-3754, but not C88-3934, attenuated myocardial necrosis, and in the second case, the NO donor improved survival and moderated the indices of shock. In both cases, C87-3754 preserved the endothelium of the ischemic-reperfused vasculature and exerted anti-PMN effects (i.e., reduced PMN adherence to the endothelium or attenuated PMN release of superoxide radicals). Thus, an NO donor infused at a rate calculated to replace the lost NO from the vascular endothelium of the ischemic region exerts significant protective effects on reperfusion of that ischemic vascular bed.

Pirsidomine, a novel nitric oxide donor, suppresses ischemic arrhythmias in anesthetized pigs.

The hemodynamic profile and antiarrhythmic properties of pirsidomine, a nitric oxide donor, were examined in pigs. Intravenous administration of pirsidomine (1 mg/kg) to chloralose-anesthetized open-chest pigs resulted in a decreased afterload, and a reduced myocardial contractility and myocardial oxygen consumption (assessed by rate-pressure product), with no alterations in heart rate. After induction of regional myocardial ischemia by occlusion of the left anterior descending coronary artery, pigs given pirsidomine experienced fewer ventricular ectopic beats (119 +/- 29) than control animals did (217 +/- 53; p < 0.05), seen primarily as a reduction in the number of couplets and triplets. Although the incidence of ventricular fibrillation was unaffected by pirsidomine, the time to onset of this arrhythmia was significantly prolonged by this intervention (21.3 +/- 0.9 min versus 16.1 +/- 2.5 min in controls; p < 0.05). Furthermore, the ST-segment depression seen throughout the 30-min occlusion period in controls was not sustained beyond 5 min postocclusion in pirsidomine-treated pigs. Taken together, and in the absence of an ex vivo antiplatelet effect with this dose of pirsidomine, these results suggest that the antiarrhythmic effect of pirsidomine lies in its hemodynamic effects, resulting in a reduction of ischemia. The ex vivo effect of pirsidomine on free radical generation from isolated leukocytes was also investigated. Luminol-enhanced chemiluminescence produced by leukocytes in response to phorbol myristate acetate was markedly depressed in cells isolated from blood withdrawn after administration of pirsidomine, compared with cells tested before drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Some new aryl-sydnones: effects on murine tumours.

The effects of new aryl-sydnones: 3-[4-X-3-nitrophenyl]-1,2,3-oxadiazolium-5-olates, where X = Cl (SYD-1); pyrrolidino (SYD-2); piperidino (SYD-3) and morpholino (SYD-4) on the survival of mice bearing Sarcoma 180, Ehrlich carcinoma, B10MCII (Fibrous histiocytoma) and L1210 leukemia ascitic tumours, on the proliferation of cultured tumour cells and on the synthesis of DNA in L1210 leukemia were determined. SYD-1 and SYD-2 in vivo significantly enhanced the survival of S180, Ehrilich and B10MCII tumour-bearing mice. Furthermore, SYD-2 showed significant activity against L1210. SYD-3 and SYD-4 did not show antitumour activity. SYD-1, in vitro was the most cytotoxic against all the above tumour cells. All of the drugs tested inhibited thymidine uptake by L1210 cells, SYD-4 being the least active.

Cardioprotection and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischemia-reperfusion.

The effects of two nitric oxide (NO) donors were evaluated in a 6-h model of feline myocardial ischemia-reperfusion. After 80 min of a 90-min ischemic period, SIN-1 or C87-3754 or their respective controls (i.e., 0.9% NaCl or C88-3934, a control compound which does not release NO) were given i.v. as a bolus (0.1 mg/kg) and infused at 1 mg/kg/h for the entire 4.5-h reperfusion period. Administration of the active NO donors significantly decreased the necrotic area/area-at-risk ratio from 29 +/- 3% in the vehicle group to 9 +/- 2 and 11 +/- 5% in the SIN-1 and C87-3754 groups, respectively (P less than .001). The inactive NO donor C88-3934 failed to reduce infarct size (31 +/- 3%). Neither NO donor reduced the accumulation of neutrophils in the necrotic area when compared to their respective control groups, but both agents significantly attenuated coronary endothelial dysfunction as shown by a vasorelaxation to acetylcholine of 62 +/- 2 and 64 +/- 3% in the SIN-1- and C87-3754-treated arteries, as compared to only a 27 +/- 3 and 34 +/- 4% vasorelaxation in the vehicle and inactive NO donor groups, respectively (P less than .001). Our studies show that SIN-1 and C87-3754 exert beneficial effects in a 6-h model of myocardial ischemia-reperfusion. Both NO donors decreased myocardial necrosis and decreased the reperfusion-induced endothelial dysfunction without significantly altering the pressure-rate index (i.e., an index of myocardial oxygen demand).

