Myocardial Infarct Size-Limiting and Anti-Arrhythmic Effects of Mildronate Orotate in the Rat Heart

Vilšķe̅rsts, Reinis; Liepinsh, Edgars; Kuka, Janis; Cirule, Helena; Veveris, M. M.; Kalvinsh, Ivars; Dambrova, Maija

doi:10.1007/s10557-009-6179-2

Cited by 27 publications

(10 citation statements)

References 31 publications

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“…Improvements in post-ischemic function were observed in the ex vivo perfused heart with a 50% increase in RPP following a 30-minute period of low-ow ischemia. This result agrees with the work of Vilskersts et al [39] and Sesti et al [40] who have shown that Meldonium treatment leads to a smaller infarct size post ischemia-reperfusion. Mildronate treatment has also previously been shown to improve diastolic heart function and increase left ventricular ejection fraction in patients with type 2 diabetes, with blood glucose levels also reduced in these patients [41].The mechanistic link between these improvements and Meldonium's effect on L-carnitine availability has been demonstrated by simultaneous treatment with Meldonium and L-carnitine, which prevents these bene cial effects [42].…”

Section: Meldoniumtreatment In Diabetic Animalssupporting

confidence: 93%

Hyperpolarized Magnetic Resonance Shows that the Anti-Ischemic Drug, Meldonium, Leads to Increased Flux Through Pyruvate Dehydrogenase In Vivo Resulting in Improved Post-Ischemic Function in the Diabetic Heart.

Savić

Ball

Holzner

et al. 2020

Preprint

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Background: The diabetic heart has a decreased ability to metabolize glucose. The anti-ischemic drug, Meldonium, may provide a route to counteract this by reducing L-carnitine levels, resulting in improved cardiac glucose utilization. Therefore, the aim of this study was to use the novel technique of hyperpolarized magnetic resonance to investigate the in vivo effects of treatment with Meldonium on cardiac metabolism and function in control and diabetic rats. Methods: 36 male Wistar rats were injected with either placebo or streptozotocin (55mg/kg) to induce a model of type-1 diabetes. Daily treatment with either saline or Meldonium (100mg/kg/day) was undertaken for three weeks. In vivo cardiac function and metabolism were assessed with CINE MRI and hyperpolarized magnetic resonance respectively. Isolated perfused hearts were challenged with low-flow ischemia/reperfusion to assess the impact of Meldonium on post-ischemic recovery.Results: Meldonium had no significant effect on blood glucose levels or on baseline cardiac function. However, hyperpolarized magnetic resonance revealed that Meldonium treatment elevated pyruvate dehydrogenase flux by 3.1-fold and 1.2-fold in diabetic and control animals respectively, indicating an increase in cardiac glucose oxidation. Hyperpolarized magnetic resonance further demonstrated that Meldonium reduced acetylcarnitine by 2.1-fold in both diabetic and control animals. The increase in in vivo glucose oxidation was accompanied by an improvement in ex vivo post-ischemic function, where Meldonium elevated rate pressure product by 1.3-fold and 1.5-fold in the control and diabetic animals respectively. Conclusion: Meldonium improves in vivo glucose utilization in the diabetic heart, contributing to improved cardiac recovery post-ischemia.

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Section: Meldoniumtreatment In Diabetic Animalssupporting

confidence: 93%

Hyperpolarized Magnetic Resonance Shows that the Anti-Ischemic Drug, Meldonium, Leads to Increased Flux Through Pyruvate Dehydrogenase In Vivo Resulting in Improved Post-Ischemic Function in the Diabetic Heart.

Savić

Ball

Holzner

et al. 2020

Preprint

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“…The treatment was continued for 3 days, with one daily administration of the same dose. The doses of mildronate used were based on previous studies (22,28,40,42,44).…”

Section: Experimental Groupsmentioning

confidence: 99%

Vasorelaxant and neuroprotective effects of mildronate in a rabbit subarachnoid hemorrhage model

