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Mildronate: An Antiischemic drug with multiple indications

Authors:
Nikolajs Sjakste at University of Latvia
Nikolajs Sjakste
Ivars Kalvins at Latvian Institute of Organic Synthesis
Ivars Kalvins
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Mildronate (3-(2,2,2-trimethylhydrazine)propionate; THP; MET-88; meldonium, quaterine) is an anti-ischemic drug developed in the Latvian Institute of Organic Synthesis. Mildronate was designed as a promising inhibitor of carnitine biosynthesis aimed to prevent accumulation of cytotoxic intermediate products of fatty acid beta-oxidation in ischemic tissues and to block this highly oxygen-consuming process. Actually Mildronate is used in several countries in cardiology (treatment of chronic heart ischemic disease, stable angina pectoris, chronic heart failure, functional disorders of heart and vessels, cardiomyopathy, heart infarction), neurology (acute and chronic ischemic brain circulation disorders, decreased work capabilities, physical and emotional overload, recovery period after various diseases), pulmonology (bronchial asthma and obstructive bronchitis), narcology (abstinence syndrome in chronic alcoholism), ophthalmology (hemophthalm and retina haemorrhages of different aetiology, thrombosis of central vein and its branches in retina, diabetic and hypertonic retinopathies). The main mechanism of action of Mildronate is based on carnitine biosynthesis inhibition aimed to prevent accumulation of cytotoxic intermediate products of fatty acid beta-oxidation in ischemic tissues and to block this highly oxygen-consuming process. Alternatively the drug acts via stimulation of the nitric oxide production in the vascular endothelium through a modification of the γ-butyrobetaine and γ-butyrobetaine ester pools. The present review will summarize data on the Mildronate on different indications of the drug and its mechanisms of action.
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... Meldonium reduces the formation of carnitine from its predecessorgamma-butyrobetaine, the accumulation of the latter stimulates the synthesis of NO and exhibits anti-ischemic and cardioprotective properties. Meldonium reduces the level of l-carnitine due to the influence on the enzyme synthesis of l-carnitine -butyro-beta-hydroxylase and the carnitine/electric cation transporter type 2 (OCTN2), inhibits the oxidation of fatty acids, exhibits a mitoprotective effect, stimulates glucose metabolism and reduces metabolic concentration of l -carnitines such as long chain acyl carnitines and trimethylamine N-oxide; increases the synthesis of ATP during ischemia [10]. ...
... 3. L-arginine (42% solution for injection in vial, Tivortin, Yuria-pharm, Ukraine), an NO precursor; it mitigates disruptions in the nitroxidergic system in ischemia, 200 mg/kg, i/p [14,15]. 4. Meldonium preparation (2-(2-carboxyethyl)-1,1,1-trimethylhydrazinium) (10% solution for injection in ampoules, Grindex, Latvia), metabolitotropic agent, 100 mg/kg, i/p [10]. ...
... Meldonium compensatory increases the activity of acyl-CoA synthetase and сarnitine palmitoyl transferase I in mitochondria and increases peroxisomal fatty acid oxidation. Treatment with meldonium is accompanied by a compensatory increase in the expression in the myocardium of a number of genes encoding lipid metabolism enzymeslipoprotein lipase, fatty ac-id translocase, carnitine palmitoyltransferase I and triacylglycerol synthesis enzymes [10,20]. Meldonium is able to improve myocardial contractility, hexokinase activity, as well as the ratio of ATP/ADP/AMP due to the activation of AMPactivated protein kinase, which restores the level of ATP [3,9]. ...
