Molsidomine decreases hyperoxia-induced lung injury in neonatal rats.

BACKGROUND: The study's objective is to evaluate if Molsidomine (MOL), an anti-oxidant, anti-inflammatory, and anti-apoptotic drug, is effective in treating hyperoxic lung injury (HLI). METHODS: The study consisted of four groups of neonatal rats characterized as the Control, Control+MOL, HLI, HLI + MOL groups. Near the end of the study, the lung tissue of the rats were evaluated with respect to apoptosis, histopathological damage, anti-oxidant and oxidant capacity as well as degree of inflammation. RESULTS: Compared to the HLI group, malondialdehyde and total oxidant status levels in lung tissue were notably reduced in the HLI + MOL group. Furthermore, mean superoxide dismutase, glutathione peroxidase, and glutathione activities/levels in lung tissue were significantly higher in the HLI + MOL group as compared to the HLI group. Tumor necrosis factor-α and interleukin-1ß elevations associated with hyperoxia were significantly reduced following MOL treatment. Median histopathological damage and mean alveolar macrophage numbers were found to be higher in the HLI and HLI + MOL groups when compared to the Control and Control+MOL groups. Both values were increased in the HLI group when compared to the HLI + MOL group. CONCLUSIONS: Our research is the first to demonstrate that bronchopulmonary dysplasia may be prevented through the protective characteristics of MOL, an anti-inflammatory, anti-oxidant, and anti-apoptotic drug. IMPACT: Molsidomine prophylaxis significantly decreased the level of oxidative stress markers. Molsidomine administration restored the activities of antioxidant enzymes. Molsidomine prophylaxis significantly reduced the levels of inflammatory cytokines. Molsidomine may provide a new and promising therapy for BPD in the future. Molsidomine prophylaxis decreased lung damage and macrophage infiltration in the tissue.

Nitric Oxide-Based Treatment of Poor-Grade Patients After Severe Aneurysmal Subarachnoid Hemorrhage.

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.

New approach to molsidomine active metabolites coming from the results of 2 models of experimental cardiology.

Molsidomine is a well-known vasodilatating, antianginal drug. Despite earlier studies with its metabolites (3-morpholino-syndnonimine (SIN-1) and N-nitroso-N-morpholino-amino-acetonitrile (SIN-1A)), which indicated a potential favorable cardioprotective activity, a lot of controversy remains. The aim of our research was to compare molsidomine, SIN-1, SIN-1A, and lidocaine influence on arrhythmias and hemodynamic parameters in 2 experimental models in rats. In the Langendorff heart study, SIN-1A markedly elevated left ventricular systolic pressure, maximum rise and fall of the first pressure derivative, coronary flow, and myocardial oxygen consumption. In addition, SIN-1A more so than SIN-1 significantly lowered creatine kinase release. The antiarrhythmic action of SIN-1 was observed, while lidocaine significantly diminished ventricular arrhythmias duration in comparison with the control. In the ischemia-reperfusion-induced arrhythmias model, hypotensive action of molsidomine was observed as well as the reduction in pressure rate product. Molsidomine also prolonged ventricular tachycardia duration. On the other hand, no significant effects on hemodynamic parameters as well as on ventricular arrhythmias were found in any of the SIN-1 and SIN-1A groups. In conclusion, our research suggests a possible direct, cardioprotective action of SIN-1A. It seems worthwhile to further investigate molsidomine derivatives, especially SIN-1A, because of its potential use in invasive cardiology procedures such as percutaneous transluminal coronary angioplasty.

Molsidomine Attenuates Ventricular Electrical Remodeling and Arrhythmogenesis in Rats With Chronic ß-Adrenergic Receptor Activation Through the NO/cGMP/PKG Pathway.

This study investigated the effects and associated underlying mechanisms of molsidomine, a nitric oxide (NO) donor, on cardiac electrical remodeling and ventricular tachycardias (VTs) induced by chronic isoprenaline (ISO) stimulation in rats. The rats were randomly divided into groups that were treated with saline (control group), ISO (ISO group), ISO + molsidomine (ISO + M group), and ISO + molsidomine + the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, ISO + M + O group) for 14 days. An electrophysiological study was performed to assess cardiac repolarization, action potential duration restitution, and the induction of action potential duration alternans and VTs in vitro. The properties of the Ca transients, Ca handling-related proteins, and NO/guanosine 3'5'-cyclic monophosphate (cGMP)/protein kinase G (PKG) pathway were examined. Compared with the control group, chronic ISO stimulation prolonged the cardiac repolarization, decreased the Ca transient alternans and action potential duration alternans thresholds, and increased the maximum slope (Smax) of the action potential duration restitution curve and incidence of VTs in vitro. All these effects were attenuated by molsidomine treatment (P < 0.05). Moreover, molsidomine activated cGMP/PKG signaling and stabilized the expression of calcium handling-related proteins compared with the ISO group. However, the protective effects of molsidomine were partially inhibited by ODQ. Our results suggest that molsidomine stabilizes calcium handling and attenuates cardiac electrical remodeling and arrhythmogenesis in rats with chronic ß-adrenergic receptor activation. These effects are at least partially mediated by the activation of NO/cGMP/PKG pathway.

