Metadoxine

Metadoxine, also known as pyridoxine-pyrrolidone carboxylate, is a drug used to treat chronic and acute alcohol intoxication.[1] Metadoxine accelerates alcohol clearance from the blood.[2]

Metadoxine
Clinical data
Routes of
administration		Oral, IV
ATC code
  • N07BB
Identifiers
CAS Number
PubChem CID
ChemSpider
ECHA InfoCard100.070.809
Chemical and physical data
FormulaC13H18N2O6
Molar mass298.29 g/mol g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

Metadoxine is an ion pair salt of pyridoxine and pyrrolidone carboxylate (PCA).[1] Pyridoxine (vitamin B6) is a precursor of coenzymes including pyridoxal 5’-phosphate (PLP), which accelerates the metabolic degradation of ethanol and prevents adenosine triphosphate (ATP) inactivation by acetaldehyde. Pyridoxal phosphate dependent enzymes also play a role in the biosynthesis of four important neurotransmitters: serotonin (5-HT), epinephrine, norepinephrine and GABA: see vitamin B6 functions. L-PGA is present in the diet and is produced endogenously by enzymatic conversion of gamma-glutamyl amino acids to L-PGA and free amino acids. In the central nervous system (CNS), L-PGA was found to have a role in composition of neuro-active molecules. Its production has been linked to hepatic gamma-glutamyl transferase activity and levels of reduced glutathione (GSH). Lastly, it was shown that L-PGA facilitates ATP synthesis by stimulating de novo synthesis of purines.

Medical uses

As a treatment for alcohol intoxication and liver disease, metadoxine is typically given intravenously as immediate release formulation.

Acute alcohol intoxication

In clinical studies, metadoxine has been reported to reduce half-life of ethanol in healthy volunteers and in acutely intoxicated patients; to accelerate the metabolism of alcohol and acetaldehyde into less toxic higher ketones and to improve their urinary clearance; to restore laboratory variables such as alcohol, ammonia, γ-GT, and alanine aminotransferase; and to improve clinical symptoms of alcohol intoxication, including psychomotor agitation, depression, aggressiveness, and equilibrium disorders.[1][3] There is also evidence that metadoxine has an effect on reducing craving for alcohol.[4] Data from clinical studies also support an effect of metadoxine on reducing indices of liver cell necrosis and fat accumulation in alcoholic fatty liver.[4]

Liver disease

Metadoxine may block the differentiation step of preadipocytes by inhibiting CREB phosphorylation and binding to the cAMP response element, thereby repressing CCAAT/enhancer-binding protein b during hormone-induced adipogenesis.[5] Metadoxine, when given in an immediate release form in doses from 300 mg twice a day to 500 mg three times a day of up to 3 months, has been shown to improve biochemical indices of liver function as well as reduce ultrasonic evidence of fatty liver disease.[6][7][8]

Pharmacology

Mechanism of action

Metadoxine is a selective antagonist of the serotonin receptor subtype 5-HT2B and displays high affinity to the gamma-aminobutyric acid (GABA) transporter. In vitro enzymatic assay revealed that metadoxine reduced the activity of the GABA transaminase enzyme, responsible for the degradation of GABA. Electrophysiological studies also showed that metadoxine increased inhibitory GABAergic synaptic transmission via a presynaptic effect. As it does not affect dopamine, norepinephrine or serotonin levels, metadoxine displays a novel mechanism of action as a monoamine-independent GABA modulator.[9]

In animal studies, metadoxine increased the activity of acetaldehyde dehydrogenase enzyme, prevented the decrease in alcohol dehydrogenase activity in chronic ethanol-fed rats, accelerated plasma and urinary clearance of ethanol, inhibited the increase of fatty acid esters in the liver of ethanol-treated rats, prevented the formation of fatty liver in rats exposed to a dose of ethanol sufficient to induce fatty liver, increased glutathione levels in the hepatocytes of acutely and chronically alcohol-intoxicated rats, prevented glutathione depletion, lipid peroxidation damage, collagen deposition, and TNF-α secretions induced by alcohol and acetaldehyde in hepatocytes and hepatic stellate cells.[1]