Indicators of Bioelectrical Activity of the Rat Heart After Prenatal Hypoxia and Pharmacological Correction
Article
Full-text available
  • Jan 2022
Background. Posthypoxic cardiopathy is one of the risk factors for the development of cardiovascular pathology (rhythm disturbances, vascular dystonia, etc.) in subsequent age periods and requires the development of treatment approaches. Objective. to evaluate the cardioprotective effect of modulators of the NO system by the effect on the ECG of rats after intrauterine hypoxia. Methods. Modeling of prenatal hypoxia (PH) by daily intraperitoneal administration of sodium nitrite solution to pregnant female white rats weighing 220–240 g, aged 4.5 months, from the 16th to the 21st day of pregnancy at a dose of 50 mg/kg. The offspring were administered daily from the 1st to the 30th day of life – tiazotic acid (morpholinium 3-methyl-1,2,4-triazolyl-5-thioacetic acid), 50 mg/kg, angiolin ([S]-2,6-diaminohexane acid 3-methyl-1,2,4-triazolyl-5-thioacecate), 50 mg/kg, L-arginine, 200 mg/kg, meldonium (2-(2-carboxyethyl)-1,1,1-trimethylhydrazinium), 100 mg/kg. Аnd then after 2 months of life, an ECG was recorded using the ECG TUNNEL system (without anesthesia). Results. Postponed PG leads to a decrease in heart rate and significant dominance of parasympathetic innervation in regulation of electrical activity of the heart, which can be caused by sinus blockade and may be a reflection of parasympathetic regulation of the heart instead of sympathetic control of electrical activity in the norm. The effectiveness of drugs can be presented in descending order: angiolin > tiazotic acid > meldonium. Angiolin proved to be more effective than tiazotic acidin normalizing the electrical activity of the heart and restoring the neurogenic regulation of the automatism of the function of the sinus node. Сonclusions. The prospects of further study of modulators of the NO system with different mechanisms of action as means of cardioprotection of posthypoxic disorders of the cardiovascular system in newborns are experimentally substantiated.
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... It also acts as a bronchodilator in asthmatics; however, this mechanism has yet to be elucidated. 49 ...
... 6 However, with appropriate posology, this substance can be applied for other clinical disorders such as asthma, bronchoconstriction, gastric ulcers, cocleovestibular dysfunction, glaucoma, diabetes, and vaccine adjuncts. 14,29,49 There may be differences in meldonium dosage and treatment time according to the symptoms, but the usual regimen is 500 mg twice daily for 4-6 weeks. Glucose levels and cardiac parameters change after 4 weeks of treatment (100 or 200 mg/kg orally daily). ...
... Meldonium decreases methemoglobin concentrations and consequently allows greater O 2 transport by erythrocytes. 49 The structural similarity of meldonium to L-carnitine probably allows it to bind to erythrocytes. According to Mescka, 76 L-carnitine supplementation increases glutathione levels in erythrocytes. ...
Meldonium: Pharmacological, toxicological, and analytical aspects
Article
Full-text available
  • Mar 2020
Meldonium is the active molecule from Mildronate® with similar chemical structure to an amino acid, and it is known as (3-(2,2,2-trimethylhydrazine) propionate) (CAS 76144-81-5). This pharmaceutical substance is approved in Eastern Europe for cerebral and myocardial ischemia and has been on the World Doping Association’s banned substances list since January 2016. The goal of this review is to relate the use of meldonium as a doping agent, considering its pharmacological, toxicological, and analytical aspects. This review is based on the scientific literature from digital platforms. The main mechanism of action of meldonium is based on a decrease in l-carnitine levels and increase of peroxisomes activity in the cytosol. Females were more susceptible to the substance in animal experiments for toxicological tests. There is currently no report in the scientific literature about acute or chronic intoxication cases by meldonium in humans. Based on the literature findings, meldonium showed ergogenic effect in animals and human volunteers. For anti-doping analysis, urine is the biological matrix of choice, and dilute-and-shoot is the most common sample treatment in addition to liquid chromatography–mass spectrometry analysis. Other approaches could be used to determine meldonium levels, mainly for screening tests, such as l-carnitine or gamma-butyrobetaine levels.
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... Due to these properties, meldonium is used for the treatment of myocardial infarction, heart failure, ischemic cerebral diseases, and arrhythmia. In 2016, World Anti-Doping Agency (WADA) added meldonium to the list of suppressed sub-stances for athletes to use because they enhance performance and endurance [1][2][3]. Meldonium dihydrate is described in the European Pharmacopoeia [4,5]; for assay of meldonium, European Pharmacopoeia proposes acidimetric non-aqueous titration. By surveying the literature review, it was found that numerous methods have been reported for the determination of meldonium in biological fluids [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] and food products [22], but only a few methods have been reported for the determination of medonium in dosage forms medicines [23][24][25][26]. ...
