Mildronate
Mildronate | |
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IUPAC name 2-(2-carboxyethyl)-1,1,1-trimethylhydrazinium | |
Identifiers | |
CAS number | 86426-17-7 |
PubChem | 123868 |
ChemSpider | 110405 |
Jmol-3D images | {{#if:C[N+](C)(C)NCCC(=O)[O-]|Image 1 |
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Properties | |
Molecular formula | C6H15N2O2+ |
Molar mass | 147.19 g/mol |
Appearance | white to off-white powder |
Solubility in water | H2O: >40 mg/mL |
Hazards | |
MSDS | MSDS |
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa) | |
Infobox references | |
Mildronate (also known as THP, MET-88, Meldonium, Mildronāts or Quaterine[1]) is a clinically used anti-ischemic & nootropic drug that is currently manufactured and marketed by Grindeks, a pharmaceutical company based in Latvia.[2]
Mildronate is clinically used to treat angina and myocardial infarction.[3][4][5] The first clinical trial testing the efficacy of using a combination of mildronate and lisinopril, an angiotensin-converting enzyme inhibitor, to treat chronic heart failure was reported in 2005.[6] The report demonstrated that the combined treatment of mildronate and lisinopril may improve the quality of life, exercise capacity and mechanisms of peripheral circulation of patients with chronic heart failure.[6] A later report in 2008 further demonstrated the efficacy of combined mildronate-lisinopril treatment by showing improved carotid baroreceptor reflex in patients with chronic heart failure.[7] In February 2010, the clinical trial testing the efficacy and safety of mildronate treatment in combination with standard exercise tolerance therapy on angina patients was successfully completed.[8] The studies revealed that mildronate treatment significantly improves the exercise tolerance of stable angina patients.[9][10] A phase II clinical trial on the efficacy and safety of mildronate for acute ischemic stroke was completed in August 2013 and the studies showed that mildronate is as effective and safe as cinepazide injection.[11][12]
Besides clinical trials, a number of scientific research projects have also been conducted to improve the efficacy of mildronate and its applicability to other diseases. For example, a report published by Vilskersts et al. suggested that the effect of mildronate treatment may be enhanced with co-treatment of other compounds such as orotic acid.[13]
Using animal models, the applications of mildronate, sometimes in tandem with other drugs such as metformin, have shown beneficial effects on neurological disorder[14][15] and diabetes.[16]
Mildronate may also be beneficial for the treatment of seizures and alcohol intoxication.[17]
Recent reports also suggest that mildronate may improve the ability of learning and memory, as the drug changes the expression of hippocampal proteins related to synaptic plasticity using rat model.[18]
Mildronate was reported to elevate the concentrations of γ-butyrobetaine hydroxylase in testes tissues;[4] in addition, long term (90 days) administration of mildronate was reported to improve sexual performance, sperm motility and concentration of testosterone in boars, although further studies are needed to confirm the potential of using mildronate as a sperm motility and sperm quality-enhancing agent.[19]
To date, mildronate is one of Latvia's most exported products, and can be readily obtained in countries including Russia, Ukraine, Moldova, Belarus, Azerbaijan and Armenia.[20][21][22]
Mechanism of action
The active substance of mildronate is 3-(2,2,2-trimethylhydraziniumyl)propionate,[23][24] a structural analogue of γ-butyrobetaine, with a NH group replacing the CH2 at the C-4 position of γ-butyrobetaine. γ-Butyrobetaine is a precursor in the biosynthesis of carnitine.[25]
The mechanism of action of mildronate is to act as a fatty acid oxidation inhibitor, presumably by inhibiting enzymes in the carnitine biosynthesis pathway such as γ-butyrobetaine hydroxylase.[26] γ-Butyrobetaine hydroxylase is an enzyme that belongs to the 2-oxoglutarate (2OG) oxygenase superfamily and catalyses the formation of L-carnitine from γ-butyrobetaine.[27][28] X-ray crystallographic and in vitro biochemical studies suggest mildronate binds to the substrate pocket of γ-butyrobetaine hydroxylase and acts as a competitive substrate/inhibitor to form malonic acid semialdehyde, dimethylamine, formaldehyde, 3-amino-4-(methyamino)butanoic acid and (1-methylimidazolidin-4-yl)acetic acid,[29][30] likely via a Steven's type rearrangement mechanism.[31] Mildronate is a potent γ-butyrobetaine hydroxylase inhibitor, with a half maximal inhibitory concentration (IC50) value of 62 μM.[32] Mildronate is an example of a non-peptidyl substrate mimic inhibitor for human 2OG oxygenase.[33]
Mildronate has also been shown by NMR to bind to carnitine acetyltransferase.[34] Carnitine acetyltransferase belongs to a family of ubiquitous enzymes that play pivotal roles in cellular energy metabolism.[35] Mildronate therefore may act as a regulator of energy metabolism. Mildronate is a relatively weak inhibitor to carnitine acetyltransferase (when compared to γ-butyrobetaine hydroxylase), with an inhibition constant (KI) of 1.6 mM.
