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FDA approves Alcobra’s protocol for Phase IIb study of metadoxine drug candidate



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The salt pyridoxine-pyrrolidone carboxylate.png



Alcobra Ltd.


Israel-based Alcobra has received approval from the US Food and Drug Administration (FDA) for its protocol for planned Phase IIb clinical study of Metadoxine Extended Release (MDX) drug candidate for the treatment of Fragile X Syndrome.



The multi-center, randomized, placebo-controlled, Phase IIb study, will be conducted primarily in the US and patient enrollment is expected to begin in the near future.

The study is supported by data collected from multiple earlier pre-clinical studies which demonstrated significant improvement in behavioral and cognitive outcomes based on evaluations of memory, learning, and social interaction.



Metadoxine, or Pyridoxol L-2-pyrrolidone-5-carboxylate, whose structure formula is reported hereinbelow


is known for its effectiveness in acute and chronic alcoholism and for the prevention of alcohol related pathology



The salt pyridoxine-pyrrolidone carboxylate.png
Systematic (IUPAC) name
L-Proline, 5-oxo-, compd. with 5-hydroxy-6-methylpyridine-3,4-dimethanol (1:1)
Clinical data
Legal status PHASE 2
Routes Oral, IV
CAS number 0074536-44-0
ATC code N07BB
Chemical data
Formula C13H18N2O6 
Mol. mass 298 g/mol


Metadoxine, also known as pyridoxine-pyrrolidone carboxylate, is a drug used to treat chronic and acute alcohol abuse.[1] Metadoxine improved the clinical signs of acute alcohol intoxication and accelerated alcohol clearance from the blood [2]It is presently in human clinical trials as an attention-deficit/hyperactivity disorder predominantly inattentive treatment.[3]

Pyridoxine is one form of vitamin B6 and a precursor to the metabolically active pyridoxal phosphate. Pyridoxal phosphate is a coenzyme to many enzymes: see vitamin B6 metabolic functions.

Pyrrolidone carboxylate is involved in amino acid metabolism through the glutathione pathway.[4] Glutathione is an important antioxidant and combats redox imbalance. It also supports de novo ATP synthesis.[5]

Alcohol-induced liver diseases are a common disorder in modern communities and societies. For example, in Europe there are more than 45 million individuals showing signs of alcohol-related damage such as liver disease and myopathies. Chronic alcohol consumption increases hepatic accumulation of triglycerides and leads to hepatic steatosis, which is the earliest and most common response to severe alcohol intoxication.

Thus, severe alcohol intoxication is a serious disease that should be treated with medication in order to reduce the damage to the human body of the alcohol intoxicated individual. For example, alcohol intoxication can be treated with metadoxine (pyridoxine L-2-pyrrolidone-5-carboxylate). Metadoxine is a salt of the corresponding anion of L-2-pyrrolidone-5-carboxylic acid (L-2-pyroglutamic acid) (1) and the protonated derivative of pyridoxine (vitamin B6) (2), having the following structures:

(1) (2)

WO 2008/066353 discloses the use of Metadoxine in the treatment of alcohol intoxication either alone or in combination with other active agents. WO 2008/066353 mentions that metadoxine does not inhibit the expression and activation of an alcohol-induced cytochrome P450 2El, which is the key enzyme involved in alcohol-induced toxicity. Thus, the use of metadoxine may be limited.


Several studies have shown that in order to effectively treat alcohol intoxication, there is a need for a relatively high daily dose (ca. 900 mg) administered intravenously (see, e.g., Lu et al. Chin. Med. J. 2007, 120 (2), 155-168 and Shpilenya et al. Alcohol Clin. Exp. Res. 2002, 26 (3), 340-346). These studies disclose side effects associated with the use of metadoxine, including nausea and vomiting.

Thus, there exists a need in the art for effective and safe drugs for treating alcohol intoxication and other associated diseases.



Metadoxine is predominantly used in developing nations for acute alcohol intoxication. 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; Micro HC, India), Viboliv (Dr. Reddy’s, India), and Xin Li De (Zhenyuan Pharm, China).[6]

Fatty liver refers to a pathogenic condition where fat comprises more than 5% of the total weight of the liver. Liver diseases including the fatty liver, hepatitis, fibrosis and cirrhosis are known to be the most serious disease next to cancer causing death in people with ages 40 to 50, in the advanced countries. In advanced countries, nearly about 30% of the population is with fatty liver, and about 20% of people with fatty liver progresses to cirrhosis. About half of the cirrhosis patients die of liver diseases within 10 years after the diagnosis. Fatty liver and steatohepatitis are frequently found in people who intake excessive alcohols and who have obesity, diabetes, hyperlipemia, etc. Among them, alcoholic steatohepatitis (ASH), which is caused by excessive alcohol intake, is at high risk of progressing to hepatitis, cirrhosis and hepatoma, along with non-alcoholic steatohepatitis (NASH).