Application of salts of chaotropic anions in the development of hplc methods for the determination of meldonium in dosage forms
Article
Full-text available
  • Feb 2023
The aim of the work was to create an approach for the development of HPLC methods for the determination of meldonium in dosage forms with the usage of salts of chaotropic anions in mobile phases. Material and methods. Analytical equipment: Shimadzu UPLC system LC-40 PDA; Shimadzu Nexera-i LC-2040C 3D-Plus, controlled by software Lab Solution version 5.97, electronic laboratory balance RAD WAG AS 200/C, pH-meter I-160MI. Meldonium dihydrate (purity 99.3 %) was purchased from Sigma-Aldrich (Switzerland), and Vasopro capsules 500 mg were purchased from a local pharmacy. Chromatographic conditions: Agilent Zorbax C-18 SB 150 mm x 4.6 mm 3.5 μm column was used (Agilent Technologies, USA). Mobile phases: 1) 0.25 % KPF6 w/v – 0.1 % v/v 85 %H3PO4 95 % – 5 % ACN, 2) 0.3 % bis-(trifluoromethane)sulfonimide lithium salt 97 % w/v – 0.1 %v/v 85 % H3PO4 80 % – 20 % acetonitrile. Flow rate - 1mL/min, T=32 °C, detection UV=at 4 channels - 190 nm, 195 nm, 200 nm, 205 nm. Results and discussion. We have proposed two approaches using two different salts of chaotropic anions - potassium hexafluorophosphate and bis-(trifluoromethane)sulfonimide lithium salt – for the HPLC method development. The chaotropic effects of these anions toward meldonium strongly influenced the analyte migratory behaviour. Both mobile phases involved, in addition to the use of a chaotrope, also the use of acetonitrile and pH adjustment with 0.1 % v/v 85 % H3PO4 solution. The detection wavelength (190 nm, 195 nm, 200 nm, 205 nm) was selected experimentally. The results were obtained for 8 concepts. Parameters of the chromatographic system confirm the conclusions and results of this investigation for the influence of chaotropic salts on N-containing molecules in an acidic pH medium, by increasing their retentivity and improving peak shape and uniformity homogeneity, even on the column without end-capping and base-deactivating. Validation of the analytical method was carried out following the requirements of SPhU. Conclusions. HPLC methods for the determination of meldonium in dosage forms have been developed, using positive impacts of chaotropic salts on the molecules containing N-atoms in their molecule on their retentions and peak symmetries on the chromatogram. The validation of the analytical methods showed their suitability for pharmaceutical analysis
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... In the arsenal of pharmacological agents that can affect the metabolic processes in the myocardium in ischemic conditions, a new class of antianginal drugs-partial fatty acid oxidation inhibitors (p-FOX). The mechanism of action of meldonium, which is a representative of partial inhibitors of fatty acid oxidation, is to reduce the rate of biosynthesis of carnitine from its predecessor-gamma-butyrobetaine [1,2]. On the other hand, the accumulation of gamma-butyrobetaine stimulates the biosynthesis of nitric oxide (NO) [3], which leads to the normalization of the functional state of the endothelium and, consequently, to normalize the vascular tone (vasodilatory effect of meldonium), reduces platelet aggregation. ...
Concepts for a New Rapid and Simple HPLC Method for Simultaneous Determination of Metoprolol and Meldonium in Pharmaceutical Dosage Forms
Article
Full-text available
Simultaneous determination of the tandem of drugs, like meldonium and metoprolol, with enormous polarity differences between them, requires thorough research and careful selection of chromatographic conditions. The three different CN-cyano groups with link-based particle columns, LiChrospher CN, Waters Spherisorb CNRP, Zorbax CN SB stationary phases, were tested, in an isocratic elution system, with a running mobile phase containing various concepts of composition contents. They were first with buffering salts which included acetonitrile and ammonium phosphate in one group, and then without buffering salts but with diluted acids, composed of acetonitrile and diluted acids as the second group. We can conclude that the most optimal concepts, in terms of expressiveness and environmental friendliness, were concepts using of column Zorbax CN SB (4.6 mm i.d.× 250 mm, 5 μm) and mobile phase ACN—0.15% NH4H2PO4 (50:50 and 60:40, v/v). There are very poor available data about ideas and usable information about the development of methods for simultaneous determination of these two active substances with polarity differences between them. We suggest that our work offered detailed and successful solutions for the mentioned aim using less sophisticated equipment for quality control and a lab for routine manufacturing control.