Forms
- 250 mg capsules N60[36]
- 500 mg capsules N60
- Injection 10% 5 ml N10
See also
References
- ↑ Patent Number: 1429753. http://www.surechem.org/index.php?Action=document&docId=679316&db=EPB&tab=desc&lang=EN&db_query=2%3A0%3A&markupType=all (accessed August 16, 2012).
- ↑ JSC Grindeks. http://www.grindeks.lv (accessed May 17, 2012).
- ↑ Sesti C, Simkhovich BZ, Kalvinsh I, Kloner RA (March 2006). "Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics". J. Cardiovasc. Pharmacol. 47 (3): 493–9. doi:10.1097/01.fjc.0000211732.76668.d2. PMID 16633095.
- ↑ 4.0 4.1 Liepinsh E, Vilskersts R, Loca D, Kirjanova O, Pugovichs O, Kalvinsh I, Dambrova M (December 2006). "Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction". J. Cardiovasc. Pharmacol. 48 (6): 314–9. doi:10.1097/01.fjc.0000250077.07702.23. PMID 17204911.
- ↑ Hayashi Y, Kirimoto T, Asaka N, Nakano M, Tajima K, Miyake H, Matsuura N (May 2000). "Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction". Eur. J. Pharmacol. 395 (3): 217–24. doi:10.1016/S0014-2999(00)00098-4. PMID 10812052.
- ↑ 6.0 6.1 Dzerve V, Matisone D, Kukulis I, Romanova J, Putane L, Grabauskiene˙V, Skarda I, Berzina D, Strautmanis J (2005). "Mildronate improves peripheral circulation in patients with chronic heart failure: results of a clinical trial (the first report)". Semin Cardiol 11 (2): 56–64. ISSN 1648-7966.
- ↑ Vitols A, Voita D, Dzerve V (2008). "Mildronate improves carotid baroreceptor reflex function in patients with chronic heart failure". Semin Cardiovasc Med 13: 6.
- ↑ JSC Grindeks. http://www.grindeks.lv/en/for-investors/stock-news/mildronate_clinical_trial (accessed May 17, 2012).
- ↑ Dzerve V, Matisone D, Pozdnyakov Y, Oganov R (2010). "Mildronate improves the exercise tolerance in patients with stable angina: results of a long term clinical trial". Semin Cardiovasc Med 16: 3.
- ↑ Dzerve V, MILSS I Study Group (2011). "A Dose-Dependent Improvement in Exercise Tolerance in Patients With Stable Angina Treated With Mildronate: A Clinical Trial "MILSS I"". Medicina (Kaunas) 47 (10): 544–51. PMID 22186118.