History

Metadoxine is predominantly used as metadoxine immediate release formulation in developing nations for acute alcohol intoxication and chronic alcoholic liver disease. Alternate names include:

  • Abrixone (Eurodrug, Mexico)
  • Alcotel (Il Yang, South Korea)
  • Ganxin (Qidu Pharmaceutical, China)
  • Metadoxil (Baldacci, Georgia; Baldacci, Italy; Baldacci, Lithuania; CSC, Russian Federation; Eurodrug, Colombia; Eurodrug, Hungary; Eurodrug, Thailand)
  • NEXT LABS (India)
  • Alkodez ІС (Ukraine)
  • Viboliv (Dr. Reddy's, India)
  • EXTOL (Next Labs, India)
  • Xin Li De (Zhenyuan Pharm, China)[10]

Research

ADHD

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders of childhood and is among the most prevalent chronic health conditions affecting school-aged children. The core symptoms of ADHD include inattention, difficulty staying focused, hyperactivity, and impulsivity.[11]

Metadoxine exhibited cognition enhancing effect in the rat social recognition animal model.

An extended release formulation of metadoxine (MDX), combining immediate and slow release formulations of metadoxine into a single oral dose, was developed to extend the half-life of the drug and to allow for the use of MDX in indications that require a longer therapeutic window, such as cognitive impairment-related disorders. MDX has demonstrated significant and clinically meaningful improvements in multiple measures of cognition, ADHD symptoms, and quality of life, across multiple studies of adults with ADHD.[9]

Several Phase II ADHD studies demonstrated a consistent signal of efficacy reaching statistical significance, as measured by neuropsychological testing (such as the computerized Test of Variables of Attention (TOVA) in acute settings) and clinical scales (in chronic administration studies), with no treatment-related serious adverse events or major differences in adverse events profiles between drug and placebo groups.[12][13] The most common adverse events were nausea, fatigue, and headache.[12][13] A phase 3 study in 300 adults with ADHD was completed in 2014.[14]

Alcobra Ltd., which was conducting the Phase III trial announced on January 17, 2017 that the drug had failed the trial. The failure announcement came a week after Alcobra won FDA agreement to review data collected to date in the MEASURE study and consider it in a future NDA submission of MDX for ADHD. The FDA also agreed to change a full clinical hold for the trial to a partial clinical hold pending review and approval of the company's proposed protocol for a 6-month, Phase I study to assess the potential relevance of adverse findings observed in long-term animal studies of metadoxine in relation to human exposure, Alcobra said.[15]

Fragile X syndrome

Fragile X syndrome (FXS) is a genetic disorder that is the most common single gene cause of intellectual disability and autism.[16] Individuals with FXS often have a number of behavioral symptoms, including cognitive impairment, inattention, hyperactivity, impulsivity, autistic symptoms, shyness, aggression, anxiety, hand flapping, hand biting, and a high sensitivity to being touched.[17][18] Autism spectrum disorder is seen in approximately 30% of males and 20% of females with FXS, and an additional 30% of FXS individuals display autistic symptoms without having the autism diagnosis.[16] ADHD is commonly diagnosed in FXS and has been reported to occur in 59-80% of individuals with FXS.[16][19]

In a FXS animal model (Fmr1 knockout mouse model), metadoxine treatment improved behavioral impairments of learning, memory, and social interaction and reversed the overactivation of the biomarkers Akt and extracellular signal-regulated kinase (ERK) in blood and brain of juvenile and adult mice. Metadoxine also demonstrated restoration of abnormal neuronal morphology as well as reduced the exaggerated basal protein production, both implicated in the pathophysiology of FXS and presumed to be responsible for impaired learning and memory.[20][21]

