INTERNATIONAL JOURNAL OF IMMUNOI'ATIIOLOGY AND I'IIARMACOLOGY Vol. 16, no. 3, 207·214 (2003)

REVIEWARTICLE METADOXINE IN THE TREATMENT OF ACUTE AND CHRONIC ALCOHOLISM: A REVIEW

G. ADDOLORATO, C. ANCONA, E. CAPRISTO and G. GASBARRINI

Institute ofInternal Medicine, Catholic University ofRome, Italy

Received February 27, 2003 - Accepted August 5, 2003

Alcohol abuse and alcoholism are responsible for a wide variety of medical problems. The pharmaco­ therapeutic aspect of alcoholism includes the use of drugs, with different actions and objectives. Among them, metadoxine seems to be of interest. Metadoxine is able to accelerate the elimination of alcohol from the blood and tissues, to help restore the functional structure of the liver and to relieve neuro-psychological disorders associated with alcohol intoxication. Metadoxine also seems to be safe; in more than 15 years of post-marketing surveillance only minor aspecific and reversible events were monitored in patients exposed to the treatment. In this review the preclinical and clinical results obtained using metadoxine in acute and chronic alcohol intoxication are reported.

Alcoholism is a multifactorial disorder in which major contributing factors to road accidents, suicide biologic and genetic factor interact along withcultural and violent death in young adults (11). and social factors (1,2). Alcohol addiction represents The pharmaco-therapeutic aspect of alcoholism a social problem and a relatively common disease of includes the use of drugs, with different actions and western countries like Europe and the USA. From 20 objectives (12). Among them, metadoxine seems to to 40% of subjects admitted to hospitals have alcohol­ be of interest. The present review evaluates the related problems (3) and in elderly people alcohol­ pharmacology and the therapeutic use ofmetadoxine related disorders represent as frequent a reason for (figure I), a drug promoted for the treatment of acute hospitalization as myocardial infarction (4). and chronic alcohol intoxication and alcoholic liver The most lasting damaging actions of ethanol disease. are exerted on the liver function and structure (5). A liver disease is often present in patients affected by Enzymatic activity ofMetadoxine compounds alcohol abuse and/or alcoholism; however the Metadoxine is formed by the salification of two mechanisms responsible for the liver toxicity of components, pyrrolidone carboxylic acid (PCA) and ethanol are still not completely understood (6). pyridoxol, in a single product. PCA is usually present Ethanol also modifies the GABA-mediated in the diet and produced endogenously by enzymatic neurotransmission (7). Probably it preferentially conversion of the gammaglutamyl amino acids to stimulates the dopaminergic transmission in the PCA and free amino acids in several mammalian mesolimbic system (8), interferes withserotoninergic tissues, including the central nervous system, where transmission (9) and with the release of glutamate in ithasaroleinthecompositionof neuroactivemolecules the central synapses (10). The neuropathological (13). PCA is an intermediate in the gammaglutamyl manifestations usually appear after many years of cycle, it is transformed into glutathione by two excessive drinking. In addition to the effects of subsequent reactions catalyzed by gamma­ alcohol on the nervous system, it may be one of the glutamylcysteinesynthetaseandglutathion synthetase

Key words: nietadoxine, alcoholism, acute and chronic alcohol intoxication

Mailing address: Dr. Giovanni Addolorato 0394-6320 (2003) Institute of lnterrnal Medicine, Catholic University of Rome Copyright © hy BIOLlFE, s.a.s.. This publicationand/urarticle is fur individualusc only and may not he further Largo A.Gemelli 8,00168 Rome, Italy. reproduced without writtenpermission fromthecopyright holder. Phone +39-06- 30154334. Fax +39-06-35502775 Unauthorized reproduction mayresultin financial amiotherpenalties e-mail: g.addoloratotsm.unicau.it 207 208 G. ADDOLORATO ET AL.