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... The effect of mildronate on the cardiovascular system, based on its anti-ishemic and cytoprotective effect has been investigated under experimental and clinical conditions (coronary heart disease, congestive heart failure, cerebral disorders and their experimental models), especially during the last 10 years [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. ...
Original paper Partial inhibition of fatty acid oxydation increases the exercise tolerance of patients with peripheral arterial disease: the Mildronate Study
Article
Full-text available
  • Jan 2011
The objective of the study was to assess the efficacy and safety of the treatment with mildronate (1 g/day) in combination with standard therapy for the exercise tolerance of patients with peripheral arterial disease (PAD). Design and Methods: The study was a prospective, randomized, double-blind, placebo controlled phase II study with two treatment groups. The study totally included 62 male and female patients with PAD and intermittent claudication as a limiting factor for physical load (the treadmill test). The follow-up time comprised 33 weeks: a 5-week run-in period plus 24 weeks of randomized therapy followed by a 4-week follow-up period. Results: The mean value of the change in the absolute claudication distance (ACD) during the treadmill test in the mildronate group after 24 weeks of treatment was 231.22±179.02 meters, while the placebo group patients had the mean value of 126.67 ± 120.72 meters. The difference between the treatment groups was significant (p-value = 0.026). The mean value of the change in the initial claudication distance (ICD) before and after 24 weeks of double-blind therapy during the treadmill test in the mildronate group was 123.93 ±114.73 meters, while the placebo group patients had the mean value of 50.30 ±62.56 meters. The difference between the treatment groups was significant (p-value = 0.033). The mean value of the change in the ACD from visit T24 (24 weeks of treatment) till one month after the discontinuation of the treatment (visit PT) during the treadmill test in the mildronate group was 19.68 ± 85.58 meters, while the placebo group patients had the mean value-31.43 ±79.17 meters. The difference between the treatment groups was significant (p-value = 0.032). Conclusions: The study confirms the superiority of treatment with mildronate (1 g/day) versus placebo in combination with standard therapy for the improvement of exercise tolerance in patients with PAD. The 4 weeks interruption of the mildronate course without loosing the effect could be acceptable in cases of the long-term use of mildronate. Seminars in Cardiovascular Medicine 2011; 17: 3
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New data on well-known drug: focus on meldonium
Article
  • Oct 2021
The article reviews the efficacy of meldonium in patients with various diseases, which are based on secondary mitochondrial dysfunction. Mitochondria are complex cellular organelles that control many metabolic processes, including fatty acid oxidation, the Krebs cycle, oxidative phosphorylation in the electron transport chain, and many other processes. Many conditions can lead to secondary mitochondrial dysfunction and affect other diseases. Damage to mitochondria can promote the activation of free radical processes and the initiation of the mechanisms of programmed cell death, mitochondrial dysfunction decrease in the immune response, increase in the activity of the body’s inflammatory response in various infections. Mitochondria appear to be important in COVID-19 pathogenesis because of its role in innate antiviral immunity, as well as inflammation. The article presents data on the effectiveness of using meldonium as a drug that helps to arrest pathological processes in mitochondria. The main mechanism of action of meldonium is based on a decrease in L-carnitine levels and increase of peroxisomes activity in the cytosol Meldonium was designed as a inhibitor of carnitine biosynthesis aimed to prevent accumulation of cytotoxic intermediate products of fatty acid beta- oxidation in ischemic tissues and to block this highly oxygen- consuming process. It is based on the correction of the energy metabolism of the cell. There was a positive trend in the use of meldonium in patients with diseases of the cardiovascular system (chronic ischemic diseases, chronic heart failure, arterial hypertension, etc.), neurological disorders (stroke, cerebrovascular insufficiency, etc.), respiratory diseases. The data on the beneficial effect of meldonium on the immune response in patients with coronavirus, bronchial asthma, chronic obstructive pulmonary disease, during vaccination with anti-influenza serum are presented. A decrease in asthenia was noted against the background of the use of meldonium in patients who had undergone coronavirus infection.
