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Compelling evidence indicates that nitric oxide (NO) exerts a significant influence on the central nervous system, participates in the modulation of neurotransmitter release, contributes to the regulation of cognitive functions, and plays a crucial role in modulating various aspects of neural activity. We aimed to explore the influence of two NO donors, molsidomine (MSD) and V-pyrro/NO, on the innate spontaneous psychomotor abilities and short-term memory in rats. Using an actimeter test, the locomotor activity, stress-sensitive behavior, and anxiety level were investigated. The influence on the animal's cognitive functions was evaluated usingthe Y-maze test to assess the spontaneous alternation percentage, number of arms visited, number of alternations, and the preference index. Four distinct groups of five white male Wistar rats were exposed to the intraperitoneal treatments as follows: Control batch—0.3 mL/100 g of body weight saline solution, Mg batch—200 mg/kbwof magnesium chloride, MSD batch—1 mg/kbw of molsidomine, and V-pyrro/NO batch—5 mg/kbwof V-pyrro/NO. The intraperitoneal administration of MSD resulted in a significant reduction in spontaneous behavior and exploratory skills but was less pronounced than the positive control drug, magnesium chloride. Conversely, treatment with V-pyrro/NO led to only a slight decrease in horizontal movements during the actimeter test. MSD administration, but not V-pyrro/NO, notably increased the rate of spontaneous alternation in the Y-maze test. Additionally, the use of MSD resulted in an increase in the blood level of brain-derived neurotrophic factor and the intensification of the antioxidant enzymes, superoxide dismutase, and glutathione peroxidase activity. In our experimental setup, we demonstrated that MSD exposure led to a decrease in spontaneous behavior, showed anxiolytic effects and antioxidant activity, and improved spatial memory acquisition in rats. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest that scarcity of the gaseous molecule nitric oxide (NO) is associated with the pathogenesis of schizophrenia. Therefore, compounds, such as NO donors, that can normalize NO levels might be of utility for the treatment of this pathology. It has been previously shown that the NO donor molsidomine attenuated schizophrenia-like behavioral deficits caused by glutamate hypofunction in rats. The aim of the current study was to investigate the efficacy of molsidomine and that of the joint administration of this NO donor with sub-effective doses of the non-typical antipsychotics clozapine and risperidone to counteract memory deficits associated with dysregulation of the brain dopaminergic system in rats. Molsidomine (2 and 4 mg/kg) attenuated spatial recognition and emotional memory deficits induced by the mixed dopamine (DA) D1/D2 receptor agonist apomorphine (0.5 mg/kg). Further, the joint administration of sub-effective doses of molsidomine (1 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted non-spatial recognition memory impairments caused by apomorphine. The present findings propose that molsidomine is sensitive to DA dysregulation since it attenuates memory deficits induced by apomorphine. Further, the current findings reinforce the potential of molsidomine as a complementary molecule for the treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

The deficiency of the gaseous molecule nitric oxide (NO) seems to be critically involved in the pathogenesis of schizophrenia. Thus, molecules that can normalize NO levels, as are NO donors, might be of utility for the medication of this psychiatric disease. The aim of the present study was to detect the ability of the NO donor molsidomine to reduce schizophrenia-like impairments produced by the blockade of the N-methyl-D-aspartate (NMDA) receptor in rats. Molsidomine's ability to attenuate social withdrawal and spatial recognition memory deficits induced by the NMDA receptor antagonist ketamine were assessed using the social interaction and the object location test, respectively. Further, the efficacy of the combination of sub-effective doses of molsidomine with sub-effective doses of the atypical antipsychotic clozapine in alleviating non-spatial recognition memory deficits was evaluated utilizing the object recognition task. Molsidomine (2 and 4 mg/kg) attenuated social withdrawal and spatial recognition memory deficits induced by ketamine. Co-administration of inactive doses of molsidomine (1 mg/kg) and clozapine (0.1 mg/kg) counteracted delay-dependent and ketamine-induced non-spatial recognition memory deficits. The current findings suggest that molsidomine is sensitive to glutamate hypofunction since it attenuated behavioral impairments in animal models mimicking the negative symptoms and cognitive deficits of schizophrenia. Additionally, the present results support the potential of molsidomine as an adjunctive drug for the therapy of schizophrenia. [ABSTRACT FROM AUTHOR]

Compelling evidence indicates that nitric oxide (NO) exerts a significant influence on the central nervous system, participates in the modulation of neurotransmitter release, contributes to the regulation of cognitive functions, and plays a crucial role in modulating various aspects of neural activity. We aimed to explore the influence of two NO donors, molsidomine (MSD) and V-pyrro/NO, on the innate spontaneous psychomotor abilities and short-term memory in rats. Using an actimeter test, the locomotor activity, stress-sensitive behavior, and anxiety level were investigated. The influence on the animal`s cognitive functions was evaluated usingthe Y-maze test to assess the spontaneous alternation percentage, number of arms visited, number of alternations, and the preference index. Four distinct groups of five white male Wistar rats were exposed to the intraperitoneal treatments as follows: Control batch—0.3 mL/100 g of body weight saline solution, Mg batch—200 mg/kbwof magnesium chloride, MSD batch—1 mg/kbw of molsidomine, and V-pyrro/NO batch—5 mg/kbwof V-pyrro/NO. The intraperitoneal administration of MSD resulted in a significant reduction in spontaneous behavior and exploratory skills but was less pronounced than the positive control drug, magnesium chloride. Conversely, treatment with V-pyrro/NO led to only a slight decrease in horizontal movements during the actimeter test. MSD administration, but not V-pyrro/NO, notably increased the rate of spontaneous alternation in the Y-maze test. Additionally, the use of MSD resulted in an increase in the blood level of brain-derived neurotrophic factor and the intensification of the antioxidant enzymes, superoxide dismutase, and glutathione peroxidase activity. In our experimental setup, we demonstrated that MSD exposure led to a decrease in spontaneous behavior, showed anxiolytic effects and antioxidant activity, and improved spatial memory acquisition in rats.

