Metadoxine

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Metadoxine
Metadoxine.svg
Clinical data
Routes of
administration 		Oral, IV
ATC code
Identifiers
  • L-Proline, 5-oxo-, compd. with 5-hydroxy-6-methylpyridine-3,4-dimethanol (1:1)
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard 100.070.809 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C13H18N2O6
Molar mass 298.295 g·mol−1
3D model (JSmol)
  • Cc1c(c(c(cn1)CO)CO)O.C1CC(=O)N[C@@H]1C(=O)O
  • InChI=1S/C8H11NO3.C5H7NO3/c1-5-8(12)7(4-11)6(3-10)2-9-5;7-4-2-1-3(6-4)5(8)9/h2,10-12H,3-4H2,1H3;3H,1-2H2,(H,6,7)(H,8,9)/t;3-/m.0/s1
  • Key:RYKKQQUKJJGFMN-HVDRVSQOSA-N
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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]

Contents

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.

Medical uses

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

Acute alcohol intoxication

In clinical studies, metadoxine has been reported to reduce the 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]

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. [8]

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:

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. [10]

Metadoxine exhibited cognition enhancing effect in the rat social recognition animal model.[ citation needed ]

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. [8]

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. [11] [12] The most common adverse events were nausea, fatigue, and headache. [11] [12] A phase 3 study in 300 adults with ADHD was completed in 2014. [13]

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. [14]

Fragile X syndrome

Fragile X syndrome (FXS) is a genetic disorder that is the most common single gene cause of intellectual disability and autism. [15] 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. [16] [17] 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. [15] ADHD is commonly diagnosed in FXS and has been reported to occur in 59-80% of individuals with FXS. [15] [18]

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. [19] [20]

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. [21]

Related Research Articles

<span class="mw-page-title-main">Alcohol intoxication</span> Negative effects due to ethanol (alcohol)

Alcohol intoxication, also known in overdose as alcohol poisoning, commonly described as drunkenness or inebriation, is the behavior and physical effects caused by a recent consumption of alcohol. In addition to the toxicity of ethanol, the main psychoactive component of alcoholic beverages, other physiological symptoms may arise from the activity of acetaldehyde, a metabolite of alcohol. These effects may not arise until hours after ingestion and may contribute to the condition colloquially known as a hangover.The term intoxication is commonly used when large amount of alcohol is consumed along with physical symptoms and deleterious health effects.

<span class="mw-page-title-main">Fragile X syndrome</span> X-linked dominant genetic disorder

Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common, and seizures occur in about 10%. Males are usually more affected than females.

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<span class="mw-page-title-main">Alcoholic hepatitis</span> Medical condition

Alcoholic hepatitis is hepatitis due to excessive intake of alcohol. Patients typically have a history of at least 10 years of heavy alcohol intake, typically 8–10 drinks per day. It is usually found in association with fatty liver, an early stage of alcoholic liver disease, and may contribute to the progression of fibrosis, leading to cirrhosis. Symptoms may present acutely after a large amount of alcoholic intake in a short time period, or after years of excess alcohol intake. Signs and symptoms of alcoholic hepatitis include jaundice, ascites, fatigue and hepatic encephalopathy. Mild cases are self-limiting, but severe cases have a high risk of death. Severe cases may be treated with glucocorticoids. The condition often comes on suddenly and may progress in severity very rapidly.

<span class="mw-page-title-main">Liver disease</span> Medical condition

Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.

<span class="mw-page-title-main">Dexmethylphenidate</span> CNS Stimulant

Dexmethylphenidate, sold under the brand name Focalin among others, is a potent central nervous system (CNS) stimulant used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years. It is taken by mouth. The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours. It is the more active enantiomer of methylphenidate.

<span class="mw-page-title-main">Alcoholic polyneuropathy</span> Medical condition

Alcoholic polyneuropathy is a neurological disorder in which peripheral nerves throughout the body malfunction simultaneously. It is defined by axonal degeneration in neurons of both the sensory and motor systems and initially occurs at the distal ends of the longest axons in the body. This nerve damage causes an individual to experience pain and motor weakness, first in the feet and hands and then progressing centrally. Alcoholic polyneuropathy is caused primarily by chronic alcoholism; however, vitamin deficiencies are also known to contribute to its development. This disease typically occurs in chronic alcoholics who have some sort of nutritional deficiency. Treatment may involve nutritional supplementation, pain management, and abstaining from alcohol.