[Functional changes of the cardiovascular system and their pharmacological correction during suited immersion]. / Funktsional'nye izmeneniia serdechnososudistoi sistemy i ikh farmakologicheskaia korrektsiia v usloviiakh kostiumnoi immersii.

In the course of 126 man/exposures of 3 hours to 3 days in duration, in which 39 test subjects took part, circulation responses to the upright and supine body position during suited immersion as well as orthostatic and exercise tolerance after immersion were investigated. During 24 man/exposures for 2 days the subjects were administered per os placebo or one of the four neurotrophic drugs: sydnocarb, sydnogluton, sydstrigluton, estrigluton. Clinical observations, instrumented data and methodical features of the immersion model used give evidence that the suited immersion has advantages over currently used procedures simulating the effects of hypogravity. The drugs allowed cardiovascular correction that increased aerobic capacity of the body and enhanced cardiovascular orthostatic and exercise tolerance.

[Antiulcerogenic (therapeutic and preventive) properties of a phenylalkyl syndonimine psychostimulant]. / Antiul'tserogennoe (lechebnoe i profilakticheskoe) svoistvo odnogo iz psikhostimuliatorov fenilalkil sidnoniminovogo riada.

Intragastric administration of 96% ethanol, 1 ml/100 g of body mass, induced ulcerous impairments of rat gastric mucosal membrane, which were marked within 8 min after ethanol administration and reached the maximal size within 3 hrs. Psychostimulants of the phenylalkyl sydnonimime series OF 743, administered after the ethanol treatment, decreased distinctly the ethanol-induced impairments of gastric mucosal membrane and this effect was higher in simultaneous inoculation of the drug and ethanol. The data obtained suggest that preparation OF 743 exhibited both protective and curative antiulcerogenic efficiency.

[Differentiated psychopharmacotherapy of anergic conditions and the search for predictors of its effectiveness]. / Differentsirovannaia psikhofarmakoterapiia anergicheskikh sostoianii i poisk prediktorov ee éffektivnosti.

A nosologically nonuniform group of patients with predominant anergy in the clinical symptomatology were examined and treated. During examination, use was made of the rating scale and of the "biological" tests: the dexamethasone test, response to a single intake of psychostimulants (methylphenidate or sydnocarb) and tranquilizers (the diazepam test). The treatment was carried out by means of different methods: with antidepressants (desipramine/petytyl) and incazane, with the "actoprotector" bemityl, the psychostimulant sydnocarb, the neuroleptic pimozide as well as with combinations of the two latter ones with incazane. Analysis of the correlations between the treatment results and the data of the clinico-nosological assessment and tests made it possible to reveal the efficacy predictors in 6 out of 7 methods employed. It should be noted that for three of them the correlations with the parameters of the tests offered turned out maximal, which supports advisability of the use of the given tests for differential diagnosis and choice of the treatment for patients with anergic conditions.

[The antiulcer action of antidepressants. II. The effect of the antidepressants inkazan, azafen, and OF-743 in combination with arginine on ethanol-evoked damage to the gastric mucosa in rats]. / Protivoiazvennoe deistvie nekotorykh antidepressantov. II, Vliianie antidepressantov inkazana, azafena i OF-743 v kombinatsii s argininom na vyzvannye étanolom povrezhdeniia slizistoi obolozhki zheludka krys.

Mucosal gastric damages in rats induced by intragastric ethanol introduction decreased considerably on the background of action of one of the antidepressants (asaphen, inkasan and OF-743) in combination with arginine. The combination OF-743 with arginine has the largest protective action, the least one--asaphen with arginine. A comparison of protective action of some antidepressants with action of antidepressants in combination with arginine revealed a tendency to more expressed antiulcerogenic effect in studied combinations.

[The immunization of white rats with a covalent conjugate of sidnofen and serum albumin suppresses chronic ethanol consumption]. / Immunizatsiia belykh krys kovalentnym kon''iugatom sidnofena s serumal'buminom podavliaet khronicheskoe potreblenie étanola.

The influence of white rats of alcohol abuse formation of immunization by covalent conjugates of serum albumin with psychostimulant sydnophen was investigated. Immunization by conjugates where the molar sydnophen: protein ratio was 18:1-33: 1 results in significant depression of 15% ethanol consumption (in the condition of free choice between water and ethanol solution).