Pyridoxine in Clinical Toxicology: a Review Philippe Lheureux, Andrea Penaloza and Mireille Gris

78 Review

Pyridoxine in clinical toxicology: a review Philippe Lheureux, Andrea Penaloza and Mireille Gris

Pyridoxine (vitamin B6) is a co-factor in many enzymatic controversial. This paper reviews the various indications pathways involved in amino acid metabolism: the main of pyridoxine in clinical toxicology and the supporting biologically active form is pyridoxal 5-phosphate. literature. The potential adverse effects of excessive Pyridoxine has been used as an antidote in acute pyridoxine dosage will also be summarized. intoxications, including isoniazid overdose, Gyromitra European Journal of Emergency Medicine 12:78–85 mushroom or false morrel (monomethylhydrazine) c 2005 Lippincott Williams & Wilkins. poisoning and hydrazine exposure. It is also recommended as a co-factor to improve the conversion of glyoxylic acid European Journal of Emergency Medicine 2005, 12:78–85 into glycine in ethylene glycol poisoning. Other indications Keywords: Antidotes, crimidin, drug-induced neuropathy, ethylene glycol, are recommended by some sources (for example crimidine hydrazine, isoniazid, metadoxine, pyridoxine poisoning, zipeprol and theophylline-induced seizures, adjunct to d-penicillamine chelation), without significant Department of Emergency Medicine, Erasme University Hospital, Brussels, Belgium. supporting data. The value of pyridoxine or its congener Correspondence to Philippe Lheureux, Department of Emergency Medicine, metadoxine as an agent for hastening ethanol metabolism Erasme University Hospital, 808 route de Lennik, 1070 Brussels, Belgium. or improving vigilance in acute alcohol intoxication is E-mail: [email protected]

Introduction ing. More controversial issues include alcohol intoxication Pyridoxine or vitamin B6 is a highly water-soluble and zipeprol or theophylline-induced seizures. vitamin. Its main biologically active form is a phosphate ester of its aldehyde form, pyridoxal 5-phosphate (P5P). The purpose of this paper is to review the literature It plays a major role in many biological pathways, allowing supporting these indications as well. the proper functioning of over 60 enzymes, especially involved in amino acid metabolism including decarbox- Isoniazid overdose ylation, desamination, transamination and transsulphura- Isoniazid has been used as a first-line agent for the tion. Examples are the metabolism of tryptophan to prophylaxis and treatment of tuberculosis since 1952. It niacin, methionine to cysteine and glutamic acid to undergoes nearly complete gastrointestinal absorption, is gamma-aminobutyric acid (GABA). The normal adult poorly protein bound ( < 10%), and has a short elimina- needs (1–2 mg/day) are usually fully provided by nutri- tion half-life (0.7 h or 2–4 h in rapid or slow acetylators, tional sources, especially meats and vegetables, but respectively); 75–95% of the ingested dose is eliminated requirements are increased during pregnancy. In addition, as metabolites in urine within 24 h [1]. some individuals are likely to suffer pyridoxine deficiency, including malnourished patients, those with HIV infec- Acute life-threatening toxicity may develop rapidly tion, alcoholism, or diabetes, or those taking drugs or (30–45 min after ingestion), but is usually short lived exposed to substances that promote pyridoxine depletion (less than 24 h). Although acute ingestions of 20 mg/kg (isoniazide, cycloserine, hydralazine, phenelzine, penicil- (approximately 1.5 g in adults) usually result in only mild lamine, theophylline, carbon disulphidey). toxicity, ingestions greater than 30 mg/kg may produce generalized tonic–clonic seizures [2]. Higher doses Pyridoxine hydrochloride is available as an antidote, in ( > 80 mg/kg, 10–15 g in adults) are responsible for the form of ampoules (commonly 100 mg/2 ml and 200 or recurrent seizures, lactic acidosis and coma, the classical 250 mg/5 ml) or vials (1 g/10 ml) for parenteral use, triad of INH poisoning that may result in death if not usually intravenously. It is sensitive to light and alkali; properly managed [3,4]. The prognosis is, however, good it must be stored in the dark and should never be mixed when the adequate treatment is instituted early [1,2,5,6]. with sodium bicarbonate. INH intoxications from long-term over-ingestions (1200 mg a day for 6 weeks) resulting in encephalopathy Commonly recommended indications include isoniazid and coma have also been reported [7]. (or isonicotinic acid hydrazide; INH) overdose, Gyromitra mushroom (false morel) poisoning (monomethylhydra- Central nervous system (CNS) hyperexcitability mainly zine or monomethylhydrazine syndrome), hydrazine revolves around the effect of INH on pyridoxine meta- exposure, crimidine poisoning or ethylene glycol poison- bolism Three additive mechanisms are involved. The first