<span class="mw-page-title-main">Holiday heart syndrome</span> Medical condition

Holiday heart syndrome, also known as alcohol-induced atrial arrhythmias, is a syndrome defined by an irregular heartbeat and palpitations associated with high levels of ethanol consumption. Holiday heart syndrome was discovered in 1978 when Philip Ettinger discovered the connection between arrythmia and alcohol consumption. It received its common name as it is associated with the binge drinking common during the holidays. It is unclear how common this syndrome is. 5-10% of cases of atrial fibrillation may be related to this condition, but it could be as high 63%.

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<span class="mw-page-title-main">Acamprosate</span> Medication

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<span class="mw-page-title-main">Organic brain syndrome</span> Disorder of mental function whose cause is alleged to be known as physiological

Organic brain syndrome, also known as organic brain disease, organic brain damage, organic brain disorder, organic mental syndrome, or organic mental disorder, refers to any syndrome or disorder of mental function whose cause is alleged to be known as organic (physiologic) rather than purely of the mind. These names are older and nearly obsolete general terms from psychiatry, referring to many physical disorders that cause impaired mental function. They are meant to exclude psychiatric disorders. Originally, the term was created to distinguish physical causes of mental impairment from psychiatric disorders, but during the era when this distinction was drawn, not enough was known about brain science for this cause-based classification to be more than educated guesswork labeled with misplaced certainty, which is why it has been deemphasized in current medicine. While mental or behavioural abnormalities related to the dysfunction can be permanent, treating the disease early may prevent permanent damage in addition to fully restoring mental functions. An organic cause to brain dysfunction is suspected when there is no indication of a clearly defined psychiatric or "inorganic" cause, such as a mood disorder.

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<span class="mw-page-title-main">Hangover</span> Discomfort following alcohol consumption

A hangover is the experience of various unpleasant physiological and psychological effects usually following the consumption of alcohol, such as wine, beer, and liquor. Hangovers can last for several hours or for more than 24 hours. Typical symptoms of a hangover may include headache, drowsiness, concentration problems, dry mouth, dizziness, fatigue, gastrointestinal distress, absence of hunger, light sensitivity, depression, sweating, hyper-excitability, irritability, and anxiety.

<span class="mw-page-title-main">Alcohol withdrawal syndrome</span> Medical condition

Alcohol withdrawal syndrome (AWS) is a set of symptoms that can occur following a reduction in alcohol use after a period of excessive use. Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever. More severe symptoms may include seizures, and delirium tremens (DTs); which can be fatal in untreated patients. Symptoms start at around 6 hours after last drink. Peak incidence of seizures occurs at 24-36 hours and peak incidence of delirium tremens is at 48-72 hours.

<span class="mw-page-title-main">Short-term effects of alcohol consumption</span> Overview of the short-term effects of the consumption of alcoholic beverages

The short-term effects of alcohol consumption range from a decrease in anxiety and motor skills and euphoria at lower doses to intoxication (drunkenness), to stupor, unconsciousness, anterograde amnesia, and central nervous system depression at higher doses. Cell membranes are highly permeable to alcohol, so once it is in the bloodstream, it can diffuse into nearly every cell in the body.

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<span class="mw-page-title-main">Auto-brewery syndrome</span> Medical condition

Auto-brewery syndrome(ABS) (also known as gut fermentation syndrome, endogenous ethanol fermentation or drunkenness disease) is a condition characterized by the fermentation of ingested carbohydrates in the gastrointestinal tract of the body caused by bacteria or fungi. ABS is a rare medical condition in which intoxicating quantities of ethanol are produced through endogenous fermentation within the digestive system. The organisms responsible for ABS include various yeasts and bacteria, including Saccharomyces cerevisiae, S. boulardii, Candida albicans, C. tropicalis, C. krusei, C. glabrata, C. kefyr, C. parapsilosis, Klebsiella pneumoniae, and Enterococcus faecium. These organisms use lactic acid fermentation or mixed acid fermentation pathways to produce an ethanol end product. The ethanol generated from these pathways is absorbed in the small intestine, causing an increase in blood alcohol concentrations that produce the effects of intoxication without the consumption of alcohol.