Molsidomine is a vasodilator with an action similar to organic nitrates, but with many advantages over this class of medicines. With the present material, we make a brief review on the effectiveness of Molsidomine and present our own data on the benefits of the medicine usage to improve endothelial function, in chronic coronary occlusions, in order to prevent the spasm of the radial artery before invasive procedures, in patients with COVID-19 and Acute Coronary syndrome (ACS), and to influence the symptoms in post-COVID-19 conditions. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest that the intra- and inter-cellular messenger nitric oxide (NO) is critically involved in anxiety. Contrasting findings are reported, however, regarding the effects of NO donors in preclinical models of anxiety. Previous research has shown that challenge with a low dose range of the NO donors sodium nitroprusside (SNP) and molsidomine induce anti-anxiety-like effects in rodents. There is poor information concerning the effects of these NO donors on preclinical models mimicking the obsessive-compulsive disorder (OCD) and the post-traumatic stress disorder (PTSD). The present research was designed to investigate this issue in the rat. To this end, the mCPP-induced excessive self-grooming and the contextual fear conditioning (CFC) test which are behavioural paradigms resembling OCD and PTSD respectively in rodents were used. Acute administration of SNP (1 mg/kg) and molsidomine (4 mg/kg) attenuated excessive self-grooming induced by the 5-HT 2C receptor agonist mCPP (0.6 mg/kg). Further, at the same dosage, both these NO donors reduced freezing behaviour evidenced in the CFC test. The present results suggest that NO donors are efficacious in attenuating abnormal behaviours revealed in animal models of OCD and PTSD which are among the most severe pathologies of anxiety. • The effects of a low dose range of NO donors on OCD and PTSD were studied in rats. • Acute exposure to SNP and to molsidomine attenuated excessive self-grooming induced by mCPP. • Acute exposure to SNP and to molsidomine reduced freezing behaviour. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest that scarcity of the gaseous molecule nitric oxide (NO) is associated with the pathogenesis of schizophrenia. Therefore, compounds, such as NO donors, that can normalize NO levels might be of utility for the treatment of this pathology. It has been previously shown that the NO donor molsidomine attenuated schizophrenia-like behavioral deficits caused by glutamate hypofunction in rats. The aim of the current study was to investigate the efficacy of molsidomine and that of the joint administration of this NO donor with sub-effective doses of the non-typical antipsychotics clozapine and risperidone to counteract memory deficits associated with dysregulation of the brain dopaminergic system in rats. Molsidomine (2 and 4 mg/kg) attenuated spatial recognition and emotional memory deficits induced by the mixed dopamine (DA) D1/D2 receptor agonist apomorphine (0.5 mg/kg). Further, the joint administration of sub-effective doses of molsidomine (1 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted non-spatial recognition memory impairments caused by apomorphine. The present findings propose that molsidomine is sensitive to DA dysregulation since it attenuates memory deficits induced by apomorphine. Further, the current findings reinforce the potential of molsidomine as a complementary molecule for the treatment of schizophrenia.

Varicose vein therapy has historically relied significantly on invasive surgical procedures, which frequently resulted in poor compliance among patients. The tendency could stem from the past use of abrasive surgical procedures and a lack of documented drug-induced animal models. To address this challenge, we envisaged an innovative approach for animal model development that uses niacin-induced recurrent flushing. And to further treat the condition, we used liquid crystal nanoparticles (LCNPs) as carriers for the antiangiogenic, cardio protective, and anti-inflammatory drug molsidomine. After the successful initiation of reticular perforant varicose veins, the animals were administered and treated with molsidomine-loaded liquid crystal nanoparticles (MD-LCNPs) that were simultaneously synthesized via a straightforward homogenization method. The preparation of MD-LCNPs involved inducing the disruption of a cubic-phase gel of glyceryl monostearate (GMS) by Milli-Q water in the presence of a Tween-80. Characterization of MD-LCNPs encompassed an assessment of their physicochemical properties. Microscopic studies revealed monodispersity with an average size of 195 ± 55.94 nm. In vitro evaluations demonstrated commendable antioxidant potential, excellent swelling behavior, and sustained release behavior of MD-LCNPs. Furthermore, MD-LCNPs exhibited nontoxicity toward cells, with minimal generation of reactive oxygen species (ROS) or nitric oxide (NO). Histopathological and hematological analysis indicated the efficacy of MD-LCNPs in ameliorating niacin-induced varicose veins, the absence of detrimental and toxic effects on blood cells and visceral organs, and safety for intravenous administration. Following the administration of nanoparticles, the formulation demonstrated appropriate levels of prostaglandins (PGDs), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and vascular endothelial growth factor (VEGF). This substantiates the formulation's suitability for the treatment and management of varicose veins. In conclusion, our work shows an efficient method that induces varicose veins in rodents, and also a promising nanocarrier-based drug delivery approach using MD-LCNPs for effective and safe varicose vein therapy.