When taken in, alcohol is carried to the liver and oxidized to acetaldehyde by such enzymes as alcohol dehydrogenase, catalase, etc. The acetaldehyde is metabolized and converted into acetate and is used as energy source. Repeated alcohol intake induces the increase of NADH and NADP+ during the metabolism and acetaldehyde which as the metabolite product of alcohol depletes GSH, thereby changing intracellular oxidation-reduction homeostasis and inducing oxidative stress. Oxidative stress may cause mitochondrial dysfunction, lipid peroxidation and protein modification, thereby leading to death of hepatocytes, inflammation, activation of astrocytes, and the like. In addition, the increase of NADH promotes lipid synthesis, thereby inducing fatty liver.

At present, there are few therapeutically effective drugs for treating fatty liver. Exercise and controlled diet are recommended, but these are not so effective in treating fatty liver. The development of an effective treatment drug is in desperate need. As it is known that fatty liver is related with insulin resistance which is found in diabetes and obesity, the therapeutic effect of some anti-diabetic drugs, e.g., metformin, on fatty liver has been reported. But, the drug has the problem that it may induce adverse reactions such as hepatotoxicity or lactic acidosis. Betaine, glucuronate, methionine, choline and lipotrophic agents are often used as alternative supplementary drug therapy, but they are not fully proven on medical or pharmaceutical basis. Accordingly, development of a fatty liver treatment having superior effect and safety with no adverse reactions is in need.

Metadoxine (pyridoxol 1-2-pyrrolidone-5-carboxylate) is a complex compound of pyridoxine and pyrrolidone carboxylate represented by the formula (1) below:



Metadoxine is a drug used to treat alcoholic liver disease. It is used to treat liver fibrosis and fatty liver through increasing alcohol metabolism and turnover, reducing toxicity of free radicals and restoring the level of ATP and glutathione (Arosio, et al., Pharmacol. Toxicol. 73: 301-304, 1993; Calabrese, et al., Int. J. Tissue React. 17: 101-108, 1995; Calabrese, et al., Drugs Exp. Clin. Res. 24: 85-91, 1998; Caballeria, et al., J. Hepatol. 28: 54-60, 1998; and Muriel, et al., Liver Int. 23: 262-268, 2003).

However, metadoxine is unable to inhibit the expression and activation of alcohol-induced cytochrome P4502E1 (CYP2E1), which is a key enzyme involved in alcohol-induced toxicity, and thus unable to control the augmentation of inflammation mediated by CYP2E1. Therefore, the treatment of alcohol-induced fatty liver using metadoxine is very limited. Further, the expression of CYP2E1 is related with insulin resistance, thus metadoxine cannot not overcome insulin resistance.

Garlic oil is a liquid including about 1% of allicin along with reduced allicin and other sulfur-containing substances. Upon binding to vitamin B1, allicin is turned into allithiamin, which is chemically stable, acts swiftly, and is easily absorbed by the digestive organs. The substance inhibits carcinogenesis induced by chemicals in white rats (Brady, et al., Cancer Res. 48: 5937-5940, 1988; and Reddy, et al., Cancer Res. 53: 3493-3498, 1993), induces phase II enzyme (Hayes, et al., Carcinogenesis 8: 1155-1157, 1987; and Sparnins, et al., Carcinogenesis 9: 131-134, 1988), and inactivates CYP2E1 (Brady, et al., Chem. Res. Toxicol. 4:642-647, 1991). In addition, garlic oil is reported to have antithrombotic, anti-atherosclerotic, antimutagenic, anticancer and antibacterial activities (Agarwal, Med. Res. Rev. 16: 111-124, 1996; and Augusti, Indian J. Exp. Biol. 34: 634-660, 1996).



Treatment for acute alcohol abuse

In an animal model, metadoxine treatment increased the clearance of alcohol and acetaldehyde, reduced the damaging effect of free radicals, and enabled cells to restore cellular ATP and glutathione levels. [7][8] It increases the urinary elimination of ketones, which are formed when the oxidation rate of acetaldehyde into acetate is exceeded on massive alcohol intoxication.[8][4]

As a medical treatment, it is typically given intravenously.

Treatment for AD/HD-PI

Metadoxine is a selective antagonist to the 5-HT2B receptor, a member of the serotonin receptor family.[3] Electrophysiological studies also showed that Metadoxine caused a dose-dependent, reversible reduction in glutamatergic excitatory transmission and enhancement of GABAergic inhibitory transmission, changes that may be associated with cognitive regulation.[3] It is given orally in an extended release pill, which differs from the instant release alcohol treatment.