respectively, and its production is linked to the probably synthesised via the g-glutamil cycle. (21). gammaglutamyl transferase activity of the liver cell Excretionoccursapproximatelyinthesameproportion membraneandto hepaticlevelsof reducedglutathione through the urine and the feces, between 40 and 45% (GSH) (14).It hasalso beenshownthatPCAfacilitates in 24 hours in the urine, and between 35 and 50% in ATP synthesis by stimulating the "de novo" synthesis 96 hours in the feces (21). This information justifies of the purine nucleotide. (15). Pyridoxol is aprecursor the dosage scheme recommended for the therapeutic of coenzymes such as pyridoxal phosphate which use in humans. accelerates the metabolic degradation of ethanol and prevents ATP inactivation by acetaldehyde, the main Preclinical studies ethanol metabolite (16). Metadoxine has been shown to induce profound In Metadoxine PCA and Pyridoxol are linked by alterations of alcohol metabolism in rats. It increases salification and in this form their pharmacological the activity of acetaldehyde dehydrogenase and properties seem to be synergic as shown by their preventsthedecreaseinalcoholdehydrogenaseactivity superior activity when given together, with respect shown in chronic ethanol fed rats (22,23). Its to separate administration (17,18). administration accelerates plasma and urinary clearance of ethanol and acetaldehyde in a dose­ Pharmacokinetic profile dependent manner (22). The accelerated urinary Metadoxine exerts a metabolic effect, the clearance could be due to the inhibiting effect of efficiencies of which depend on the presence of both metadoxine on the formation of macroaggregates moieties, pyridoxine (PDX) and pyrrolidone between albumin and acetaldehyde shown in alcohol carboxylate (PCA); in the same tissue with the same treated rats. Metadoxine significantly inhibits the profile, and both in concentrations able to trigger the increase of fatty acid esters in the liver of ethanol metabolic biotransformations in which they are treated rats (24), restoring the correct ratio between implicated. Pharmacokinetic studies have been hepatic saturated and unsaturated fatty substances performedinrats,dogs,monkeyandhealthyvolunteers (25). At 160 mg/kg, Metadoxine also prevented the (\ 8-20). These studies mainly showed that the oral formation of fatty liver in 50% of rats exposed to a absorption ofthedrugisfast,withhighandreproductive dose of ethanol able to induce fatty liver in 100% of absolutebioavailability(60to80%)andwithextensive the rats in the control group (23). tissue distribution, as shown by the large apparent In normal untreated rats, Metadoxine has been distribution volume. The half-life is 40 to 60 minutes shown to increase hepatic ATP content through an without appreciable differences between oral or activation of the purine "de novo" synthesis (15,17), intravenous administration. The kinetic profile is and in hepatocytes of acutely and chronicaIly alcohol specific to metadoxine as such. The extemporaneous intoxicated rats it is able to restore the activity of the administration of the two individual components can aldehyde dehydrogenase and to increase the reduced not compete in terms of the blood concentration, thus glutathione levels (26). Pretreatment of animals with of tissue distribution and ultimately of therapeutic Metadoxine one hour before ethanol administration effect, with Metado·xine. produced significant protection against glutathione . This is the consequence of Metadoxine being an depletion and oxidoreductive stress in hepatic and ion-pair, and was very easily seen comparing the extrahepatictissue(27,28),andanincrementin alcohol kinetic profile of pyridoxine administered as a metabolism and turnover (25). Recently Metadoxine component of Metadoxine, with that of the same has been shown to prevent glutathione depletion, pyridoxine administered alone (21), which yields lipid peroxidation damage, coIlagen deposition and lower concentrations with a very long delay. TNF alf'a secretions induced by alcohol and The identified metabolites are those expected acetaldehyde in hepatocytes and hepatic steIlate ceIls from the metabolism of glutamate and of pyridoxine. (29) These mechanisms could be implicated in the In particular, the radioactivity given with metadoxine ability of Metadoxine to prevent hepatic wasfound in glutamate, glutamine, glutamylcysteine, necroinflammation, fibrosis and progression to glutathione, a-ketoglutarate, pyridoxal, pyridoxal cirrhosis in rats chronically exposed to hepatotoxic phosphate and pyridoxamine. Approximately 12% agents as shown in rat models of hepatic cirrhosis of total radioactivity wasfound inpeptide derivatives, (14,30) (Fig. 2). loL J. Immuoopalhol. Phanoacol. 209