Abstract Diabetic neuropathy is a disorder that affects various regions of the nervous system and there is no specific treatment available for it. This study evaluated the protective effect of molsidomine in diabetic neuropathy in rats. Diabetes was induced in male Wistar rats by administrating streptozotocin (52 mg/kg ip). Diabetic rats were treated with molsidomine 5 mg/kg po and 10 mg/kg po. After 8 weeks of treatment, motor coordination, mechanical allodynia, mechanical hyperalgesia, nerve conduction velocity, and glycosylated hemoglobin were assessed. Thereafter, animals were killed and the sciatic nerve was isolated for measurement of reduced glutathione and lipid peroxidation, and histopathological analysis. Treatment with molsidomine significantly improved motor coordination, paw withdrawal threshold, mechanical threshold, and nerve conduction velocity. Furthermore, molsidomine treatment also reduced malondialdehyde levels and prevented depletion of reduced glutathione in the sciatic nerve homogenate. Histopathology revealed that molsidomine treatment maintained normal architecture of the sciatic nerve. The results of our study strengthen the alternative use of molsidomine in diabetic neuropathy.

The red blood cell (RBC) L-arginine/NO system was assessed at different values of the oxygen partial pressure, which were modeled in a glove box by substituting nitrogen for oxygen. The intracellular NO level was determined by flow cytometry and spectrofluorimetry using a diacetyl derivative of 4-amino-5-methylamino-2',7'-difluorofluorescein. The RBC surface area was measured by morphodensitometry. Flow cytometry revealed the phenomenon of a spontaneous increase in the fluorescence intensity of a NO-specific intracellular probe, which was blocked by pre-administration of an NO synthase (NOS) inhibitor. It was found that oxygen partial pressure and the exposure to experimental gas mixtures affect the intracellular NO level in RBCs. Hemoglobin–oxygen affinity under hypoxic conditions depends on NOS, but not molsidomine, activity. The RBC L-arginine/NO system is involved in the activity of these cells during hypoxia without changing their surface area for ion diffusion. Molsidomine evoked an increase in the RBC surface area. [ABSTRACT FROM AUTHOR]

Emine Turkmen Samdanci,1 Mustafa Huz,1 Onural Ozhan,2 Kevser Tanbek,3 Esra Pamukcu,4 Ayse Nur Akatli,1 Hakan Parlakpinar21Department of Pathology, Inonu University School of Medicine, Malatya, Turkey; 2Department of Pharmacology, Inonu University School of Medicine, Malatya, Turkey; 3Department of Physiology, Inonu University School of Medicine, Malatya, Turkey; 4Department of Statistics, Firat University Faculty of Science, Elaziğ, TurkeyIntroduction and aim: Methotrexate (Mtx) is an antineoplastic and immunosuppressive drug that may cause hepatotoxicity, whereas molsidomine (Mol) is a vasodilating and antioxidant agent. This study aimed to investigate the potential protective effects of Mol in Mtx-induced liver toxicity in rats.Materials and methods: Forty Wistar albino rats were equally divided into five groups: control, Mol, Mtx, Mol–Mtx, and Mtx–Mol. Following treatment, the animals were sacrificed, and liver tissue samples were histopathologically evaluated using Roening grading and Bcl-2 antibody staining. Tissue oxidants, antioxidants, and serum transaminases were measured and statistically compared across all groups.Results: No hepatic fibrosis or steatosis was observed in any of the groups. In the Mtx group, grade 2 liver injury and score 2 Bcl-2 antibody staining were observed; however, in the Mol–Mtx group, these were lower (grade 1, score 1). There were no statistically significant differences in serum transaminase levels among groups. Malondialdehyde levels were higher in all rats that received Mtx, but no differences in myeloperoxidase levels were observed among the groups. Levels of tissue antioxidants, including superoxide dismutase, glutathione (GSH) peroxidase (GSH-Px), and reduced GSH, were significantly higher in the Mol-treated and Mol pre-treated groups. Catalase (CAT) levels were elevated in all Mol-treated groups, but only in that group were CAT levels statistically significantly higher than in the control group.Conclusion: Our results suggest that some oxidant levels could increase following Mtx administration in the liver, possibly contributing to liver damage, whereas Mol could mitigate the histopathological and biochemical effects of hepatotoxicity. However, molecular studies are required to understand the exact mechanisms of these alterations.Keywords: methotrexate, molsidomine, hepatotoxicity, hepatic fibrosis