<span class="mw-page-title-main">Alcohol (drug)</span> Active ingredient in alcoholic beverages

Alcohol, sometimes referred to by the chemical name ethanol, is a depressant drug that is the active ingredient in fermented drinks such as beer, wine, and distilled spirits. It is one of the oldest and most commonly consumed recreational drugs, causing the characteristic effects of alcohol intoxication ("drunkenness"). Among other effects, alcohol produces happiness and euphoria, decreased anxiety, increased sociability, sedation, impairment of cognitive, memory, motor, and sensory function, and generalized depression of central nervous system (CNS) function.

<span class="mw-page-title-main">Alcohol intolerance</span> Medical condition

Alcohol intolerance is due to a genetic polymorphism of the aldehyde dehydrogenase enzyme, which is responsible for the metabolism of acetaldehyde. This polymorphism is most often reported in patients of East Asian descent. Alcohol intolerance may also be an associated side effect of certain drugs such as disulfiram, metronidazole, or nilutamide. Skin flushing and nasal congestion are the most common symptoms of intolerance after alcohol ingestion. It may also be characterized as intolerance causing hangover symptoms similar to the "disulfiram-like reaction" of aldehyde dehydrogenase deficiency or chronic fatigue syndrome. Severe pain after drinking alcohol may indicate a more serious underlying condition.

References

  1. 1 2 3 4 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 (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. ↑ Díaz Martínez MC, Díaz Martínez A, Villamil Salcedo V, Cruz Fuentes C (2002). "Efficacy of metadoxine in the management of acute alcohol intoxication". The Journal of International Medical Research. 30 (1): 44–51. doi: 10.1177/147323000203000107 . PMID   11921498. S2CID   72850459.
  4. 1 2 Shpilenya LS, Muzychenko AP, Gasbarrini G, Addolorato G (March 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 YM, Kim HE, Ki SH, Kim SG (August 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 J, Parés A, Brú C, Mercader J, García Plaza A, Caballería L, et al. (January 1998). "Metadoxine accelerates fatty liver recovery in alcoholic patients: results of a randomized double-blind, placebo-control trial. Spanish Group for the Study of Alcoholic Fatty Liver". Journal of Hepatology. 28 (1): 54–60. doi:10.1016/s0168-8278(98)80202-x. PMID   9537864.
  7. ↑ Shenoy KT, Balakumaran LK, Mathew P, Prasad M, Prabhakar B, Sood A, et al. (June 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.
  8. 1 2 "Metadoxine extended release (MDX) for adult ADHD". Alcobra Ltd. 2014. Archived from the original on 2014-09-04. Retrieved 2014-05-07.
  9. ↑ "Metadoxine - Drugs.com". Drugs.com. 2014. Archived from the original on 2019-08-17. Retrieved 2014-05-08.
  10. ↑ Wolraich M, Brown L, Brown RT, DuPaul G, Earls M, Feldman HM, et al. (November 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.
  11. 1 2 Manor I, Ben-Hayun R, Aharon-Peretz J, Salomy D, Weizman A, Daniely Y, et al. (December 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.
  12. 1 2 Manor I, Rubin J, Daniely Y, Adler LA (September 2014). "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. S2CID   25669853.
  13. ↑ Weisler R, Adler LA, Rubin J, Daniely Y, Manor I (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. Archived from the original (PDF) on 2016-12-30. Retrieved 2016-12-30.
  14. ↑ "Alcobra ADHD Candidate MDX Fails Phase III Trial | GEN". Archived from the original on 2017-12-28.
  15. 1 2 3 Hersh JH, Saul RA (May 2011). "Health supervision for children with fragile X syndrome". Pediatrics. 127 (5): 994–1006. doi:10.1542/peds.2010-3500. PMID   21518720. S2CID   25190676.
  16. ↑ Garber KB, Visootsak J, Warren ST (June 2008). "Fragile X syndrome". European Journal of Human Genetics. 16 (6): 666–72. doi:10.1038/ejhg.2008.61. PMC   4369150 . PMID   18398441.
  17. ↑ Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, et al. (January 2009). "Advances in the treatment of fragile X syndrome". Pediatrics. 123 (1): 378–90. doi:10.1542/peds.2008-0317. PMC   2888470 . PMID   19117905.
  18. ↑ Tranfaglia MR (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.
  19. ↑ 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.
  20. ↑ Dölen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, et al. (December 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.
  21. ↑ "Alcobra announces results from Phase 2 clinical trial of MDX for Fragile X Syndrome". Alcobra Ltd. 2015. Archived from the original on 2019-02-13. Retrieved 2015-06-24.
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