OH Fig. 1. Chemical structure of metadoxine (pyridoxine L-2-pyrrolidone-5-carboxylate). (Modifiedfrom: Metadoxine. Drugs ofToday 1988; 24:217-219) N coo- H~ i H

60 , ------Fig. 2. Serum levels (Itg/ml: meanti:standarddeviations) of immunoreactive prolyl 50 hydroxylase (SIRPH). The

CCL 4-treated animals have 40 significantly higher SIRPH than controls or rats protectedwith metadoxine. (Modified from: 30 AnnoniG, Contu L, Tronci MA, et al PyridoxolL, 2-Pyrrolidon­ 20 5 Carboxylate prevents active fibroplasia in CCl4-treated 10 ra~.PharmacoIRes1992,25 (1): 87-93) O -l-_ ---l ---L..__-.--__..L-__---l.__----.__...l- L-_

Controls CCl4 CCl4 treated with metadoxine

Fig. 3. Proportion ofpatients who started to recover (decrease ofblood alcohol concentration by at least one category) from acute alcohol intoxication within 1 hr after treatment with metadoxine or placebo. With metadoxine the proportion was 62.1% (59% CI: 43 to 100 ------l 79%); with placebo it was 17.2% (95% CI: 6 to 37%). The difference inproportion ...... · ·· ·· ·· ·· ·· ··· ····· · ·· · · ···· ··· · ·· · · · · ··· ·1 80 is statistically significant I (0.0013) and corresponds ...... 1 to 44.8 ± 11.4 % (95% CI: 60 22 to 67%), yelding a NNT of2 (95% CI: 1 to 5). I ...... ·························· ··· ··· ····· ··· ··1 (Modifiedfrom: Shpilenya 40 , LS, Muzy chenko AP, Gasbarrini G. Addolorato G: Metadoxine in Acute 20 Alcohol Intoxication: A Double-Blind, Randomized, Placebo-ControlledStudy. o Alcohol Clin Exp Res 2002, Metadoxine Placebo 26:340-346) 210 G. ADDOLORATO ET AL.

Symptom Time Metadoxine Placebo

Agitation a 1.83 ± 0.80 2.31 ±0.76 0.5 1.83 ± 0.85 2.3H 0.72 1 1.03± 0.82 1.86 ± 0.92 2 0.52 ± 0.69 1.28 ± 0.88 3 0.17 ± 0.38 0.82 ± 0.82 6 O.OO± 0.00 0.50± 0.64 9 0.00 ± 0.00 0.11 ± 0.31 12 0.00 ± 0.00 O.OO± 0.00 plor differencein time course (repealed-measures ANOVA) 0.001 Aggressivebehavior a 0.66 ± 0.77 1.76 ± 0.99 0.5 0.55 ± 0.95 1.83 ± 1.00 1 1.00 ± 0.71 1.41 ± 0.95 2 0.41 ± 0.68 0.76 ± 0.79 3 0.07 ± 0.26 0.50 ±0.84 6 O.OH 0.19 0.14 ± 0.36 9 0.00 ± 0.00 0.00 ± 0.00 12 0.00 ± 0.00 0.00 ± 0.00 p for differencein time course (repeated-measures ANOVA) 0.400 Impairedmentalfunction 0 2.10 ± 0.72 2.62 ± 0.56 0.5 01.28 ± 0.75 2.48 ±0.83 1 1.62 ± 0.68 2.31 ± 0.97 2 1.10±0.77 1.83 ± 0.89 3 0.76 ± 0.83 1.50 ±0.79 6 0.36 ± 0.56 0.61 ± 0.63 9 0.07 ± 0.26 0.29± 0.53 12 0.03 ± 0.19 0.18 ± 0.67 p for differencein time course (repeated-measures ANOVA) 0.016 Jerky movements a 0.90 ± 0.67 0.90± 0.90 0.5 0.62 ± 0.73 0.72 ± 0.88 1 0.54 ± 0.88 0.45 ± 0.74 2 0.10 ± 0.31 0.21 ± 0.49 3 0.10±0.41 0.07 ± 0.38 6 0.04 ± 0.19 0.04 ± 0.19 9 O.OH 0.19 0.00 ± 0.00 12 0.00 ± 0.00 0.00 ± 0.00 p for differencein time course (repealed-measures ANOVA) 0.873 Drowsiness 0 0.38 ± 0.78 0.38 ± 0.62 0.5 0.45 ± 0.83 0.41 ± 0.68 1 0.93 ± 0.92 0.76 ±0.79 2 1.14 ± 0.99 0.79 ± 0.82 3 1.59 ± 0.87 U8± 0.94 6 1.54 ± 0.79 1.32 ± 0.82 9 1.41±1.05 1.82± 1.16 12 1.76±1.12 1.93+ 1.18 P for differencein time course (repealed-measures ANOVA) 0.199 '; ~ .~ -