Introduction. Since the end of 2019, the pandemic caused by SARS-CoV2 has affected hundreds of millions of people, and the number of indirectly affected is many times higher. In addition to directly affecting lung tissue, the coronavirus infection predisposes patients to thrombotic events responsible for the occurrence of cardiovascular complications. The aim of our study was to observe patients with COVID-19 and acute coronary syndrome (ACS) and to evaluate the efficacy of anti-ischemic therapy with beta-blockers, molsidomine and trimetazidine. Results: We included 20 patients with COVID-19 and acute coronary syndrome. The mean age in the group was 67.5 ± 8.3 years, 40% (8) were women, 95% (19) had hypertension, dyslipidemia -- 90% (18 people), diabetes mellitus -- 35% (7). Selective coronary angiography was performed in all patients. In 55% of the patients (n= 11) we found a coronary lesion responsible for myocardial ischemia ("infarct-related artery") and percutaneous coronary intervention (PCI) was performed, while in the remaining 9 cases (45%) angiography did not reveal any significant coronary stenosis. In all patients we included anti-ischemic therapy with molsidomine 2 mg three times daily and trimetazidine MR 35 mg twice daily, as well as a beta-blocker, in addition to antiplatelet, antilipemic and other necessary medications. During hospitalization angina symptoms were resolved in all patients except one who required additional PCI. During the one-month follow-up, all patients remained asymptomatic and without subsequent hospitalizations. Reduction of the angina symptoms in patients with COVID-19 and ACS was valid for all the patients -- those with PCI and those without significant coronary stenosis. Conclusion: A significant percentage of patients with COVID-19 and ACS do not have coronary lesions, which suggests the presence of involvement of the small vessels. In this group, the administration of antiischemic therapy with beta-blockers, molsidomine and trimetazidine, in combination with antiplatelet and antilipemic therapy, results in rapid resolution and lasting response to angina symptoms. [ABSTRACT FROM AUTHOR]

Background: Patients with aneurysmal subarachnoid hemorrhage (aSAH) require close treatment in neuro intensive care units (NICUs). The treatments available to counteract secondary deterioration and delayed ischemic events remain restricted; moreover, available neuro-monitoring of comatose patients is undependable. In comatose patients, clinical signs are hidden, and timing interventions to prevent the evolution of a perfusion disorder in response to fixed ischemic brain damage remain a challenge for NICU teams. Consequently, comatose patients often suffer secondary brain infarctions. The outcomes for long-term intubated patients w/wo pupil dilatation are the worst, with only 10% surviving. We previously added two nitroxide (NO) donors to the standard treatment: continuous intravenous administration of Molsidomine in patients with mild-to-moderate aSAH and, if required as a supplement, intraventricular boluses of sodium nitroprusside (SNP) in high-risk patients to overcome the so-called NO-sink effect, which leads to vasospasm and perfusion disorders. NO boluses were guided by clinical status and promptly reversed recurrent episodes of delayed ischemic neurological deficit. In this study, we tried to translate this concept, the initiation of intraventricular NO application on top of continuous Molsidomine infusion, from awake to comatose patients who lack neurological-clinical monitoring but are primarily monitored using frequently applied transcranial Doppler (TCD).Methods: In this observational, retrospective, nonrandomized feasibility study, 18 consecutive aSAH comatose/intubated patients (Hunt and Hess IV/V with/without pupil dilatation) whose poor clinical status precluded clinical monitoring received standard neuro-intensive care, frequent TCD monitoring, continuous intravenous Molsidomine plus intraventricular SNP boluses after TCD-confirmed macrospasm during the daytime and on a fixed nighttime schedule.Results: Very likely associated with the application of SNP, which is a matter of further investigation, vasospasm-related TCD findings promptly and reliably reversed or substantially weakened (p < 0.0001) afterward. Delayed cerebral ischemia (DCI) occurred only during loose, low-dose or interrupted treatment (17% vs. an estimated 65% with secondary infarctions) in 17 responders. However, despite their worse initial condition, 29.4% of the responders survived (expected 10%) and four achieved Glasgow Outcome Scale Extended (GOSE) 8-6, modified Rankin Scale (mRS) 0-1 or National Institutes of Health Stroke Scale (NIHSS) 0-2.Conclusions: Even in comatose/intubated patients, TCD-guided dual-compartment administration of NO donors probably could reverse macrospasm and seems to be feasible. The number of DCI was much lower than expected in this specific subgroup, indicating that this treatment possibly provides a positive impact on outcomes. A randomized trial should verify or falsify our results. [ABSTRACT FROM AUTHOR]

Highlights • NO improves the behavioral and biochemical response altered by 192 IgG-saporin. • MOLS counteracted the impaired recognition memory of rats exposed to 192-IgG-SAP. • MOLS modulated the nitrergic activity and nNOS expression in rats with 192-IgG-SAP. Abstract Nitric oxide (NO) plays a leading role in learning and memory processes. Previously, we showed its ability to modify the deleterious effect of immunotoxin 192 IgG-saporin (192-IgG-SAP) in the cholinergic system. The aim of this study was to analyze the potential of a NO donor (molsidomine, MOLS) to prevent the recognition memory deficits resulting from the septal cholinergic denervation by 192 IgG-SAP in rats. Quantification of neuronal and endothelial nitric oxide synthase (nNOS and eNOS, respectively) expression was evaluated in striatum, prefrontal cortex, and hippocampus. In addition, a choline acetyltransferase immunohistochemical analysis was performed in medial septum and assessed the effect of MOLS treatment on the spatial working memory of rats through a recognition memory test. Results showed that 192-IgG-SAP reduced the immunoreactivity of cholinergic septal neurons (41%), compared with PBS-receiving control rats (p < 0.05). Treatment with MOLS alone failed to antagonize the septal neuron population loss but prevented the progressive abnormal morphological changes of neurons. Those animals exposed to 192-IgG-SAP immunotoxin exhibited a reduction of cortical nNOS expression against the control group, whereas expression was enhanced in the 192-IgG-SAP + MOLS group. The most relevant finding was the recovering of the discrimination index exhibited by the 192-IgG-SAP + MOLS group. When compared with the rats exposed to the 192-IgG-SAP immunotoxin, they reached values similar to those observed in the PBS group. Our results show that although MOLS failed to block the cholinergic neurons loss induced by 192-IgG-SAP, it avoided the neuronal damage progression. [ABSTRACT FROM AUTHOR]