The safety and efficacy of MDX in adolescents and adults with FXS has been evaluated in a Phase II study, which was completed in 2015.[22]

References
  1. Addolorato, G; Ancona, C; Capristo, E; Gasbarrini, G (2003). "Metadoxine in the treatment of acute and chronic alcoholism: A review". International Journal of Immunopathology and Pharmacology. 16 (3): 207–14. doi:10.1177/039463200301600304. PMID 14611722.
  2. Vonghia, L; Leggio, L; Ferrulli, A; Bertini, M; Gasbarrini, G; Addolorato, G; Alcoholism Treatment Study, Group. (December 2008). "Acute alcohol intoxication". European Journal of Internal Medicine. 19 (8): 561–7. doi:10.1016/j.ejim.2007.06.033. PMID 19046719.
  3. Martinez, M. D.; Martinez, A. D.; Salcedo, V. V.; Fuentes, C. C. (2002). "Efficacy of Metadoxine in the Management of Acute Alcohol Intoxication". Journal of International Medical Research. 30 (1): 44–51. doi:10.1177/147323000203000107. PMID 11921498.
  4. Shpilenya, Leonid S.; Muzychenko, Alexander P.; Gasbarrini, Giovanni; Addolorato, Giovanni (2002). "Metadoxine in Acute Alcohol Intoxication: A Double-Blind, Randomized, Placebo-Controlled Study". Alcoholism: Clinical and Experimental Research. 26 (3): 340–6. doi:10.1111/j.1530-0277.2002.tb02543.x. PMID 11923586.
  5. Yang, Yoon Mee; Kim, Hyun Eun; Ki, Sung Hwan; Kim, Sang Geon (2009). "Metadoxine, an ion-pair of pyridoxine and l-2-pyrrolidone-5-carboxylate, blocks adipocyte differentiation in association with inhibition of the PKA-CREB pathway". Archives of Biochemistry and Biophysics. 488 (2): 91–9. doi:10.1016/j.abb.2009.07.007. PMID 19607801.
  6. Caballería, Joan; Parés, Albert; Brú, Concepció; Mercader, José; Plaza, Antonio Garcia; Caballería, Llorenç; Clemente, Gerardo; Rodrigo, Luis; Rodés, Joan (1998). "Metadoxine accelerates fatty liver recovery in alcoholic patients: Results of a randomized double-blind, placebo-control trial". Journal of Hepatology. 28 (1): 54–60. doi:10.1016/s0168-8278(98)80202-x. PMID 9537864.
  7. Cacciatore, L; Antoniello, S; Nigro, C; Vatiero, V; Lingetti, M (1988). "Metadoxine Treatment of Fatty Liver Associated with Chronic Hepatitis". Clinical Trials Journal. 25 (3): 220–6.
  8. Shenoy, Kotacherry T.; Balakumaran, Leena K.; Mathew, Philip; Prasad, Mohan; Prabhakar, Boddu; Sood, Ajit; Singh, Shivaram P.; Rao, Nagaraj P.; Zargar, Shoukat A.; Bignamini, Angelo A. (2014). "Metadoxine Versus Placebo for the Treatment of Non-alcoholic Steatohepatitis: A Randomized Controlled Trial". Journal of Clinical and Experimental Hepatology. 4 (2): 94–100. doi:10.1016/j.jceh.2014.03.041. PMC 4116708. PMID 25755546.
  9. "Metadoxine extended release (MDX) for adult ADHD". Alcobra Ltd. 2014. Retrieved 2014-05-07.
  10. "Metadoxine - Drugs.com". Drugs.com. 2014. Retrieved 2014-05-08.
  11. Subcommittee on Attention-Deficit/Hyperactivity Disorder.; Steering Committee on Quality Improvement Management.; Wolraich, M; Brown, L; Brown, R. T.; Dupaul, G; Earls, M; Feldman, H. M.; Ganiats, T. G.; Kaplanek, B; Meyer, B; Perrin, J; Pierce, K; Reiff, M; Stein, M. T.; Visser, S (2011). "ADHD: Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents". Pediatrics. 128 (5): 1007–22. doi:10.1542/peds.2011-2654. PMC 4500647. PMID 22003063.