Beneficial effect of a nitric oxide donor in an ex vivo model of pig-to-human pulmonary xenotransplantation.

BACKGROUND: Nitric oxide (NO) can reduce platelet adhesion and vascular resistance. Tempol can scavenge the reactive oxygen species (ROS) that induce tissue injury. As xenograft rejection attenuates endogenous NO production and generates ROS, we evaluated the potential effect of an NO donor (SIN-1, 3-morpholinosydnonimine) and tempol on hyperacute xenograft dysfunction using an ex vivo porcine lung perfusion model. METHODS: For the evaluation of von Willebrand factor (vWF) secretion, human endothelial cells were stimulated with thrombin. Porcine lungs were perfused with either fresh human whole blood (unmodified control group [n = 4]), SIN-1 (n = 4), or SIN and tempol (n = 4). RESULTS: SIN-1 and tempol significantly inhibited vWF secretion from endothelial cells in vitro. However, they did not suppress xenogeneic complement activation. In an ex vivo pulmonary perfusion model, SIN-1 improved pulmonary xenograft function by reducing pulmonary vascular resistance (PVR), inhibiting complement activation, and inhibiting thrombin generation. Combined treatment with tempol and SIN-1 potentiated PVR reduction, but slightly enhanced complement activation. CONCLUSIONS: An NO donor is expected to improve pulmonary xenograft function through inhibition of vWF secretion, vasoconstriction, thrombin generation, and indirectly through inhibition of complement activation. The additional effects of tempol on an NO donor were not considered significant in an ex vivo xenograft system.

Topical combinations to treat microvascular dysfunction of chronic postischemia pain.

BACKGROUND: Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle, and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain. METHODS: Mechanical allodynia was induced in the hindpaws of rats with chronic postischemia pain (CPIP). Allodynia was assessed before and after topical application of vehicle, single drugs or combinations of an α2A receptor agonist (apraclonidine) or an NO donor (linsidomine), with PA or PDE inhibitors (lisofylline, pentoxifylline). A topical combination of apraclonidine + lisofylline was also evaluated for its effects on a measure of microvascular function (postocclusive reactive hyperemia) and tissue oxidative capacity (formazan production by tetrazolium reduction) in CPIP rats. RESULTS: Each of the single topical drugs produced significant dose-dependent antiallodynic effects compared with vehicle in CPIP rats (N = 30), and the antiallodynic dose-response curves of either PA or PDE inhibitors were shifted 5- to 10-fold to the left when combined with nonanalgesic doses of α2A receptor agonists or NO donors (N = 28). The potent antiallodynic effects of ipsilateral treatment with combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors were not reproduced by the same treatment of the contralateral hindpaw (N = 28). Topical combinations produced antiallodynic effects lasting up to 6 hours (N = 15) and were significantly enhanced by low-dose systemic pregabalin in early, but not late, CPIP rats (N = 18). An antiallodynic topical combination of apraclonidine + lisofylline was also found to effectively relieve depressed postocclusive reactive hyperemia in CPIP rats (N = 61) and to increase formazan production in postischemic tissues (skin and muscle) (N = 56). CONCLUSIONS: The present results support the hypothesis that allodynia in an animal model of CRPS is effectively relieved by topical combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors. This suggests that topical treatments aimed at improving microvascular function by increasing both arterial and capillary blood flow produce effective analgesia for CRPS.

Nitric oxide sustains long-term skeletal muscle regeneration by regulating fate of satellite cells via signaling pathways requiring Vangl2 and cyclic GMP.

