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Also known as pyridoxine-pyrrolidone carboxylate, it is a drug used to treat chronic and acute alcohol intoxication.
Metadoxine accelerates the removal of alcohol from the blood.
Metadoxine is a salt of an ion pair of pyridoxine and pyrrolidone carboxylate (PCA).
Pyridoxine (vitamin B6) is a precursor to coenzymes, including pyridoxal 5′-phosphate (PLP), which accelerates the metabolic breakdown of ethanol and prevents the inactivation of adenosine triphosphate (ATP) by acetaldehyde.
Pyridoxal phosphate-dependent enzymes also play a role in the biosynthesis of four important neurotransmitters: serotonin (5-HT), epinephrine, norepinephrine, and gamma-aminobutyric acid.
L-PGA is present in the diet and is produced endogenously by the 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 play a role in the composition of neuroactive molecules.
Its production has been linked to liver gamma-glutamyl transferase activity and reduced glutathione (GSH) levels. Finally, L-PGA was shown to facilitate adenosine triphosphate synthesis by stimulating de novo purine synthesis.
Functions of vitamin B6
Pyridoxal phosphate, the metabolically active form of vitamin B6, is involved in macronutrient metabolism, neurotransmitter synthesis, histamine synthesis, hemoglobin synthesis and function, and gene expression.
Pyridoxal phosphate generally serves as a coenzyme (cofactor) for many reactions, including decarboxylation, transamination, racemization, elimination, replacement, and interconversion of the beta group. The liver is the site for the metabolism of vitamin B6.
Amino acid metabolism
Pyridoxal phosphate is a cofactor in the biosynthesis of five major neurotransmitters: serotonin, dopamine, epinephrine, norepinephrine, and gamma-aminobutyric acid (GABA). Pyridoxal phosphate is also involved in the synthesis of histamine.
Transaminases break down amino acids with pyridoxal phosphate as a cofactor. The proper activity of these enzymes is crucial to moving amine groups from one amino acid to another.
The serine racemase that the neuromodulator d-serine synthesizes from its enantiomer is a pyridoxal phosphate-dependent enzyme.
Pyridoxal phosphate is a coenzyme necessary for the proper function of the enzymes cystathionine synthase and cystathionase. These enzymes catalyze reactions in the catabolism of methionine. Part of this pathway (the reaction catalyzed by cystathionase) also produces cysteine.
Selenomethionine is the primary dietary form of selenium. Pyridoxal phosphate is necessary as a cofactor for enzymes that allow selenium to be used in the dietary form.
Pyridoxal phosphate also plays a role as a cofactor in releasing selenium from selenohomocysteine to produce hydrogen selenide, which can then be used to incorporate selenium into selenoproteins.
Pyridoxal phosphate is required to convert tryptophan to niacin, so the low level of vitamin B6 impairs this conversion.
Glucose metabolism
Pyridoxal phosphate is a required coenzyme of glycogen phosphorylase, the enzyme necessary for glycogenolysis to occur.
Pyridoxal phosphate can catalyze transamination reactions essential to providing amino acids as a substrate for gluconeogenesis.
lipid metabolism
Pyridoxal phosphate is an essential component of the enzymes that facilitate the biosynthesis of sphingolipids. Notably, the synthesis of ceramide requires pyridoxal phosphate.
In this reaction, serine decarboxylates and combines with palmitoyl-CoA to form sphinganine, which combines with a fatty acyl-CoA to create dihydroceramide. The dihydroceramide was further desaturated to form ceramide.
Furthermore, the breakdown of sphingolipids is also dependent on vitamin B6, as sphingosine-1-phosphate lyase, the enzyme responsible for breaking down sphingosine-1-phosphate, is also dependent on pyridoxal phosphate.
Synthesis and function of hemoglobin
Pyridoxal phosphate aids in the synthesis of hemoglobin by serving as a coenzyme for the enzyme aminolevulinic acid synthase. It also binds to two sites on hemoglobin to enhance the oxygen binding of hemoglobin.
