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

Ehlert, Angelika; Schmidt, Christoph; Wölfer, Johannes; Manthei, Gerd; Brüning, R.; Heindel, Walter; Ringelstein, E. B.; Stummer, Walter; Pluta, Ryszard; Heßelmann, Volker

doi:10.3171/2014.12.jns13846

Cited by 21 publications

(21 citation statements)

References 33 publications

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“…Because Molsidomine does not seem to have a clear influence on the spasms of the large vessels but instead appears to exert its effects on the microcirculation, a synergism may have developed from the combination of Molsidomine and SNP, which exerts its effect both on the macro-and in the microcirculation. This notion is supported by earlier reports, both experimental [14,35] and clinical [17,18], of the pathophysiological importance and clinical usefulness of NO-based therapy after aSAH.…”

Section: Discussionsupporting

confidence: 79%

“…Molsidomine was started intravenously at 1.6 mg/h (2 ampoules/20 mg diluted in 50 ml saline and started at 2 ml/h) within 12-36 h after aSAH. The Molsidomine dose was increased in a stepwise manner (1.6 mg/h) every 3-4 h to achieve a dose of 16 mg/h within 2-3 days [17]. No more than 500 µg/h of noradrenaline was needed to keep MAP > 65 mmHg.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, an intravenous infusion of NO-donor Molsidomine [17,18] (see "Appendix") demonstrated a significant improvement in outcomes with lower rates of DCI [17] in all-grade aSAH patients but had no impact on macrovasospasm; its effect is thought to be on microcirculation. Additionally, in an awake female patient and guided by her clinical status, multiple clinical DCIs and radiologically confirmed vasospasms were rapidly reversed by combining intravenous Molsidomine with intraventricular sodium nitroprusside (SNP) boluses, which achieved excellent outcomes [18].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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, vasospasmrelated 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.

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Section: Discussionsupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…This supports the therapeutic approach in patients with aSAH to sustain the basal level of NO. 76,78,85,86 Beyond NO depletion and plasmalemmal Ca 2þ entry via L-type Ca 2þ channels also Ca 2þ release from internal stores seems to contribute to SI, providing a new therapeutic target which could potentially complement nimodipine prophylaxis against DCI. The caveat is added, though, that thapsigargin is not suitable for use as a drug since SERCA inhibition eventually leads to apoptosis in any mammalian cell.…”

Section: Discussionmentioning

confidence: 99%

A role of the sodium pump in spreading ischemia in rats

Major

Petzold

Reiffurth

et al. 2016

J Cereb Blood Flow Metab

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In rats, spreading depolarization induces vasodilation/hyperemia in naïve tissue but the inverse response when artificial cerebrospinal fluid is topically applied to the brain containing (a) a nitric oxide-lowering agent and (b) elevated K þ . The inverse response is characterized by severe vasoconstriction/ischemia. The perfusion deficit runs together with the depolarization in the tissue (¼spreading ischemia). Here, we found in male Wistar rats that pre-treatment with artificial cerebrospinal fluid containing elevated K þ in vivo led to a selective decline in a 2 /a 3 Na þ /K þ -ATPase activity, determined spectrophotometrically ex vivo. Moreover, spreading ischemia, recorded with laser-Doppler flowmetry and electrocorticography, resulted from artificial cerebrospinal fluid containing a nitric oxide-lowering agent in combination with the Na þ /K þ -ATPase inhibitor ouabain at a concentration selectively inhibiting a 2 /a 3 activity. Decline in a 2 /a 3 activity results in increased Ca 2þ uptake by internal stores of astrocytes, vascular myocytes, and pericytes since Ca 2þ outflux via plasmalemmal Na þ /Ca 2þ -exchanger declines. Augmented Ca 2þ mobilization from internal stores during spreading depolarization might enhance vasoconstriction, thus, contributing to spreading ischemia. Accordingly, spreading ischemia was significantly shortened when intracellular Ca 2þ stores were emptied by pre-treatment with thapsigargin, an inhibitor of the sarco(endo)plasmic reticulum Ca 2þ -ATPase (SERCA). These findings might have relevance for clinical conditions, in which spreading ischemia occurs such as delayed cerebral ischemia after subarachnoid hemorrhage.

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“…So ikarugamycin is possibly to treat COVID-19. Molsidomine is an orally active, longacting vasodilator [29]. It is a nitric oxide (NO) donor and there is a case that inhalation of NO alleviated the symptom of severe acute respiratory syndrome (SARS) [30].…”

Section: Potential Covid-19 Drugs Predicted By the Cmapmentioning

confidence: 99%

Discovery of potential drugs for COVID-19 based on the connectivity map

Li¹,

Bai²,

Yang³

et al. 2020

Preprint

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Background: Corona virus infective disease 19 is the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and spreads very rapidly, which become a worldwide public healthy crisis. Until now, there is no effective antivirus drugs or vaccines specifically used for its treatment. So it is urgent to discover efficient therapeutic methods. The same as SARS-CoV, SARS-CoV-2 also invades organism by combining with Angiotensin-converting enzyme 2 (ACE2). Recently, there are reports about SARS-CoV-2 infected host not only through the respiratory tract, but also gastrointestinal tract. However, it is proved that ACE2 plays a key role in protecting subjects from lung injury and resisting the inflammation caused by intestinal epithelial damage. Interestingly, the expression of ACE2 protein is reduced after SARS-CoV infection.Methods: According to the dataset of genes co-expressed with ACE2 in the colonic epithelial cells, we established a protein-protein interaction (PPI) Network and selected hub genes from them. The cluster analysis was performed to find out the dense region of the PPI Network. Then, gene ontology (GO) and pathway enrichment analysis were performed to explore the main function of genes co-expressed with ACE2. Finally, we predicted the potential drugs for the treatment of COVID-19 based on the connectivity map (Cmap) .Results: We constructed a PPI network containing 125 hub genes of genes co-expressed with ACE2 in the colonic epithelial cells and obtained two modules through cluster analysis. The GO analysis and the KEGG pathway revealed these genes were aggregated in ribosome, exosomes, extracellular cellular components; structure constituent of ribosome, G-protein coupled receptor activity, MHC class I and II receptor activity biological processes; immune response, protein metabolism, signal transduction biological processes; and ribosome, graft-versus-host disease, viral myocarditis pathways. The result

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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

Cited by 21 publications

References 33 publications

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

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

A role of the sodium pump in spreading ischemia in rats

Discovery of potential drugs for COVID-19 based on the connectivity map

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