Satellite cells are myogenic precursors that proliferate, activate, and differentiate on muscle injury to sustain the regenerative capacity of adult skeletal muscle; in this process, they self-renew through the return to quiescence of the cycling progeny. This mechanism, while efficient in physiological conditions does not prevent exhaustion of satellite cells in pathologies such as muscular dystrophy where numerous rounds of damage occur. Here, we describe a key role of nitric oxide, an important signaling molecule in adult skeletal muscle, on satellite cells maintenance, studied ex vivo on isolated myofibers and in vivo using the α-sarcoglycan null mouse model of dystrophy and a cardiotoxin-induced model of repetitive damage. Nitric oxide stimulated satellite cells proliferation in a pathway dependent on cGMP generation. Furthermore, it increased the number of Pax7(+)/Myf5(-) cells in a cGMP-independent pathway requiring enhanced expression of Vangl2, a member of the planar cell polarity pathway involved in the Wnt noncanonical pathway. The enhanced self-renewal ability of satellite cells induced by nitric oxide is sufficient to delay the reduction of the satellite cell pool during repetitive acute and chronic damages, favoring muscle regeneration; in the α-sarcoglycan null dystrophic mouse, it also slowed disease progression persistently. These results identify nitric oxide as a key messenger in satellite cells maintenance, expand the significance of the Vangl2-dependent Wnt noncanonical pathway in myogenesis, and indicate novel strategies to optimize nitric oxide-based therapies for muscular dystrophy.

Vasospastic angina with J-wave pattern and polymorphic ventricular tachycardia effectively treated with quinidine.

BACKGROUND: Myocardial ischemia during coronary spasm may generate malignant ventricular arrhythmias. The J-wave pattern was suggested to be a marker of a disorder associated with life-threatening arrhythmias. RESULTS: We report the case of a patient with vasospastic angina and J-wave pattern in inferior and lateral leads associated with polymorphic ventricular tachycardia which was effectively treated only with quinidine-vasodilating drugs were not able to prevent the arrhythmia although they were effective in preventing ischemic events. CONCLUSION: The J-wave pattern in inferolateral leads may be a sign of electrical vulnerability to lethal ventricular arrhythmia in patients suffering from vasospastic angina--quinidine can effectively prevent such arrhythmias in these patients.

Postconditioning attenuates myocardial injury by reducing nitro-oxidative stress in vivo in rats and in humans.

In the present study, we hypothesized that postcon (postconditioning) confers cardioprotection in vivo by reducing the production of ONOO- (peroxynitrite) and nitro-oxidative stress subsequent to the inhibition of the iNOS (inducible NO synthase). Patients with AMI (acute myocardial infarct) were randomly assigned to undergo percutaneous coronary intervention without (control) or with ischaemic postcon by three episodes of 30-s inflation and 30-s deflation of the angioplasty balloon. Animal models of MI/R (myocardial ischaemia/reperfusion) injury were induced in rats by occluding the left coronary artery for 40 min followed by 4-h reperfusion. Rats were randomized to receive vehicle, postcon (three cycles of 10-s reperfusion and 10-s coronary re-occlusion preceding full reperfusion), the selective iNOS inhibitor 1400W or postcon plus 3-morpholinosydnonimine (an ONOO- donor). Postcon in patients reduced iNOS activity in white blood cells, decreased plasma nitrotyrosine, a fingerprint of ONOO- and an index of nitro-oxidative stress, and improved cardiac function (P<0.01 compared with control). In rats, postcon reduced post-ischaemic myocardial iNOS activity and nitrotyrosine formation, reduced myocardial infarct size (all P<0.05 compared with control) and improved cardiac function. Administration of 1400W resembled, whereas 3-morpholinosydnonimine abolished, the effects of postcon. In conclusion, reduction in ONOO--induced nitro-oxidative stress subsequent to the inhibition of iNOS represents a major mechanism whereby postcon confers cardioprotection in vivo.

The effects of nitric oxide donor molsidomine on skeletal muscle damage in a rat hind limb model of ischemia-reperfusion.

BACKGROUND: In this experimental study, we aimed to examine the protective effect of molsidomine (MS), a nitric oxide (NO) donor, against ischemia-reperfusion (I-R) injury in a rat skeletal muscle model. METHODS: Ischemia was achieved by application of an elastic rubber band as high as possible on the left thigh of the rats. Group 1: the control group received a sham operation. Group 2: the I-R group received I-R injury to the left hind limbs. Group 3: the I-R/MS group underwent the same model of I-R injury and received MS. Group 4: the I-R/L-NAME (N-omega-nitro-L-arginine-methyl ester) group underwent the same model of I-R injury and received L-NAME, an inhibitor of NO synthase. RESULTS: In groups 2 and 4, malondialdehyde increased significantly when compared to groups 1 and 3. Superoxide dismutase, catalase and glutathione peroxidase increased significantly in group 3 compared to groups 2 and 4. The NO levels were significantly elevated in group 3 compared to groups 2 and 4. In addition, the histopathological score was considerably lower in group 3 than in group 4. The number of necrotic muscle fibers and infiltration of neutrophils were significantly reduced in the MS-treated group. CONCLUSIONS: These findings suggest that MS can exert a protective effect against skeletal muscle injury caused by I-R in the rats.