Gene expression
Pyridoxal phosphate has been implicated in increasing or decreasing the expression of specific genes. Increased intracellular levels of the vitamin lead to a decrease in glucocorticoid transcription.
Furthermore, vitamin B6 deficiency leads to increased gene expression of albumin messenger RNA (mRNA).
Furthermore, pyridoxal phosphate influences the expression of glycoprotein IIb by interacting with various transcription factors. The result is the inhibition of platelet aggregation.
Side effects of methadone
Metadoxine is used to treat severe and long-term alcohol intoxication. This medicine works by speeding up the removal of alcohol from the blood.
It is also being used today to treat ADHD (attention deficit hyperactivity syndrome) and fragile X syndrome.
Side effects or unfavorable reactions do not always occur during treatment with methadone, confirming the safety of this molecule.
But it has been reported that when using Metadoxine, you may experience side effects of diarrhea, rash, drowsiness, and numbness. If your reactions don’t go away, even after a few days, see your doctor right away.
Before starting your treatment with Metadoxine, talk to your doctor if:
Are you taking prescription or non-prescription medications, vitamins, herbal and dietary supplements, pregnant, planning to become pregnant, breastfeeding a baby, or have been scheduled for surgery shortly.
The dose of Metadoxine is determined by your doctor, taking into account your age, gender, medical history, current condition, and responses to treatment.
The prescribed dose is about 500-1000 mg per day. Try to take your doses at the same time each day.
Medical uses
As a treatment for alcohol poisoning and liver disease, methadone is usually given intravenously as an immediate-release formulation.
Acute alcohol poisoning
In clinical studies, methadone has been reported to reduce the half-life of ethanol in healthy volunteers and patients with acute poisoning.
To accelerate the metabolism of alcohol and acetaldehyde into less toxic higher ketones and improve your urinary clearance.
To restore laboratory variables such as alcohol, ammonia, γ-GT, and alanine aminotransferase; and improve the clinical symptoms of alcohol intoxication, including psychomotor agitation, depression, aggression, and balance disorders.
There is also evidence that methadone’s effects reduce the desire for alcohol.
Data from clinical studies also support the effect of methadone in reducing rates of liver cell necrosis and fat accumulation in alcoholic fatty liver.
Liver disease
Metadoxine can block the differentiation step of preadipocytes by inhibiting CREB phosphorylation and binding to the response element cAMP, thereby repressing CCAAT / enhancer-binding protein b during hormone-induced adipogenesis.
Metadoxine, administered in the immediate-release form at doses of 300 mg twice daily to 500 mg three times daily for three months, has been shown to improve biochemical indices of liver function and reduce the ultrasonic evidence of liver disease. Fatty liver.
Pharmacology
Alcohol abuse and alcoholism are responsible for a wide variety of medical problems. The pharmacotherapeutic aspect of alcoholism includes drugs with different actions and objectives.
Among them, methadone appears to be of interest. Metadoxine can accelerate the elimination of alcohol from the blood and tissues to help restore the functional structure of the liver and alleviate the neuro-psychological disorders associated with alcohol intoxication.
Metadoxine also appears to be safe; In more than 15 years of post-marketing surveillance, only specific and irreversible minor events were monitored in patients exposed to treatment.
Mechanism of action
Metadoxine is a selective antagonist of the serotonin 5-HT2B receptor subtype and shows a high affinity for the gamma-aminobutyric acid transporter.
The in vitro enzyme assay revealed that methadone reduced the activity of the gamma-aminobutyric acid transaminase enzyme responsible for the degradation of gamma-aminobutyric acid.
Electrophysiological studies showed that methadone increased inhibitory GABAergic synaptic transmission through a presynaptic effect.
Because it does not affect dopamine, norepinephrine, or serotonin levels, methadone exhibits a novel mechanism of action as a monoamine-independent gamma-aminobutyric acid modulator.
In animal studies, methadone increased the activity of the enzyme acetaldehyde dehydrogenase and prevented the decrease in the exercise of alcohol dehydrogenase in ethanol-fed rats.