Abstract Ischemic heart conditions are among the main causes of sudden cardiac death worldwide. One of the strategies for avoiding myocardial infarction is the low-dose, prophylactic use of acetylsalicylic acid (ASA), an inhibitor of platelet aggregation. To avoid the gastrointestinal damage, ASA prodrugs bearing nitric oxide (NO)-donating moiety covalently conjugated to ASA have been synthesized and evaluated extensively worldwide. Herein the synthesis of a new hybrid ASA ester covalently attached to the NO donor linsidomine, an active metabolite of molsidomine (MOL) is reported. Cell viability assay and hemolysis tests were performed in H9c2 cells and rat erythrocytes, respectively. Our new compound, the ERJ-500 not affected negatively the viability of living cells in the concentration range of 100 nM to 100 μM. Using the ex vivo Langendorff method on hearts originated from female rats, compound ERJ-500 displayed a dose-dependent, outwashable vasodilative effect in coronary arteries. Vasodilation was observed on isolated working heart model as well, with elevated stroke volume in hearts treated with ERJ-500. Furthermore, a decreased infarct size was also noticed in ERJ-500 treated hearts after ischemia/reperfusion. Based on these observations it can be expected that our new hybrid ASA may contribute to new pharmacological tool in the therapy of ischemic heart conditions and associated syndromes. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Aim: Postoperative pelvic adhesions (PPAs) are a common complication that leads to many problems. This study aimed to compare the role of Seprafilm (a protective barrier), and molsidomine (MOL), recognized for its antioxidative and antiproliferative effects, in preventing pelvic adhesion. Material and Methods: A total of 30 of female Wistar albino rats were randomly divided into 3 groups. They underwent bilateral uterine horn injury. The rats in the Sham group (n=10) received no special treatment. The rats in the Seprafilm group (n=10) were treated withSeprafilm. The rats in the MOL group (n=10) received 10 mg/kg MOL orally for 14 days. Adhesion scores were evaluated using macroscopic, microscopic, and immunohistochemical grading 14 days postoperatively. Results:The Majuzi adhesion score of the rats in the MOL group [1 (0-4)] was lower than the score of the rats in the sham [4 (2-5)] and Seprafilm [4 (1-5)] (p<0.05). The glutathione peroxidase level in the MOL group [9.34 (5.45 - 19.82)] was higher than that in the sham [7.05 (2.67 - 8.9)] and Seprafilm [5.85 (3.92 - 22.55)] groups (p<0.05). Conclusions: This study showed that MOL reduced the formation of PPAs in a rat uterine horn model. The need for larger studies is an obvious need to elucidate this issue. [ABSTRACT FROM AUTHOR]

Aim. To study effects of ramipril, molsidomine and their combinations on morphofunctional heart indices and clinical status of patients with chronic heart failure (CHF), which complicated an ischemic heart disease (IHD).Material and methods. 41 patients with CHF class II-III (NYHA), which complicated IHD (postinfarction cardiosclerosis) were included in the study. Patients did not receive ACE inhibitors. Patients were split in 3 groups: patients of the 1st group received ramipril, patients of the 2nd group - molsidomine and patients of the 3rd group – combination of ramipril and molsidomine. Clinical examination, laboratory tests, electrocardiogram, cardiac ultrasonograthy, exercise tolerance test was performed before treatment and after 3 months and 1 year of treatment.Results. Improvement of clinical status and decrease of class NYHA was found in 38,5% of patients in ramipril group; in 33,3% of patients in molsidomine group and in 23,1 % of patients in combined therapy group. Increase of ejection fraction on 17 % from initial level was found in patients receiving combined therapy; on 25,2% - in patients receiving molsidomine; and on 12,4% - in patients receiving ramipril. Decrease of residual volumes of a left ventricle also was detected.Conclusion. All therapies (ramipril, molsidomine and their combination) in patients with CHF class II-III and postinfarction cardiosclerosis are clinically and hemodynamically effective in long term implementation.

Aim. To evaluate antianginal and antiischemic activity of molsidomine (Corvaton) in stable angina pectoris of II-III functional class (FC).Material and methods. 45 patients with II FC (31 persons) and III FC of angina (14 persons) were included into the study. All patients took molsidomine in individual doses during 3 months. Antianginal and antiischemic activity of molsidomine was estimated by veloergometric tests.Results. Molsidomine therapy resulted in disappearance of angina pectoris in 41, 7% of patients with stable angina of II-III FC and reduction of ST depression.Conclusion. Molsidomine is an effective antianginal and antiischemic medicine in patients with stable angina of II-III FC and provides the stable effect during long-term usage.