Eser

Bektaşoğlu²,

Gürer³

et al. 2018

Turkish Neurosurgery

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the early 1980s (46). The drug was firstly used as a carnitine biosynthesis inhibitor to inhibit fatty acid oxidation thus reducing the production of cytotoxic products and blocking the high oxygen use in ischemic conditions (38). In addition to carnitine biosynthesis inhibition, mildronate inhibits carnitine acyltransferase and attenuates carnitine incorporation into the mitochondria (32). Collectively, mildronate prevents the accumulation of ischemic precursors and toxic acylcarnitine products, by inhibiting carnitine █ INTRODUCTION C erebral ischemia is the most important cause of mortality and morbidity following subarachnoid hemorrhage (SAH)-related vasospasm (2,13). Despite numerous studies investigating treatments for SAH-induced vasospasm, effective prevention and therapy are still lacking. Mildronate (2,2,2 triethylhydrazinium, Quaterine, Meldonium, MET-88) is an anti-ischemic drug first produced in Lithuania in AIM: To investigate the effects of an anti-ischemic agent, mildronate, on subarachnoid hemorrhage-induced vasospasm. MATERIAL and METHODS: Rabbits were randomly divided into four groups: control, subarachnoid hemorrhage (SAH), vehicle, and mildronate (n = 8 animals per group). In the treatment group, 200 mg/kg of mildronate were intraperitoneally administered 5 min after the procedure and continued for 3 days as daily administrations of the same dose. At the end of the third day, the cerebrum, cerebellum, and brain stem were perfused, fixated, and removed for histopathological examination. Tissues were examined for arterial wall thickness, luminal area, and hippocampal neuronal degeneration. RESULTS: Mildronate group showed significantly increased luminal area and reduced wall thickness of the basilar artery compared with the subarachnoid hemorrhage group. In addition, the hippocampal cell degeneration score was significantly lower in the mildronate group than in the SAH and vehicle groups. CONCLUSION: These results show that mildronate exerts protective effects against SAH-induced vasospasm and secondary neural injury.

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“…This compound made headlines in 2016 when professional tennis player Maria Sharapova was suspended from the sport after testing positive for mildronate. In eastern Europe mildronate is commonly used as an anti-ischemic therapy [58-60]. Mildronate's main biologic effect is to inhibit carnitine synthesis in the liver, and it also competitively inhibits carnitine uptake via the transporter OCTN2 [61, 62].…”

Section: Advances In Understanding Pathophysiologymentioning

confidence: 99%

Advances in the Understanding and Treatment of Mitochondrial Fatty Acid Oxidation Disorders

Goetzman

2017

Curr Genet Med Rep

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Purpose of review This review focuses on advances made in the past three years with regards to understanding the mitochondrial fatty acid oxidation (FAO) pathway, the pathophysiological ramifications of genetic lesions in FAO enzymes, and emerging therapies for FAO disorders. Recent findings FAO has now been recognized to play a key energetic role in pulmonary surfactant synthesis, T-cell differentiation and memory, and the response of the proximal tubule to kidney injury. Patients with FAO disorders may face defects in these cellular systems as they age. Aspirin, statins, and nutritional supplements modulate the rate of FAO under normal conditions and could be risk factors for triggering symptoms in patients with FAO disorders. Patients have been identified with mutations in the ACAD9 and ECHS1 genes, which may represent new FAO disorders. New interventions for long-chain FAODs are in clinical trials. Finally, post-translational modifications that regulate fatty acid oxidation protein activities have been characterized that represent important new therapeutic targets. Summary Recent research has led to a deeper understanding of FAO. New therapeutic avenues are being pursued that may ultimately cause a paradigm shift for patient care.

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Myocardial Infarct Size-Limiting and Anti-Arrhythmic Effects of Mildronate Orotate in the Rat Heart

Abstract: The study provides experimental evidence that the combination of orotic acid and mildronate possesses additive pharmacological effects and that mildronate orotate might be considered as a powerful therapeutic agent facilitating recovery from ischemia-reperfusion injury.

Cited by 27 publications

References 31 publications

Hyperpolarized Magnetic Resonance Shows that the Anti-Ischemic Drug, Meldonium, Leads to Increased Flux Through Pyruvate Dehydrogenase In Vivo Resulting in Improved Post-Ischemic Function in the Diabetic Heart.

Hyperpolarized Magnetic Resonance Shows that the Anti-Ischemic Drug, Meldonium, Leads to Increased Flux Through Pyruvate Dehydrogenase In Vivo Resulting in Improved Post-Ischemic Function in the Diabetic Heart.

Vasorelaxant and neuroprotective effects of mildronate in a rabbit subarachnoid hemorrhage model

Advances in the Understanding and Treatment of Mitochondrial Fatty Acid Oxidation Disorders

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