  12. Manor, Iris; Ben-Hayun, Rachel; Aharon-Peretz, Judith; Salomy, Dana; Weizman, Abraham; Daniely, Yaron; Megiddo, Dalia; Newcorn, Jeffrey H.; Biederman, Joseph; Adler, Lenard A. (2012). "A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Evaluating the Efficacy, Safety, and Tolerability of Extended-Release Metadoxine in Adults with Attention-Deficit/Hyperactivity Disorder". The Journal of Clinical Psychiatry. 73 (12): 1517–23. doi:10.4088/jcp.12m07767. PMID 23290324.
  13. Manor, Iris; Rubin, Jonathan; Daniely, Yaron; Adler, Lenard A. (2015). "Attention Benefits after a Single Dose of Metadoxine Extended Release in Adults with Predominantly Inattentive ADHD". Postgraduate Medicine. 126 (5): 7–16. doi:10.3810/pgm.2014.09.2795. PMID 25295645.
  14. Weisler, Richard; Adler, Lenard A; Rubin, Jonathan; Daniely, Yaron; Manor, Iris (2014). A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Metadoxine Extended Release 1400 mg Compared with Placebo Once Daily in 300 Adults with Attention-Deficit/Hyperactivity Disorder (PDF). AACAP 61st meeting.
  15. "Alcobra ADHD Candidate MDX Fails Phase III Trial | GEN".
  16. Hersh, J. H.; Saul, R. A. (2011). "Health Supervision for Children with Fragile X Syndrome". Pediatrics. 127 (5): 994–1006. doi:10.1542/peds.2010-3500. PMID 21518720.
  17. Garber, Kathryn B; Visootsak, Jeannie; Warren, Stephen T (2008). "Fragile X syndrome". European Journal of Human Genetics. 16 (6): 666–72. doi:10.1038/ejhg.2008.61. PMC 4369150. PMID 18398441.
  18. Hagerman, R. J.; Berry-Kravis, E.; Kaufmann, W. E.; Ono, M. Y.; Tartaglia, N.; Lachiewicz, A.; Kronk, R.; Delahunty, C.; Hessl, D.; Visootsak, J.; Picker, J.; Gane, L.; Tranfaglia, M. (2009). "Advances in the Treatment of Fragile X Syndrome". Pediatrics. 123 (1): 378–90. doi:10.1542/peds.2008-0317. PMC 2888470. PMID 19117905.
  19. Tranfaglia, Michael R. (2011). "The Psychiatric Presentation of Fragile X: Evolution of the Diagnosis and Treatment of the Psychiatric Comorbidities of Fragile X Syndrome". Developmental Neuroscience. 33 (5): 337–48. doi:10.1159/000329421. PMID 21893938.
  20. Schumann, J; Rubin, J; Daniely, Y; Snape, M; Cogram, P (2014). Metadoxine Effects in the Fmr1 Knockout Mouse: A Novel Pharmacologic Approach to Treating Fragile X Syndrome. Gordon Research Conference in Fragile X and Autism-related Disorders.
  21. Dölen, Gül; Osterweil, Emily; Rao, B.S. Shankaranarayana; Smith, Gordon B.; Auerbach, Benjamin D.; Chattarji, Sumantra; Bear, Mark F. (2007). "Correction of Fragile X Syndrome in Mice". Neuron. 56 (6): 955–62. doi:10.1016/j.neuron.2007.12.001. PMC 2199268. PMID 18093519.
  22. "Alcobra announces results from Phase 2 clinical trial of MDX for Fragile X Syndrome". Alcobra Ltd. 2015. Retrieved 2015-06-24.
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