Tab. 1. Time course ofindividual symptom intensity (Mean ± SD) during observation. (Modifiedfrom: Shpilenya LS, Muzychenko AP, Gasbarrini C. Addolorato C: Metadoxine in Acute Alcohol Intoxication: A Double-Blind, Randomized, Placebo-Controlled Study. Alcohol Clin Exp Res 2002,'26:340-346)

Metadoxine Placebo p (n=57) (n=54) Bilirubin (mg/dl) - 0.79±1.1 - 0,41±0.7 n.s. AST (U1l) - 103.9±60.8 - 33.2±46.7 <0.001 ALT (U/l) - 85.8±60.5 - 24.9±44,4 <0.001 Gamma GT (U/I) - 335,4±323.1 - 119.1±220.5 <0.001 Alkaline phosphatase (UIl) - 139.6±221.1 - 27.8±86.8 <0.001 Prothrombin index (%) + 8.82±15.8 + 4,42+10.6 <0.05

Tab. II. Mean differences between the initial andfinal main laboratory data ofpatients treated with metadoxine and placebo. (Modifiedfront: Caballeria J. Pares A, Bru C, et al: Metadoxine acceleratesfatty liver recover)' in alcoholic patients: results ofa randomized double-blind, placebo-control trial. J Hepatol 1988; 28: 54-60) Int. .I. Immunopathol. Pharmucol. 211