Treatment for 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.[7]

Treatment for Fragile X Syndrome

Metadoxine treatment led to significant improvement in blood and brain biological markers (AKT and ERK), which may have a role in learning and memory.[3] The study also demonstrated a reduction in the amount of immature neurons and abnormally increased protein levels.[3]




Scheme 1


[0054] In another aspect, the invention provides methods of synthetically preparing, e.g., carboxylated lactam ring of formula (II) (e.g. wherein n=2 for a reactant of formula (IVb) in Scheme 2), carboxylated lactam ring of (III) (e.g. wherein n=3 for a reactant of formula (IVb) in Scheme 2) and carboxylated lactam ring of formula (IV) (e.g. wherein n=4 for a reactant of formula (IVb) in Scheme 2), as depicted in Scheme 2.

Scheme 2


Compound IVb, n=2,3,4

[0055] In another aspect, the invention provides methods of preparing a salt adduct including a positively charged pyridoxine moiety, or a derivative thereof, and a carboxylated 5- to 7-membered lactam ring, including the steps of:

(a) suspending an optionally substituted amino dioic acid in water and heating for a sufficient period of time to allow completing lactamization reaction;

(b) optionally decolorizing the reaction mixture to eliminate impurities;

(c) isolating the lactam carboxylate;

(d) optionally purifying the obtained lactam carboxylate by crystallization;

(e) admixing the obtained lactam carboxylate and a pyridoxine base or a derivative thereof in a solvent mixture optionally under heating; and

(f) isolating the product.

In certain embodiments, a solvent mixture of step (e) includes a mixture of an alcohol such as methanol, ethanol, isopropanol and the like, and water. [0059] According to yet another embodiment, there is provided methods of preparing N-substituted L-pyroglutamic acid and the carboxylate thereof, such as, for example, N-methyl-L-pyroglutamic acid (1-methyl-L-pyroglutamic acid), starting from L-pyroglutamic acid ethyl ester, as depicted in Scheme 3 below. Scheme 3



1-methyl-L-pyroglutamic acid

[0060] The invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 4 below. The starting reagent is 2-methyl-3-hydroxy-4- methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound (V)). The preparation of the corresponding salt is described in Example 1. Scheme 4

HCI NH 3 / MeOH 2 L-pyroglutamic acid

Compound V Compound Vl


Salt lid

[0061] The invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 5 below. The starting reagent in scheme 5 is 2-methyl-3-hydroxy- 4-methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound V). The preparation of the corresponding salt is described in Example 2. Scheme 5


Compound V


Compound VIII IX Compound L-pyroglutamic acid

, SaIt IIe

WO2010150261A1 * June 24, 2010 Dec 29, 2010 Alcobra Ltd. A method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition
WO2011061743A1 * Nov 18, 2010 May 26, 2011 Alcobra Ltd. Metadoxine and derivatives thereof for use in the treatment of inflammation and immune-related disorders
US8476304 Jul 3, 2012 Jul 2, 2013 Alcobra Ltd. Method for decreasing symptoms of alcohol consumption
US8710067 Jul 3, 2012 Apr 29, 2014 Alcobra Ltd. Method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition
WO2008066353A1 * Nov 30, 2007 June 5, 2008 Jae Hoon Choi Pharmaceutical composition comprising metadoxine and garlic oil for preventing and treating alcohol-induced fatty liver and steatohepatitis
WO2009004629A2 * Jul 3, 2008 Jan 8, 2009 Alcobra Ltd A method for decreasing symptoms of alcohol consumption
FR2172906A1 * Title not available
US4313952 * Dec 8, 1980 Feb 2, 1982 Maximum Baldacci Method of treating acute alcoholic intoxication with pyridoxine P.C.A.


  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.
  2. Martinez, Diaz; Villamil Salcedo; Cruz Fuentes (2001). “Efficacy of Metadoxine in the Management of Acute Alcohol Intoxication”. Journal of International Medical Research.
  3. “Metadoxine extended release (MDX) for adult ADHD” (in English). Alcobra Ltd. 2014. Retrieved 2014-05-07.
  4. Shpilenya, Leonid S.; Alexander P. Muzychenko; Giovanni Gasbarrini; Giovanni Addolorato (2002). “Metadoxine in Acute Alcohol Intoxication: A Double-Blind, Randomized, Placebo-Controlled Study”. Alcoholism:Clinical and Experimental Research.
  5. Shull, Kenneth H.; Robert Kisilevsky (1996). “Effects of Metadoxine on cellular status of glutathione and on enzymetric defence system following acute ethanol intoxication in rats”. Drugs Exp Clin Res.
  6. “Metadoxine –” (in English). 2014. Retrieved 2014-05-08.
  7. Yang, YM; HE Kim; SH Ki; SG Kim (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.
  8. Calabrese, V; A Calderone; N Ragusa; V Rizza (1971). “Effects of l-2-pyrrolidone-5-carboxylate on hepatic adenosine triphosphate levels in the ethionine-treated rat”. Biochemical Pharmacology.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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