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АНАЛІЗ ПІДХОДІВ ДО РОЗРОБКИ ТА ВАЛІДАЦІЇ МЕТОДІВ АНАЛІЗУ МЕЛЬДОНІЮ В ЛІКАРСЬКИХ ЗАСОБАХ І БІОЛОГІЧНИХ РІДИНАХ
Article
  • Feb 2020
Вступ. Розробка і валідація аналітичних методів відіграють важливу роль у створенні, розробці та виробництві лікарських засобів. Розробка методики аналізу – підтвердження того, що аналітичний метод придатний для використання з метою визначення концентрації API в комбінованій лікарській формі. Це дає можливість застосовувати спрощені процедури для перевірки того, що методика аналізу точно і послідовно забезпечить надійне визначення активного фармацевтичого інгредієнта в лікарському засобі. Валідація аналітичної методики має важливе значення для розробки аналітичних методів, і її широко перевіряють на специфічність, лінійність, правильність, прецизійність, робасність. Таким чином, розробка та валідація аналітичних методів дозволяють підтвердити можливість точного і надійного визначення ефективності активного фармацевтичного інгредієнта в лікарських засобах та біологічних рідинах. Критерієм пошуку був аналітичний метод розробки мельдонію. Огляд літератури проводили в період 1990–2019 рр., щоб зробити його оновленим та всеосяжним і показати нові підходи до розробки методів аналізу мельдонію. Джерелами були всесвітньо відомі журнали, а ключовими словами в якості фільтра – мельдоній, спектрофотометричний метод, високоефективна рідинна хроматографія, кількісне визначення, розробка методики, валідація. Мета дослідження – проаналізувати підходи до розробки та валідації методів аналізу мельдонію в лікарських засобах і біологічних рідинах. Висновки. У світлі переваг, які обговорювали в цьому огляді, можна зробити висновок, що хіміки-аналітики постійно працюють над розробкою нових методів аналізу мельдонію в лікарських засобах і біологічних рідинах та їх оптимізацією з метою економії часу і витратних матеріалів, що також забезпечує ефективність розробленої методології. Дослідження літератури показало, що для аналізу мельдонію індивідуально або в комбінації з іншими лікарськими засобами існує ряд методів. Однак немає аналітичних методів для одночасного аналізу цих препаратів у комбінованій лікарській формі.
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Involvement of Nitric Oxide Production in the Mildronate Mechanism of Action
Article
Full-text available
Probable involvement of the NO synthesis activation in the mechanism of action of the anti-ischemic drug mildronate has been tested. Changes in the NO content in different rat tissues (brain cortex, cerebellum, liver, heart, kidneys) were evaluated after administration of mildronate, its structural analogue -butyrobetaine (GBB), and neomildronate (mildronate and GBB mixture in ratio 1:1). NO concentration was measured directly with electron paramagnetic resonance method (EPR).It was revealed that mildronate (50 mg/kg, i.p.) triggers the increase of NO level in the brain cortex, cerebellum, and heart 30 min after the drug administration. Administering the nitric oxide synthase (NOS) inhibitor N-nitro L-arginine (50 mg/kg, i.p.) at the same time abolished the NO increase triggered by mildronate. This indicates the necessity of NOS activation to produce NO concentration increase and excludes possible nonenzymatic nature of the mildronate effect. GBB (50 mg/kg, i.p.; 0.5 h) triggered the NO concentration increase in the cerebellum only. Neomildronate action was the most pronounced; the NO concentration increased 30 min after the drug administration and the elevated level of NO was maintained for 2 h. The data provide evidence in favor of hypothesis of gamma-butyrobetaine esterase signalization pathway.