- ↑ Zhu Y, Zhang G, Zhao J, Li D, Yan X, Liu J, Liu X, Zhao H, Xia J, Zhang X, Li Z, Zhang B, Guo Z, Feng L, Zhang Z, Qu F, Zhao, G (2013). "Efficacy and safety of mildronate for acute ischemic stroke: a randomized, double-blind, active-controlled phase II multicenter trial". Clin Drug Investig. doi:10.1007/s40261-013-0121-x.
- ↑ ClinicalTrials.gov A service of the U.S. National Institutes of Health. http://clinicaltrials.gov/ct2/show/NCT01831011?rcv_d=14&lup_s=03%2F16%2F2013&lup_d=30 (accessed Aug 21, 2012).
- ↑ Vilskersts R, Liepinsh E, Kuka J, Cirule H, Veveris M, Kalvinsh I, Dambrova M (2009). "Myocardial infarct size-limiting and anti-arrhythmic effects of mildronate orotate in the rat heart". Cardiovasc. Drugs Ther. 23 (4): 281–8. doi:10.1007/s10557-009-6179-2.
- ↑ Sjakste N, Gutcaits A, Kalvinsh I (2005). "Mildronate: an antiischemic drug for neurological indications". CNS Drug Rev 11 (2): 151–68. doi:10.1111/j.1527-3458.2005.tb00267.x. PMID 16007237.
- ↑ Pupure J, Isajevs S, Skapare E, Rumaks J, Svirskis S, Svirina D, Kalvinsh I, Klusa V (February 2010). "Neuroprotective properties of mildronate, a mitochondria-targeted small molecule". Neurosci. Lett. 470 (2): 100–5. doi:10.1016/j.neulet.2009.12.055. PMID 20036318.
- ↑ Liepinsh E, Skapare E, Svalbe B, Makrecka M, Cirule H, Dambrova M (May 2011). "Anti-diabetic effects of mildronate alone or in combination with metformin in obese Zucker rats". Eur. J. Pharmacol. 658 (2-3): 277–83. doi:10.1016/j.ejphar.2011.02.019. PMID 21371472.
- ↑ Zvejniece L, Svalbe B, Makrecka M, Liepinsh E, Kalvinsh I, Dambrova M (September 2010). "Mildronate exerts acute anticonvulsant and antihypnotic effects". Behav Pharmacol 21 (5-6): 548–55. doi:10.1097/FBP.0b013e32833d5a59. PMID 20661137.
- ↑ Klusa V, Muceniece R, Isajevs S, Isajeva D, Beitnere U, Mandrika I, Pupure J, Rumaks J, Jansone B, Kalvinsh I, Vinters HV (May 2013). "Mildronate enhances learning/memory and changes hippocampal protein expression in trained rats". Pharmacol Biochem Behav 106: 68–76. doi:10.1016/j.pbb.2013.03.012. PMID 23537732.
- ↑ Bruveris Z, Antane V, Misane I, Rimeicans J, Lusis I, Auzans A, Mangale M, Mednis A, Stonans I (January 2013). "Effects of meldonium on sexual performance, sperm motility, testes morphology and blood biochemical markers in boars". Anim. Reprod. Sci. 136 (4): 303–9. doi:10.1016/j.anireprosci.2012.11.007. PMID 23238051.
- ↑ Biotech Intelligence. http://www.biotech-intelligence.com/html/html/pool_7/91cc83b0e3f8b4edbbda2a42ae43e1b1.html (accessed May 17, 2012).
- ↑ PMR. Pharmaceutical, Healthcare and Medical Sector in Central and Eastern Europe: Industry News, Analyses and Market Data. http://www.ceepharma.com/63359/Grindex-names-Russian-manufacturing-partner-for-Mildronate.shtml (accessed May 17, 2012).
- ↑ Evaluate Pharma. https://www.evaluatepharma.com/Universal/View.aspx?type=Story&id=137196 (accessed May 17, 2012).
- ↑ Sigma Aldrich. http://www.sigmaaldrich.com/catalog/product/sigma/m5199 (accessed May 17, 2012).