Hypoxia is accompanied by changes in metabolism and cell functioning. Erythrocyte hemoglobin can be involved in adaptation to hypoxia by acting as an oxygen sensor, providing a link between oxygen content and blood circulation. The mechanisms providing this function have not been completely established. The purpose of this study was to evaluate the effect of the gasotransmitter nitric oxide on the structural and functional organization of erythrocytes under conditions of hypoxia/reoxygenation. NO participated in adaptive reactions under hypoxia/reoxygenation conditions by changing hemoglobin conformation, followed by changes in hemoprotein spectral characteristics and hemoglobin affinity to oxygen together with increasing anisocytosis, volume and cell surface. The increase in intracellular NO concentrations under hypoxic conditions was provided by extracellular fluid nitrites. Molsidomine (a NO donor) induced a higher NO increase without involvement of the nitrite reductase mechanism, it caused an increase in the average erythrocyte volume, anisocytosis, and an increase in the cell surface.

Mechanisms of action and clinical application of vasodilator molsidomine (direct nitric oxide donor) in patients with stable coronary heart disease are considered. Results of the clinical studies are discussed; the efficacy of use and place of molsidomine (Sydnopharm) in the treatment of patients with stable angina are evaluated.

We investigated the effect of molsidomine (MOL) on ischemia/reperfusion (I/R) injury. Rabbits were assigned to four groups: group 1, sham; group 2, I/R; group 3, MOL treatment for 4 days after I/R; group 4, MOL treatment for 1 day before I/R and 3 days after I/R. Retinal I/R was produced by elevating the intraocular pressure to 150 mm Hg for 60 min. Seven days after I/R, the eyes were enucleated. Retinal changes were examined using histochemistry. The levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) also were measured. We found a significant increase in the thickness of the outer nuclear layer of group 3 compared to the other groups. In groups 3 and 4, caspase-3 stained cells in the ganglion cell layer were decreased compared to group 2. We found a significant increase in caspase-3 stained cells in the inner nuclear layer (INL) of group 2 compared to the other groups. We found a significant increase in caspase-3 stained cells in group 3 compared to group 4 in the INL. The MDA level in group 2 was significantly higher than group 1 and MOL significantly decreased MDA levels in groups 3 and 4. We found that MOL protected the retina from I/R injury by enhancing antioxidative effects and inhibiting apoptosis of retinal cells. [ABSTRACT FROM AUTHOR]

Purpose: To determine the role of Molsidomine in preventing radiation-induced retinopathy after head and neck region irradiation of rats with a single radiation dose of 15 Gy. Materials and Methods: Male Wistar albino rats were randomly grouped into five as follows: (1) control group rats, which were applied through an intraperitoneal (i.p.) vehicle without radiotherapy (RT); (2) RT group rats received a single dose of 15 Gy irradiation and after daily 0.1 ml vehicle i.p. for 5 consecutive days; (3) molsidomine (MOL) group rats were treated for 5 consecutive days by i.p. with 4 mg/kg/day MOL; (4) irradiation plus MOL group (RT+MOL) rats received irradiation and after 10 days single daily i.p. dose of MOL for 5 consecutive days; and (5) MOL+RT group rats were treated for 5 consecutive days by i.p. with MOL before RT. At the end of the work the rats were sacrificed under high-dose anesthesia on the 16thday and then eye tissues were taken for histopathological, immunohistochemical (caspase-3), and biochemical analyses (superoxide dismutase [SOD], glutathione peroxidase [GSH], and malondialdehyde [MDA]). Results: RT significantly decreased both the content of GSH and the activity of SOD, and significantly increased the production of MDA level in the rat eyes. MOL treatment significantly increased the SOD and GSH levels and significantly decreased the MDA production (p< 0.0001). In addition, RT significantly increased the number of ganglion cells (GCs;p= 0.001), whereas especially pretreatment with MOL improved (p= 0.013). RT led to significant retinopathy formation, and MOL therapy protected the retina from radiation-induced retinopathy (p< 0.0001). Conclusions: We suggest that MOL is a powerful antioxidant and free radical scavenger that prevents the rat eyes from radiation-induced retinopathy and oxidative stress. [ABSTRACT FROM AUTHOR]

We investigated the protective and therapeutic effects of molsidomine (MOL) in a rat model of whole brain radiotherapy (RT). Forty female rats were divided into five groups of eight: group 1, control; group 2, 15 Gy single dose RT (RT); group 3, 4 mg/kg MOL treated for 5 days (MOL); group 4, 4 mg/kg MOL for 5 days, 10 days after RT treatment (RT + MOL); group 5, 4 mg/kg MOL treatment for 5 days before RT treatment and for 5 days after RT treatment (MOL + RT). All rats were sacrificed on day 16. Neurodegenerative changes in the brain and tissue levels of oxidants and antioxidants were evaluated. The oxidative parameters were increased and antioxidant status was decreased in group RT compared to groups MOL + RT and RT + MOL. Histopathological examination showed that treatment with MOL after RT application and treatment with MOL before RT treatment decreased neuronal degeneration. No difference in neuronal appearance was found between groups RT + MOL and MOL + RT. MOL treatment protected the nervous system of rats and may be a treatment option for preventing RT induced neural injury. [ABSTRACT FROM PUBLISHER]