Reversal of iron-induced nephrotoxicity in rats by molsidomine, a nitric oxide donor.

Fe-NTA is a very potent nephrotoxic agent and causes oxidative renal injury as shown in various studies. Reactive oxygen species as well as nitric oxide (NO) play an important role in acute renal failure (ARF). Present study was designed to investigate the effect of NO donor, molsidomine (Mol) and inducible NO synthase inhibitor (iNOS), aminoguanidine (AG) in Fe-NTA-induced renal toxicity. Rats were pretreated with Mol (5, 7.5 and 10 mg/kg, p.o.), and AG (100 mg/kg, i.p.) before Fe-NTA challenge (8 mg iron/kg body weight, i.p.) to determine the urea and creatinine levels along with biochemical analysis of oxidative stress. Fe-NTA administration markedly increased the BUN and serum creatinine level which was coupled with a marked lipid peroxidation, reduced activity of glutathione and decreased total nitric oxide levels of rat kidneys coupled with significant morphological alterations. Fe-NTA also markedly increased the levels of tumor necrosis factor-alpha (TNF-alpha) in serum. Concomitant treatment with molsidomine significantly reduced the serum creatinine and BUN levels, decreased lipid peroxidation in a significant manner, restored the levels of reduced glutathione, increased total nitric oxide levels and restored the normal morphology. Molsidomine treatment also attenuated the serum levels of TNF-alpha. Prior administration of AG did not reverse the protective effects produced by molsidomine. Present findings strongly suggest that protection afforded by molsidomine may be due to its direct NO donor ability but not through nitric oxide synthase activity as pretreatment with aminoguanidine did not abolish the protective effects of molsidomine.

Effects of molsidomine on retinal ischemia/reperfusion injury in rabbits.

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.

Inhibition of peroxynitrite precursors, NO and O2, at the onset of reperfusion improves myocardial recovery.

AIM OF STUDY: Previous reports note an increase in both reactive oxygen species (ROS) and nitric oxide (*NO) at the onset of myocardial reperfusion. We tested the hypothesis that inhibition of *NO or ROS production at the time of reperfusion improves recovery of post-ischemic myocardial function. METHODS AND MATERIALS: Isolated rat hearts were perfused with temperature controlled (37.4 degrees C) modified Krebs Henseleit buffer solution at 85 mm Hg. Following 20 min of global ischemia, hearts were reperfused for the first 10 min with: (1) standard buffer (control), (2) buffer with a NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), (3) buffer with superoxide dismutase (SOD) or (4) buffer with N-morpholinosydnonimine hydrochloride (SIN-1), a peroxynitrite generator. Tissue O(2) and *NO were continuously measured with thin electrochemical probes embedded in the wall of the LV. ROS was measured with the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) (40 mM). LV contractile function was continuously monitored. RESULTS: Recovery of LV contractile function was significantly improved in hearts initially reperfused with L-NAME and SOD and significantly depressed in hearts reperfused with SIN-1 compared with control (p<0.01, n=5-8 per group). DMPO-adduct during reperfusion (measure of ROS) was significantly decreased with SOD (p<0.001 versus L-NAME and Control, n=4 per group) and unchanged with L-NAME and SIN-1 compared with Control. With L-NAME, tissue *NO and PO(2) were significantly decreased, independent of coronary flow, during reperfusion compared with control and SIN-1. CONCLUSIONS: Inhibition of O(2)*(-) or *NO at the time of reperfusion improves early reperfusion LV function and alters tissue oxygen tension. In contrast to pre-ischemic treatments, intervention to reduce peroxynitrite generation at the onset of reperfusion can effectively improve post-ischemic myocardial recovery.

Protective and therapeutic effects of molsidomine on radiation induced neural injury in rats.

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.

Targeting multiple pathways reduces renal and cardiac fibrosis in rats with subtotal nephrectomy followed by coronary ligation.