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Cardioprotective Effects of MET88, a Gamma-Butyrobetaine Hydroxylase Inhibitor, on Cardiac Dysfunction Induced by Ischemia/Reperfusion in Isolated Rat Hearts
Article
Inhibition of fatty acid metabolite accumulation may be beneficial for treatment of cardiac dysfunction induced by ischemia. MET-88, 3-(2,2,2-trimethylhydrazinium)propionate dihydrate, inhibits γ-butyrobetaine hydroxylase which catalyzes conversion of γ-butyrobetaine to carnitine. In this study, we investigated whether MET-88 has cardioprotective effects against cardiac dysfunction induced by ischemia/reperfusion. Rats were divided into four groups: (1) control; (2) MET-88 at 50 mg/kg; (3) MET-88 at 100 mg/kg; (4) nifedipine at 30 mg/kg. MET-88 was administered orally once a day for 10 days, and nifedipine was administered orally 30 min before the experiments. Cardiac functions (heart rate, left ventricular systolic pressure and coronary flow) were measured in rat working heart preparations for 30 min under ischemia followed by 20 min under reperfusion. Myocardial carnitine levels were measured at the end of the experiments. Before ischemia, MET-88 did not affect cardiac functions, but nifedipine significantly increased only coronary flow. Under the ischemic condition, cardiac functions were markedly decreased in all groups. During reperfusion, MET-88 and nifedipine promoted recovery of cardiac functions and decreased the incidence of ventricular fibrillation. MET-88 also prevented the accumulation of long-chain acylcarnitine induced by ischemia. These results indicated that MET-88 protected against cardiac dysfunction in ischemia/reperfusion, and preventing the accumulation of long-chain acylcarnitine may be responsible for the cardioprotective effects.
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Myocardial fatty acid oxidation during ischemia and reperfusion
Article
  • Oct 1992
Inhibition of fatty acid oxidation is an early event in myocardial ischemia that most likely contributes to tissue injury by the accumulation of potentially toxic intermediates such as acylCoA and acylcarnitine. After reperfusion both myocardial oxygen consumption and fatty acid oxidation may rapidly recover to preischemic levels, even when contractile function remains depressed. The mechanisms underlying the apparent dissociation between contractile function and oxidative metabolism early during reperfusion are still controversial. In isolated rat hearts subjected to 60 min of no-flow ischemia myocardial oxygen consumption and oxidation of palmitate were lowered during reperfusion by 3 mM of NiCl2 and by 6 M of ruthenium red. The results provide indirect evidence for the hypothesis that intracellular calcium transport may be involved in the mechanisms responsible for the high oxidative metabolic rate early after reperfusion
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Inhibition of carnitine synthesis modulates protein contents of the cardiac sarcoplasmic reticulum Ca2+-ATPase and hexokinase type I in rat hearts with myocardial infarction
Article
  • Oct 2000
It was previously reported than inhibition of carnitine synthesis by 3-(2,2,2-trimethyl-hydrazinium) propionate (MET-88) restores left ventricular (LV) systolic and diastolic function in rats with myocardial infarction (MI). Preservation of the calcium uptake function of sarcoplasmic reticulum Ca2+-ATPase (SERCA2) is one of the possible mechanisms by which MET-88 alleviates hemodynamic dysfunction. To test this hypothesis, the effects of MET-88 on protein content of SERCA2 were evaluated using the same rat model of heart failure. Myocardial protein content of hexokinase, which is one of the key enzymes of glucose utilization, was also measured. Either MET-88 (MET-88 group) or a placebo (MI group) was administered for 20 days to rats with MI induced by coronary artery ligation. The control group underwent sham surgery (no ligation) and received placebo. In LV myocardial homogenates, the myocardial SERCA2 protein content was 32% lower (p<0.05) in the MI group than in the control group. However, in the MET-88 group myocardial SERCA2 content was the same as in the control group. Hexokinase I protein content was 29% lower (p<0.05) in the MI group compared with the control. In contrast, hexokinase II protein content did not differ significantly among the three groups. Consequently, inhibition of carnitine synthesis ameliorates depression of SERCA2 and hexokinase I protein content which may reduce tissue damage caused by MI.