Duchenne muscular dystrophy (DMD), the most common and severe X-linked myopathy, is characterized by the lack of dystrophin, a sub-sarcolemmal protein necessary for normal muscle functions. In a previous study of the lipid content of skeletal muscles of dystrophic (mdx) mice, the animal model for DMD, by in situ Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry (MALDI-MS), an inversion of the phosphatidylcholine PC34:2/PC34:1 ion peaks intensity ratio was observed between destructured (abnormal fiber morphology) and structured (normal fiber morphology). A possible treatment for this dramatic disease is to introduce an exogenous nitric oxide (NO) donor into the organism, leading to an increase of utrophin and a regression of the dystrophic phenotype. In the present work, after confirmation by tandem mass spectrometry of the structure of these two phospholipids, their intensity ratio inversion was used to evidence a restoration of membrane lipid composition very similar to those of wild-type mice after the treatment of mdx mice with molsidomine, a NO donor. This was associated with the observation by immunohistology of an increase of the regeneration process in the mice.

Eight different functional monomers were used with ethylene glycol dimethacrylate as a cross-linker and molsidomine as a template to obtain molecularly imprinted polymers (MIPs). Non-covalent interactions between molsidomine and each functional monomer in DMSO prior to thermal bulk polymerization were utilized. On the basis of calculated imprinting factors, MIP prepared with N,N’-diallyltartaramide was chosen for further investigations. Examination of interactions in the prepolymerization complex between molsidomine and N,N’-diallyltartaramide was performed using the Job method. The absorbance of isomolar solutions reaching a maximum for the molar ratio of template to monomer equal to 1:4. Scatchard analysis was used for estimation of the dissociation constants and the maximum amounts of binding sites. The polymer based on N,N’-diallyltartaramide has two classes of heterogeneous binding sites characterized by two values of Kd and two Bmax: Kd(1) = 1.17 mM-1 and Bmax(1) = 0.8 μmol/mg for the higher affinity binding sites, and Kd(2) = 200 μM-1 and Bmax(2) = 2.05 μmol/mg for the lower affinity binding sites. Furthermore, effects of pH and organic solvent on binding properties of MIP and NIP were investigated, together with release of molsidomine from both MIP and NIP.

Chronic anthracycline (ANT) cardiotoxicity is a serious complication of cancer chemotherapy. Molsidomine, a NO-releasing drug, has been found cardioprotective in different models of I/R injury and recently in acute high-dose ANT cardiotoxicity. Hence, we examined whether its cardioprotective effects are translatable to chronic ANT cardiotoxicity settings without induction of nitrosative stress and interference with antiproliferative action of ANTs. The effects of molsidomine (0.025 and 0.5 mg/kg, i.v. ) were studied on the well-established model of chronic ANT cardiotoxicity in rabbits (daunorubicin/DAU/3 mg/kg/week for 10 weeks). Molsidomine was unable to significantly attenuate mortality, development of heart failure and morphological damage induced by DAU. Molsidomine did not alter DAU-induced myocardial lipoperoxidation, MnSOD down-regulation, up-regulation of HO-1, IL-6, and molecular markers of cardiac remodeling. Although molsidomine increased 3-nitrotyrosine in the myocardium, this event had no impact on cardiotoxicity development. Using H9c2 myoblasts and isolated cardiomyocytes, it was found that SIN-1 (an active metabolite of molsidomine) induces significant protection against ANT toxicity, but only at high concentrations. In leukemic HL-60 cells, SIN-1 initially augmented ANT cytotoxicity (in low and clinically achievable concentrations), but it protected these cells against ANT in the high concentrations. UHPLC–MS/MS investigation demonstrated that the loss of ANT cytotoxicity after co-incubation of the cells in vitro with high concentrations of SIN-1 is caused by unexpected chemical depletion of DAU molecule. The present study demonstrates that cardioprotective effects of molsidomine are not translatable to clinically relevant chronic form of ANT cardiotoxicity. The augmentation of antineoplastic effects of ANT in low (nM) concentrations may deserve further study. [ABSTRACT FROM AUTHOR]

Background: Diabetes-induced oxidative stress and hypertension play a major role in the development of nephropathy. Hence, the present study was undertaken to evaluate the protective effects of molsidomine, a nitric oxide donor in streptozotocin (STZ)-induced diabetic nephropathy (DN) in rats. Materials and Methods: Type 1 diabetes was induced through a single dose of STZ (52 mg/kg, i.p.) in male Wistar rats and then treated with molsidomine (5 and 10 mg/kg; p.o.) for 8 weeks. Physical parameters, vital and renal function test including blood glucose, albuminuria, blood urine nitrogen, serum creatinine, and kidney index were determined. Oxidative stress and lipid peroxidation were assessed in the kidney homogenate by means of antioxidant enzymes and malondialdehyde levels. Results: DN rats exhibited a significant renal dysfunction with a reduction in body weight, excessive oxidative stress, and pathological changes. Molsidomine treatment significantly improved vital sign, renal functions, and oxidative stress in DN rats in a dose-dependent manner. The protective effect of molsidomine was also substantiated by pathological changes in the architect of the kidney. Conclusion: Molsidomine shows a significant beneficial effect in Type 1 DN in rats. [ABSTRACT FROM AUTHOR]