The central nervous system (CNS) activity of (300 mg i.v.) and were re-examined at 2 hours metadoxine has been studied in relation to CNS ATP experienced a significantly higher improvement on a content, neuroacti ve molecu Ie release and clinical scale based on somatic and psychological neuropsychologic effects. Ethanol by systemic route symptoms with respect to the control group; these causes ATP decrease in brain cells by approximately results seem not to be directly dependent on ethanol 50%. Pre-treatment with metadoxine (50 mg/kg) not blood levels that were lower in the metadoxine group only completely prevented such a drop in ATP level, but this parameter reached statistical significance in but even resulted in an increase lasting more than only one trial. (43,44). In a double-blind controlled two hours (17). Metadoxine administration increases clinical trial versus placebo, our group has recently the release of GABA and Acetylcholine from the studied the effect of a single intravenous injection of frontoparietal cortex of freely moving guinea-pigs metadoxine (900 mg) on acute alcohol intoxication: (31) and in mice it has been shown to increase clinical symptoms decreased more rapidly in the dopaminelevelsinstriataltissue(32).Asaconsequence metadoxine group (table I) and the recovery from of the interactions with CNS neurotrasmitters intoxication began after a median time of 0.95 hours Metadoxine has shown neuro-psychological effects with metadoxine and 2.34 hours with placebo (figure on animals.Inrats,ontheother hand,theadministration 3);theproportionofcompletelysymptom-freepatients of Pyrrolidone-carboxylic acid has shown dose­ was significantly higher after treatment with dependentanxiolyticeffects(33,34)andanantagonistic metadoxine in comparison with standard treatment effect on ethanol locomotor-stimulant response in alone; once again, these results seem not only related mice (35). to ethanol blood level but also may be related to the effects of metadoxine on the CNS (45). CLINICAL STUDIES Withdrawal syndrome Acute Alcohol Syndromes: acute intoxication In a double blind controlled clinical trial, Bono In acute alcohol intoxication Metadoxine has has demonstrated the efficacy of metadoxine in the been shown to reduce the T/2 of ethanol in healthy treatment of the alcohol withdrawal syndrome. In volunteers (36) and in acutely intoxicated patients, two groups treated with bromazepam as needed and where it is significantly reduced from 7 hours and 15 either metadoxine (900 mg i.v. bid) or pyridoxine in min. to 5 hours and 50 min (37). This drug has also an equivalent dose for ten days, the metadoxine been shown to accelerate the biotrasformation of group showed a significantly higher decrease rate of alcohol and acetaldehyde into definitely less toxic somatic and psychological signs and symptoms and higher ketones, to improve the urinary clearance of asignificantly lowerneedforbenzodiazepinecompared these compounds (38) and to restore laboratory to the control group (46). variables such as alcohol, ammonia, gamma-GT and ALT (39). CHRONIC ALCOHOL ABUSE As in rats metadoxine has been shown to have an AND ALCOHOLISM anxiolytic-like effect on man exposed to a conflict Maintaining abstinence situation (40).In alcohol intoxicatedpatientsitinduces In chronic alcohol abuse and alcoholism a significant improvement in symptoms such as Metadoxine has been studied with respect to its psychomotor agitation, depression, aggressiveness, abiIityto inducealcohol abstinence through apossible sopor and equilibrium disorders, with respect to a reduction in craving and to ameliorate the clinical control group treated with supportive measures, features of alcoholism and the laboratory alterations multivitamins and electrolyte preparations, and histopathological signs of chronic alcohol Chlordiazepoxide or Valproate (41,42). assumption. In two double-blind clinical trial versus In two recent double-blind controlled clinical placebo metadoxine has been shown to improve the trials metadoxine was compared to a conventional maintenance of abstinence and to reduce alcohol treatment (parenteral solutions, multi-vitamin intake and the requirement ofbenzodiazepine andlor preparations, BDZ or neuroleptics as appropriate) neuroleptics(47,48).Inchronic alcoholicsmetadoxine for acute alcohol intoxication in the emergency unit; is, jhus hypothesized to induce a redaction of the thepatients, whoreceived a single dose ofmetadoxine craving for alcohol (47,49). However future studies 212 G. ADDOLORATO ET AL. are needed to confirm these findings and clarify the administration (45), a non-specified gastrointestinal possible anti-craving mechanisms. problem that the authors did not relate in a causal Symptoms and laboratory parameters manner to the drug (54) and a self-limiting case of The combination of pyridoxine-pyrrolidon­ diarrhoea (55). carboxylate with benzodiazepine in alcohol abusers has been shown to restore the clinical picture with a CONCLUSIONS significant improve of anxiety, mood and thinking disorders, of the sleep/awake rhythm and of the In the lastfewyears metadoxine hasdemonstrated dietarypatternwithrespecttobenzodiazepine treatment a number of effective actions in modifying alcohol alone (50-51). Metadoxine alone has also been shown metabolism, in reducing toxic effect of acute and to reduce the Munich Alcoholism Test I and 2 score chronic abuse of alcohol and in breaking the addiction and to improve insomnia, anxiety and mood disorders to ethanol. versus placebo in double-blind trials (47,48). Due to its safe and manageable pharmacology In abstinent alcoholics, Sinforiani demonstrated profile, Metadoxine could be one of the first drugs that metadoxine is able to induce a more marked for physicians who deal with patients with alcohol improvementincognitivefunctionsandtestsexploring problems, especially in the acute setting of the short-term memory after one month of treatment Emergency Unit, where it makes it possible to acce­ than a conventional Vit B6 treatment (52). lerate clinical and metabolic recovery from Several studies have shown the ability of intoxication, with a single administration and without metadoxine to reduce indices of liver cells necrosis any additional workload for the treatment centre. (AST and ALT), cholestasis indices (gammaGT and bilirubin) and/or haematologic disorders (MCV) in ACKNOWLEDGEMENTS double-blind trials versusplacebo (34,47,53,54)(table 2), versus Vit B6 (56) and versus Tiapride (57). 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