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Enhancement of activities relative to fatty acid oxidation in the liver of rats depleted for L-carnitine by D-carnitine and a γ-butyrobetaine hydroxylase inhibitor
Article
This study was designed to examine whether the depletion of l-carnitine may induce compensatory mechanisms allowing higher fatty acid oxidative activities in liver, particularly with regard to mitochondrial carnitine palmitoyltransferase I activity and peroxisomal fatty acid oxidation. Wistar rats received d-carnitine for 2 days and 3-(2,2,2-trimethylhydrazinium)propionate (mildronate), a non-competitive inhibitor of γ-butyrobetaine hydroxylase, for 10 days. They were starved for 20 hr before being sacrificed. A dramatic reduction in carnitine concentration was observed in heart, skeletal muscles and kidneys, and to a lesser extent, in liver. Triacylglycerol content was found to be significantly more elevated on a gram liver and whole liver basis as well as per mL of blood (but to a lesser extent), while similar concentrations of ketone bodies were found in the blood of d-carnitine/mildronate-treated and control rats. In liver mitochondria, the specific activities of acyl-CoA synthetase and carnitine palmitoyltransferase I were enhanced by the treatment, while peroxisomal fatty acid oxidation was higher per gram of tissue. It is suggested that there may be an enhancement of cellular acyl-CoA concentration, a signal leading to increased liver fatty acid oxidation in acute carnitine deficiency.
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Acetylcholine-like activity in subcellular particles isolated from rat brain
Article
  • Dec 1964
Brain homogenates were separated into various subcellular fractions, and extracts of each fraction were further separated chromatographically with water-saturated butanol. Specific bands from the chromatograms were examined spectrophotometrically before biological assay for acetylcholine-like activity was performed. It was observed that the crude mitochondrial fraction contained most of the acetylcholine-like activity in the original homogenate. Further treatment of this fraction by differential centrifugation in sucrose solutions of varying densities showed that the subfraction presumed to contain presynaptic vesicles had most of the acetylcholine-like activity. In both sets of experiments the acetylcholine-like activity was mainly contributed by material which, in other work, was identified as a mixture of the CoA ester derivatives of γ-butyrobetaine, crotonbetaine, 1-carnitine, and acetyl-1-carnitine.
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Purication and characterization of the rat liver gamma-butyrobetaine hydroxylase
Article
  • Jan 1998
The biosynthesis of carnitine from lysine and methionine involves five enzymatic reactions. Gamma-butyrobetaine hydroxylase (BBH; EC 1.14.11.1) is the last enzyme of this pathway. It catalyzes the reaction of hydroxylation of gamma-butyrobetaine to carnitine. This enzyme had never been purified to homogeneity from rat tissue. This paper describes the purification and characterization of the rat liver BBH. This protein has been purified some 413 fold by ion exchange, affinity and gel-filtration chromatographies and appears as a dimere of 43,000 Daltons subunits by PAGE. The affinity chromatography column used in the purification process utilizes 3-(2,2,2-trimethylhydrazinium)propionate (THP), a BBH inhibitor, as the ligand. Polyclonal antibodies were raised against the liver enzyme. They were able to precipitate BBH activity in either a crude liver extract or a purified fraction of the enzyme. Furthermore, it crossreacts with a 43 kDa protein in the liver. No evidence for extra hepatic enzyme was found.
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[The effect of mildronate on erythrocyte membrane permeability in experimental lung pathology]
Article
  • Nov 1992
With the use of the erythrocyte osmotic and acidic resistance methods, the experiments on intact albino rats by applying a model of chronic non-specific lung diseases and those in vitro have shown that mildronate has a membrane-stabilizing action only when given in high doses (500 mg/kg) and concentrations (10(-3)-10(-4) M). When used in low doses (5, 25, 50, and 200 mg/kg) and concentrations (10(-5)-10(-7) M), in produces no positive effect.
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[The characteristics of the action of mildronate (dihydrate 3-(2,2,2-trimethylhydrazine)propionate) on the red blood parameters in heart failure]
Article
  • May 1992
Mildronat potentiates the therapeutic effect of the combined treatment of heart failure, which includes the use of nitro drugs. It also decreases the level of methemoglobin in the patients' blood and improves the phosphate balance, especially that of 2,3-diphosphoglycerate to control oxygen transport by hemoglobin, which is of paramount importance in hypoxia caused by coronary heart disease.
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