0969-9546 c 2005 Lippincott Williams & Wilkins

Fig. 1 Fig. 2

(a) Dehydrazination Isoniazid hydrazones Ethylene glycol 2 Inhibition Isoniazid (INH) alcohol deshydrogenase Acetylation Glycoaldehyde and hydrolysis Pyridoxine aldehyde deshydrogenase Hydrazines Pyridoxine and phosphokinase Hydrazides Glycolic acid Pyridoxal lactate deshdrogenase and inactivates 5-phosphate glycolic acid oxidase Pyridoxine Thiamine Complexation Glyoxylic acid with Pyridoxine Isonicotinyl 1 P5P hydrazide

Glycine Oxalic acid Formic acid α-hydroxy-β-ketoadipic ac. Urinary elimination

Metabolism of ethylene-glycol: effect of pyridoxine. The main pathways of ethylene glycol metabolism. Supplementation with pyridoxine and (b) Glutamine Glutamic acid thiamine may be of theoretical benefit by shunting the conversion of glyoxylate to the less toxic metabolites glycine and alpha-hydroxy-beta- NH3 ketoadipic acid, respectively, rather than to oxalate and formate. GAD Pyridoxal 5- phosphate Inhibition by INH hydrazones

3 seizures in animal models, whereas combinations of these anticonvulsants and pyridoxine are effective (synergistic CO2 effect) [8]. Pyridoxine reduces the severity of seizures and prevents the mortality caused by a lethal dose of INH in dogs [8]. Such an efficacy was, however, not observed in rats [9]. Gamma aminobutyric acid (GABA) Clinical experience reported in humans with INH overdose is likely to be biased because it mainly consists Mechanism of isonicotinic acid hydrazide-induced central nervous of isolated case reports or short uncontrolled series system hyperexcitability (a and b). See text for details. CO2, carbon dioxide; GAD, glutamic acid decarboxylase; INH, isonicotinic acid showing favourable results, including rapid seizure hydrazide; P5P, pyridoxal 5-phosphate. control and no fatalities [10–12]. The ratio of grams of pyridoxine administered to grams of INH ingested is highly variable, ranging from 0.14 to 1.3. However, most patients received approximately a gram-for-gram amount is a pyridoxine depletion (Figure 1a; step 1): it is mainly of pyridoxine, as this ratio is commonly recommended on caused by the combination of P5P (not excreted in urine) an empirical or theoretical basis. Variable results in the with INH to form isonicotinilhydrazide, a compound control of seizures sometimes occurred in children when easily excreted in urine [2,7]. The second mechanism relatively smaller doses of pyridoxine were used. If consists of a decrease of pyridoxine activation in P5P by pyridoxine fails to control the seizures, the addition of the inhibition of pyridoxal phosphokinase (PPK) by diazepam seems to be more effective than other anti- hydrazone derivatives (Figure 1a; step 2). Finally, the convulsants such as phenytoin or barbiturates [13]. P5P depletion decreases the GABA synthesis from Thiopenthal was also used in a patient who failed to glutamic acid because P5P is an essential co-factor of respond to 12 g pyridoxine [14]. glutamic acid decarboxylase (GAD) (Figure 1b; step 3). Isoniazid hydrazones also inactivate P5P directly. The In a retrospective series by Wason et al. [15], the clinical lack of GABA and the accumulation of glutamic acid are course of five patients who received a gram-to-gram dose the presumed aetiology for CNS excitation and seizures. of pyridoxine was compared with the evolution of 41 patients in the literature who received lower doses or no The usual anticonvulsants such as phenobarbital, pheny- pyridoxine at all. In that study, pyridoxine appeared not toin or diazepam do not prevent or correct INH-induced only to be effective in treating INH-induced seizures,