AIM: Multiple interacting pathways contribute to progression of renal and cardiac damage in chronic kidney disease followed by chronic heart failure (renocardiac syndrome). We hypothesized that simultaneous pharmacological modulation of critical pathways implicated in renocardiac syndrome would effectively reduce fibrosis in and preserve function of heart and kidney. METHODS: Rats were subjected to subtotal nephrectomy followed 9 weeks later by coronary artery ligation. From week 11 until week 16, rats received vehicle or losartan, or a combination of the NF-kB inhibitor PDTC, the NO donor molsidomine and superoxide dismutase mimetic tempol, or a combination of all four of these plus metoprolol together. At week 16, renal and cardiac structure, function and gene expression were assessed. RESULTS: Individual and combined treatments were similarly effective in limiting cardiac fibrosis and further decline in systolic function. Combined treatment with all five drugs reduced renal fibrosis and CTGF gene expression more effectively than other strategies. Combining all five drugs reduced heart rate, inotropy and mean arterial pressure (MAP). CONCLUSION: Thus, in our model of chronic renocardiac syndrome, combined treatments similarly decreased cardiac fibrosis and stabilized systolic function as losartan alone, perhaps suggesting a dominant role for a single factor such as angiotensin II type 1 (AT1) receptor activation or inflammation in the network of aberrant systems in the heart. However, tubulointerstitial fibrosis was most effectively reduced by a five-drug regimen, pointing to additive effects of multiple pathophysiological pathways in the kidney.

Therapeutic action of cannabinoid on axonal injury induced by peroxynitrite.

This study examined whether the potent cannabinoid HU210 ameliorates axonal injury through its indirect action to stimulate the secretion of corticosterone. We observed that HU210 dramatically reduced peroxynitrite-induced axonal injury in rats receiving adrenalectomy and corticosterone replacement treatment. These results suggest that the ameliorating effects of cannabinoids on axonal injury associated with multiple sclerosis are achieved by its direct action, but not by its indirect action to elevate the serum corticosterone levels.

Tolerability to 1-year treatment with once-daily molsidomine in patients with stable angina.

Prolonged-release molsidomine 16 mg once daily) QD (has proved effective in the short-term treatment of patients with stable angina. The purpose of this multicenter study was to assess its long-term tolerability and clinical effectiveness. A total of 320 patients with stable angina were treated for 1 year with molsidomine 16 mg QD administered open label as monotherapy or add-on therapy, when beta blockers and/or calcium antagonists were prescribed concomitantly) in 128 patients, ie, 40% of cases), depending on the severity of disease and/or local therapeutic policies. In all, 293 patients (91.6%) completed the study. The proportion of patients who reported drug-related adverse events (AEs) was 9.1%, which is not significantly different (P=.13) from the 5.9% observed during previous short-term (2-4 wk) treatment. Headache accounted for 80.6% of all drug-related AEs and required discontinuation of the drug in one quarter of patients who reported the symptom (ie, 1.9% of the 320 patients involved in the study). No serious drug-related AEs occurred during the study. Tolerability to molsidomine, evaluated with use of a visual analog scale (VAS), improved by 20% from beginning to end of 1-year follow-up. Two-by-two Bonferroni's comparisons were significant at the .05 level between the 2-month assessment and assessments performed at 8, 10, and 12 months. No age-time interaction was noted (P=.82). Heart rate, blood pressure, electrocardiogram, and blood parameters showed no statistically significant or clinically relevant changes during the study. Compliance with treatment was satisfactory throughout the follow-up period. There was no significant change in the weekly frequency of anginal attacks and consumption of short-acting nitroderivatives during the 1-year study (P=.07 and P=.12,respectively), but their frequency was significantly (ie, approximately 50%) lower than during a preceding short-term treatment period (P<.0001 and P=.014, respectively). Subjective clinical status, evaluated through an appropriate VAS, improved by 38% from start to end of 1-year follow-up. Bonferroni's comparisons between baseline and subsequent 2-month evaluations were all significant at the .05 level. No age-time interaction could be seen for frequency of anginal attacks and consumption of short-acting nitroderivatives, nor for clinical status )P=.10, P=.11, and P=.51, respectively). Neither tolerability to molsidomine nor effectiveness of the drug was biased by concomitant antianginal therapies, insofar as none of these parameters showed a significant treatment type (ie, molsidomine administered as monotherapy or add-on therapy)-time interaction (VAS for tolerability: P=.44; angina: P=.39; nitroderivatives: P=.72; VAS for clinical status: P=.62). Molsidomine 16 mg QD administered for 1 y to patients with stable angina was well tolerated and remained effective during the entire treatment period, independent of age and concomitant antianginal therapy.