New neuroprotective treatments aimed at preventing or minimizing 'delayed brain injury' are attractive areas of investigation and hold the potential to have substantial beneficial effects on aneurysmal subarachnoid hemorrhage (aSAH) survivors. The underlying mechanisms for this 'delayed brain injury' are multi-factorial and not fully understood. The most ideal treatment strategies would have the potential for a pleotropic effect positively modulating multiple implicated pathophysiological mechanisms at once. My personal management (RFJ) of patients with aneurysmal subarachnoid hemorrhage closely follows those treatment recommendations contained in modern published guidelines. However, over the last 5 years, I have also utilized a novel treatment strategy, originally developed at the University of Maryland, which consists of a 14-day continuous low-dose intravenous heparin infusion (LDIVH) beginning 12 h after securing the ruptured aneurysm. In addition to its well-known anti-coagulant properties, unfractionated heparin has potent anti-inflammatory effects and through multiple mechanisms may favorably modulate the neurotoxic and neuroinflammatory processes prominent in aneurysmal subarachnoid hemorrhage. In my personal series of patients treated with LDIVH, I have found significant preservation of neurocognitive function as measured by the Montreal Cognitive Assessment (MoCA) compared to a control cohort of my patients treated without LDIVH (RFJ unpublished data presented at the 2015 AHA/ASA International Stroke Conference symposium on neuroinflammation in aSAH and in abstract format at the 2015 AANS/CNS Joint Cerebrovascular Section Annual Meeting). It is important for academic physicians involved in the management of these complex patients to continue to explore new treatment options that may be protective against the potentially devastating 'delayed brain injury' following cerebral aneurysm rupture. Several of the treatment options included in this review show promise and could be carefully adopted as the level of evidence for each improves. Other proposed neuroprotective treatments like statins and magnesium sulfate were previously thought to be very promising and to varying degrees were adopted at numerous institutions based on somewhat limited human evidence. Recent clinical trials and meta-analysis have shown no benefit for these treatments, and I currently no longer utilize either treatment as prophylaxis in my practice. [ABSTRACT FROM AUTHOR]

A possible treatment for Duchenne muscular dystrophies would be to compensate for dystrophin loss by increasing the expression of utrophin, another cytoskeletal protein of the muscle membrane. We previously found that l-arginine, the substrate for nitric oxide synthase, significantly increased utrophin level in muscle and targeted it to the sarcolemma. Here, we have addressed the expected benefit in the mdx mice. Magnetic resonance imaging of lower limbs revealed a 35% reduction of the necrotic zones, confirmed by histological staining of muscles. This regression of the necrosis was also supported by the drastic reduction of Evans blue incorporation, a cell impermeable dye. The creatine kinase level in the serum decreased by 57%. Utrophin level increased 2- to 3-fold in muscles. β-dystroglycan was relocalised with utrophin to the membrane. In the diaphragm, the most affected muscle in mdx mice, the isometric tension increased by 30%, with regression of collagen and of cytoplasmic lipid overloading. Finally, molsidomine, a therapeutic agent that is converted to a NO donor, also attenuated the dystrophic phenotype. Our results suggest that pharmacological activators of the NO pathway may constitute a realistic treatment for Duchenne and Becker muscular dystrophies.

Discrepancy was found between enhanced hypotension and attenuated relaxation of conduit arteries in response to acetylcholine (ACh) and bradykinin (BK) in nitric oxide (NO)-deficient hypertension. The question is whether a similar phenomenon occurs in spontaneously hypertensive rats (SHR) with a different pathogenesis. Wistar rats, SHR, and SHR treated with NO donors [molsidomine (50 mg/kg) or pentaerythritol tetranitrate (100 mg/kg), twice a day, by gavage] were studied. After 6 weeks of treatment systolic blood pressure (BP) was increased significantly in experimental groups. Under anesthesia, the carotid artery was cannulated for BP recording and the jugular vein for drug administration. The iliac artery was used for in vitro studies and determination of geometry. Compared to control, SHR showed a significantly enhanced (P < 0.01) hypotensive response to ACh (1 and 10 µg, 87.9 ± 6.9 and 108.1 ± 5.1 vs 35.9 ± 4.7 and 64.0 ± 3.3 mmHg), and BK (100 µg, 106.7 ± 8.3 vs 53.3 ± 5.2 mmHg). SHR receiving NO donors yielded similar results. In contrast, maximum relaxation of the iliac artery in response to ACh was attenuated in SHR (12.1 ± 3.6 vs 74.2 ± 8.6% in controls, P < 0.01). Iliac artery inner diameter also increased (680 ± 46 vs 828 ± 28 µm in controls, P < 0.01). Wall thickness, wall cross-section area, wall thickness/inner diameter ratio increased significantly (P < 0.01). No differences were found in this respect among SHR and SHR treated with NO donors. These findings demonstrated enhanced hypotension and attenuated relaxation of the conduit artery in response to NO activators in SHR and in SHR treated with NO donors, a response similar to that found in NO-deficient hypertension.