- ↑ Simkhovich BZ, Shutenko ZV, Meirena DV, Khagi KB, Mezapuķe RJ, Molodchina TN, Kalviņs IJ, Lukevics E (January 1988). "3-(2,2,2-Trimethylhydrazinium)propionate (THP)--a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties". Biochem. Pharmacol. 37 (2): 195–202. doi:10.1016/0006-2952(88)90717-4. PMID 3342076.
- ↑ Fraenkel G, Friedman S (1957). "Carnitine". Vitam. Horm. 15: 73–118. PMID 13530702.
- ↑ Vaz FM, Wanders RJA (2002). "Carnitine biosynthesis in mammals". Biochem. J. 361: 417–29.
- ↑ Vaz FM, van Gool S, Ofman R, IJlst L, Wanders RJ (Nov 1998). "Carnitine biosynthesis: identification of the cDNA encoding human gamma-butyrobetaine hydroxylase". Biochem Biophys Res Commun 250 (2): 506–10. doi:10.1006/bbrc.1998.9343. PMID 9753662.
- ↑ "Entrez Gene: BBOX1 butyrobetaine (gamma), 2-oxoglutarate dioxygenase (gamma-butyrobetaine hydroxylase) 1".
- ↑ Leung IK, Krojer TJ, Kochan GT, Henry L, von Delft F, Claridge TD, Oppermann U, McDonough MA, Schofield CJ (December 2010). "Structural and mechanistic studies on γ-butyrobetaine hydroxylase". Chem. Biol. 17 (12): 1316–24. doi:10.1016/j.chembiol.2010.09.016. PMID 21168767.
- ↑ Spaniol M, Brooks H, Auer L, Zimmermann A, Solioz M, Stieger B, Krähenbühl S (March 2001). "Development and characterization of an animal model of carnitine deficiency". Eur. J. Biochem. 268 (6): 1876–87. doi:10.1046/j.1432-1327.2001.02065.x. PMID 11248709.
- ↑ Henry L, Leung IKH, Claridge TDW, Schofield CJ (Aug 2012). "γ-Butyrobetaine hydroxylase catalyses a Stevens type rearrangement". Bioorg. Med. Chem. Lett. 22 (15): 4975–4978. doi:10.1016/j.bmcl.2012.06.024. PMID 22765904.
- ↑ Tars K, Rumnieks J, Zeltins A, Kazaks A, Kotelovica S, Leonciks A, Sharipo J, Viksna A, Kuka J, Liepinsh E, Dambrova M (August 2010). "Crystal structure of human gamma-butyrobetaine hydroxylase". Biochem. Biophys. Res. Commun. 398 (4): 634–9. doi:10.1016/j.bbrc.2010.06.121. PMID 20599753.
- ↑ Rose NR, McDonough MA, King ON, Kawamura A, Schofield CJ (August 2011). "Inhibition of 2-oxoglutarate dependent oxygenases". Chem Soc Rev 40 (8): 4364–97. doi:10.1039/c0cs00203h. PMID 21390379.
- ↑ Jaudzems K, Kuka J, Gutsaits A, Zinovjevs K, Kalvinsh I, Liepinsh E, Liepinsh E, Dambrova M (December 2009). "Inhibition of carnitine acetyltransferase by mildronate, a regulator of energy metabolism". J. Enzyme Inhib. Med. Chem. 24: 1269–75. doi:10.3109/14756360902829527. PMID 19912061.
- ↑ Wu D, Govindasamy L, Lian W, Gu Y, Kukar T, Agbandje-McKenna M, McKenna R (April 2003). "Structure of Human Carnitine Acetyltransferase Molecular Basis for Fatty Acyl Transfer". J. Biol. Chem. 278: 13159–65. doi:10.1074/jbc.M212356200. PMID 12562770.
- ↑ JSC Grindeks. http://www.grindeks.lv/en/products/prescription-medicine/grindeks-brand-products/mildronate (accessed May 17, 2012).