Efficacy and safety of once- and twice-daily formulations of molsidomine in patients with stable angina pectoris: double-blind and open-label studies.

Molsidomine, a sydnonimine acting as a heterocyclic direct nitric oxide donor, has been used for many years in several European countries for the treatment of patients with stable angina pectoris. The efficacy and tolerability of a novel once-daily 16-mg formulation of molsidomine (M16) were compared with those of the currently used twice-daily 8-mg molsidomine tablet (M8) in 666 patients. Study 1, a multicenter, randomized, double-blind, placebo-controlled, twin crossover study, involved 533 patients given acute and 2-week treatment with each drug formulation. Study 2, a multicenter, open-label, sequential, add-on trial, compared M16 and M8 in 133 patients. Drug effects on exercise capacity (study 1 only), frequency of anginal attacks and consumption of short-acting itroderivatives, and incidence of adverse events (AEs) were evaluated. Compared with placebo, M16 increased exercise capacity by 15% (P<.001) at the start of study 1 and by 13% (P<.001) after 2 weeks' treatment, and was not inferior to M8. In terms of anginal attack frequency and nitroderivative consumption, M16 was not inferior to M8 in either study. Moreover, compared with M8, M16 produced a statistically and clinically significant reduction in the incidence of anginal attacks in elderly (>/=75 y) but not in younger patients (<75 y) (study 2), nor in patients from study 1. No significant difference from M8 was found in either study in short-acting nitroderivative consumption. No tolerance to M8 or M16 was observed after 2-week treatment. No statistically significant differences in incidences of all AEs and drug-related AEs were observed between M16 and M8 in either study. The same held true for proportions of patients experiencing AEs and drug-related AEs on M16 vs M8: in study 1-14.3% and 11.8% for all AEs (P=.218), 6.9% and 5.4% for drug-related AEs (P=.280); in study 2-1.3% and 1.3% for all AEs, 0% and 1.3% for drug-related AEs (P>.10) in young patients; and in the elderly, 3.6% and 0% for drug-related AEs (P>.10). Only the proportion of elderly patients with all AEs was significantly higher with M16 than with M8: 14.5% vs 1.8% (P=.039). M16 once daily was effective and well tolerated in investigated patients with stable angina pectoris, particularly the elderly, affording 24 hours of therapeutic activity. M16 was not inferior to M8 given twice daily in terms of efficacy, safety profile, and tolerability.

Molsidomine for the prevention of vasospasm-related delayed ischemic neurological deficits and delayed brain infarction and the improvement of clinical outcome after subarachnoid hemorrhage: a single-center clinical observational study.

OBJECT Delayed ischemic neurological deficits (DINDs) and cerebral vasospasm (CVS) are responsible fora poor outcome in patients with aneurysmal subarachnoid hemorrhage (SAH), most likely because of a decreased availability of nitric oxide (NO) in the cerebral microcirculation. In this study, the authors examined the effects of treatment with the NO donor molsidomine with regard to decreasing the incidence of spasm-related delayed brain infarctions and improving clinical outcome in patients with SAH. METHODS Seventy-four patients with spontaneous aneurysmal SAH were included in this post hoc analysis. Twenty-nine patients with SAH and proven CVS received molsidomine in addition to oral or intravenous nimodipine. Control groups consisted of 25 SAH patients with proven vasospasm and 20 SAH patients without. These patients received nimodipine therapy alone. Cranial computed tomography (CCT) before and after treatment was analyzed for CVS-related infarcts. A modified National Institutes of Health Stroke Scale (mNIHSS) and the modified Rankin Scale (mRS) were used to assess outcomes at a 3-month clinical follow-up. RESULTS Four of the 29 (13.8%) patients receiving molsidomine plus nimodipine and 22 of the 45 (48%) patients receiving nimodipine therapy alone developed vasospasm-associated brain infarcts (p < 0.01). Follow-up revealed a median mNIHSS score of 3.0 and a median mRS score of 2.5 in the molsidomine group compared with scores of 11.5 and 5.0, respectively, in the nimodipine group with CVS (p < 0.001). One patient in the molsidomine treatment group died, and 12 patients in the standard care group died (p < 0.01). CONCLUSIONS In this post hoc analysis, patients with CVS who were treated with intravenous molsidomine had a significant improvement in clinical outcome and less cerebral infarction. Molsidomine offers a promising therapeutic option in patients with severe SAH and CVS and should be assessed in a prospective study.