It accelerated plasma and urinary ethanol clearance, inhibited the increase in fatty acid esters in the liver of ethanol-treated rats, and 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 rats acutely and chronically intoxicated with alcohol.
It prevented glutathione depletion, lipid peroxidation damage, collagen deposition, and TNF Alcohol- and acetaldehyde-induced α secretions in hepatocytes and liver stellate cells.
History
Metadoxin is predominantly used as an immediate-release formulation of methadone in developing countries for acute alcohol intoxication and chronic alcoholic liver disease. Alternative names include:
- Abrixone (Eurodrug, Mexico). Alcatel (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). Allouez ІС (Ucrania). Viboliv (Dr. Reddy’s, India). EXTOL (Next Labs, India). Xin Li De (Zhenyuan Pharm, China).
Investigation
Hyperactive disorder and attention deficit
Attention deficit hyperactivity disorder, is one of the most common neurobehavioral disorders of childhood and is among the most prevalent chronic health conditions affecting school-age children.
The main symptoms of attention deficit hyperactivity disorder include inattention, difficulty staying focused, hyperactivity, and impulsivity.
Metadoxin showed a cognition-enhancing effect in the rat social recognition animal model.
An extended-release formulation of methadone (MDX), which combines immediate and slow-release formulations of methadone in a single oral dose, was developed to prolong the drug’s half-life and allow the use of methadone in indications requiring more treatment. Prolonged, such as disorders related to cognitive impairment.
Metadoxine has shown significant and clinically significant improvements in multiple measures of cognition, symptoms of attention deficit hyperactivity disorder, and quality of life in various studies of adults with attention deficit hyperactivity disorder.
Several studies of attention deficit hyperactivity disorder in Phase II demonstrated a consistent efficacy signal that reached statistical significance.
It is measured by neuropsychological tests (such as the Computerized Variables of Attention Test (PVA) in acute settings) and clinical scales (in chronic administration studies).
There are no treatment-related severe adverse events or significant differences in negative event profiles between drug and placebo groups.
The most common adverse events were nausea, fatigue, and headache. A phase 3 study in 300 adults with attention deficit hyperactivity disorder was completed in 2014.
Alcobra Ltd., which was conducting the Phase III trial, announced on January 17, 2017, that the drug had failed the test.
The announcement of the failure came a week after Alcobra won the Food and Drug Administration’s agreement to review the collected data and consider it in a future presentation for attention deficit hyperactivity disorder.
The Food and Drug Administration also agreed to change a full clinical hold to a partial clinical hold for the trial.
Pending review and approval of the protocol proposed by the company for a 6-month Phase I study to assess the potential relevance of the adverse long-term findings observed.
Long-term animal studies of metadoxin about human exposure, Alcobra said.
X fragile syndrome
Fragile X syndrome (FXS) is a genetic disorder that is the most common genetic cause of intellectual disability and autism.
People with Fragile X syndrome often have several behavioral symptoms, including cognitive impairment, inattention, hyperactivity, impulsivity, autistic symptoms, shyness, aggression, anxiety, hand flapping, hand biting, and high sensitivity to Contact.
Autism spectrum disorder is seen in approximately 30% of men and 20% of women with Fragile X syndrome. An additional 30% of people with Fragile X syndrome show autistic symptoms without being diagnosed with autism.
Attention deficit hyperactivity disorder is commonly diagnosed in Fragile X syndrome and reported in 59-80% of people with Fragile X syndrome.
In an animal model with Fragile X syndrome (Fmr1 knockout mouse model), treatment with methadone improved:
- The behavioral problems of learning, memory, and social interaction reversed the overactivation of Akt biomarkers and extracellular signal-regulated kinase (ERK) in the blood and brain of juvenile and adult mice.
- Metadoxin also demonstrated the restoration of abnormal neuronal morphology and reduced the excessive production of basal proteins, both implicated in the pathophysiology of fragile X syndrome and are presumed to be responsible for impaired learning and memory.
