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      Use of levosimendan in the treatment of cerebral vascular vasospasm: a case study

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          Abstract

          Despite the progress in the management of cerebral arterial aneurysms, subarachnoid hemorrhage (SAH) remains the major cause of neurological disability. While SAH-related deaths usually occur as a result of brain impairment due to hemorrhage, permanent neurological deficits are caused by cerebral ischemia due to edema and spasm of cerebral arteries. Additionally, ~20%–30% of patients with SAH develop secondary cardiomyopathy; this phenomenon is known as neurogenic stress cardiomyopathy (NSC), which is associated with increased mortality and poor long-term prognosis. Levosimendan is a new inotropic drug that causes calcium sensitization of troponin C, thus increasing contraction force of myofilaments. The drug also causes opening of ATP-dependent potassium channels in vascular smooth muscles, which results in dilatation of veins and arteries, including cerebral arteries. To date, there have been several reports of levosimendan application in patients with SAH and neurogenic stress cardiomyopathy, and the effect of the drug on vasospasm has been previously advocated. This paper presents a case report of a 57-year-old patient with massive SAH, where levosimendan was used for reducing vasospasm.

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          Most cited references 23

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          Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan.

          The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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            Molecular mechanisms of early brain injury after subarachnoid hemorrhage.

            Increasing body of experimental and clinical data indicates that early brain injury after initial bleeding largely contributes to unfavorable outcome after subarachnoid hemorrhage (SAH). This review presents molecular mechanisms underlying brain injury at its early stages after SAH. PubMed was searched using term 'subarachnoid hemorrhage' and key words referring to molecular and cellular pathomechanisms of SAH-induced early brain injury. The authors reviewed intracranial phenomena and molecular agents that contribute to the early development of pathological sequelae of SAH in cerebral and vascular tissues, including cerebral ischemia and its interactions with injurious blood components, blood-brain barrier disruption, brain edema and apoptosis. It is believed that detailed knowledge of molecular signaling pathways after SAH will serve to improve therapeutic interventions. The most promising approach is the protection of neurovascular unit including anti-apoptosis therapy.
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              Delayed cerebral vasospasm and nitric oxide: review, new hypothesis, and proposed treatment.

               R Pluta (2004)
              Despite years of research, delayed cerebral vasospasm remains the feared complication of a ruptured intracranial aneurysm. Worldwide effort has led to many promising experimental treatments that reverse or prevent cerebral vasospasm but none were confirmed to be effective in clinical trials. There are several sources for this failure: (1) the pathophysiology of delayed cerebral vasospasm remains poorly understood, (2) many experimental models of subarachnoid hemorrhage (SAH) do not mimic the actual clinical entity, and (3) many researchers erroneously extrapolate the data of peripheral and cerebral vascular physiological responses to the post-SAH situation. Thus, to explain the uniqueness of vasospasm and to address nitric oxide (NO) involvement in delayed vasospasm development, the following issues are addressed in this paper: (1) pathophysiological mechanisms of vasospasm, (2) NO-related contribution to its development. In addition, (3) a two-stage hypothesis of pathogenesis of delayed cerebral vasospasm is presented developed in the Vascular Laboratory of Surgical Neurology Branch of the National Institute of Neurological Disorders and Stroke using a primate model of SAH. According to this hypothesis, initially (Phase I) NO-releasing neurons are destroyed by oxyhemoglobin (oxyHb) leading to diminished availability of NO in the vessel wall and constriction of the vessels (Phase I). Increased shear stress evoked by narrowing of the arterial lumen should stimulate endothelial nitric oxide synthase (eNOS). But further metabolism of hemoglobin to bilirubin oxidized fragments (BOXes) increases asymmetric dimethylarginine (ADMA), an endogenous inhibitor of eNOS, in the vicinity of the artery further decreasing of NO availability and sustaining vasospasm (Phase II). In Phase III, the resolution of vasospasm, elimination of BOXes increases NO production by eNOS resulting in recovery of dilatory activity of endothelium. This hypothesis suggests that the key treatment to prevent delayed cerebral vasospasm should be focused on preventing oxyHb neurotoxicity, inhibiting BOX production, and exogenous NO delivery.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                20 June 2018
                : 12
                : 1777-1783
                Affiliations
                [1 ]Department of Anesthesiology and Intensive Care, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
                [2 ]Department of Neurology, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
                [3 ]Department of Emergency Medicine, School of Medicine, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
                [4 ]Department of Pharmacology and Toxicology, Center for Experimental Medicine, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland
                Author notes
                Correspondence: Dariusz Onichimowski, Oddział Kliniczny Anestezjologii i Intensywnej Terapii, Wojewódzki Szpital Specjalistyczny, ul. Żołnierska 18, 10-561 Olsztyn, Poland, Email onichimowskid@ 123456wp.pl
                Article
                dddt-12-1777
                10.2147/DDDT.S158237
                6018894
                © 2018 Onichimowski et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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