but also the changes in mental status, suggesting that including intubation and respiratory support, as needed. pyridoxine deficiency also plays a role in the impairment Haemodialysis is highly efficient in removing INH of consciousness. However, the dose required to allow because of its small distribution volume and its low awakening may be higher than that required to control protein binding. However, the short half-life of INH seizures [15–17]. Brent et al. [16] have reported three often makes active elimination unnecessary. Although the cases of obtundation secondary to INH overdose: in use of haemodialysis may be considered in patients who two cases, status seizures were stopped by intravenous fail to respond to supportive and antidotal therapy, pyridoxine, but the patients remained comatose for and those with very high plasma levels or renal failure prolonged periods. The coma was immediately reversed [24–26], there is no consistent evidence to demonstrate by additional pyridoxine. In the last case, the patient’s an improvement in the evolution or the outcome lethargy was treated by intravenous pyridoxine on associated with its use. The adaptation of pyridoxine presentation and was followed by immediate awakening administration during dialysis has not been specifically [16]. studied; as pyridoxine is likely to be removed by haemodialysis, a repeated dose of antidote after the Lactic acidosis observed in INH poisoning mainly results procedure has been proposed [6]. from the seizures, and a rapid improvement may be expected from seizure control [15–18]. Indeed, paralysed Some textbooks recommend pyridoxine administration to animals do not develop lactic acidemia, although poi- all symptomatic alleged or definite cases of INH soned with INH [19]. However, the accumulation of overdosage to control or to prevent seizures, even if lactic acid could also be caused by an interference of INH seizures have not occurred [27], unless sufficient time or hydrazone metabolites with the Krebs cycle, resulting has elapsed from ingestion (e.g. more than 6 h) to suggest in an impairment of the transformation of lactate to that no severe toxicity will develop. No data clearly pyruvate (type B2 lactic acidosis) [1,19–21]. support such a recommendation.

The initial management of patients presenting with In the liver, INH undergoes N-acetylation to a variety of seizure should focus on the ABCs, termination of the products including acetylhydrazine, a potent hepatotoxin. seizure with benzodiazepines, regardless of the aetiology. A clinically significant and even fatal hepatic reaction, as Efforts should then be made rapidly to determine the well as rhabdomyolysis, may develop as consequences of aetiology and evaluate the need for a more specific INH poisoning [28], but do not seem to respond to approach, especially in those cases who do not respond or pyridoxine administration. only partly respond to the general regimen. False morel poisoning In moderate to severe INH overdose, pyridoxine often False morel (Gyromitra) mushrooms contain hydrazones, appears to be a key of the treatment. A gram-for-gram including the unstable toxin gyromitrin (N-methyl-N- dose based on the amount of INH ingested is usually formylhydrazone). This substance rapidly decomposes in recommended. If the quantity of ingested INH is the stomach to form acetaldehyde and N-methyl-N- unknown, an adult patient should receive a 5 g intrave- formylhydrazine (MFH). The latter is converted to nous dose in 50–100 ml 5% dextrose water (5–10% monomethylhydrazine by slow hydrolysis. MFH inhibits solution); for children, a 70 mg/kg intravenous dose (not several hepatic systems, including the cytochrome P-450 to exceed 5 g) is recommended. In the actively seizing and glutathione systems, and causes hepatic necrosis. patient, 0.5 g/min may be administered intravenously Monomethylhydrazine inhibits PPK, impairs the produc- until the seizures stop or the maximum dose has been tion of P5P and decreases GAD activity. The decrease of reached. Once the seizures stop, the remainder of the inhibitory GABA neurotransmission and the increase of dose should be infused over 4–6 h to maintain pyridoxine excitatory glutamate neurotransmission lead to the availability while INH is being eliminated. The response development of seizures and coma, similar to INH is usually observed within minutes. The dose of antidote neurotoxicity. Other targets include the red blood cells may be repeated at 20–30 min intervals if the seizures do or the kidney [29]. not resolve or if the patient does not regain consciousness. An association with benzodiazepines (for example Poisoning may occur approximately 6–10 h after the diazepam 5–10 mg intravenously or intrarectally) is ingestion of fresh or dried raw mushrooms: cooking recommended because of a synergistic effect on GABA reduces the risk of toxicity, but as monomethylhydrazine neurotransmission [6]. volatilizes off during the procedure, poisoning may result from the inhalation of the vapors [30–32]. Pyridoxine may be associated with early gastrointestinal decontamination with gastric lavage or activated charcoal By analogy with INH poisoning, pyridoxine is thought when indicated [22–24] and supportive measures, to reduce CNS toxicity in monomethylhydrazine

intoxication [33]. An anticonvulsant efficacy has been liver function tests of a confused, lethargic, and restless shown in animal studies with hydrazine derivatives man who had ingested a mouthful of hydrazine. However, [34–36]. Clinical experience only consists of a limited this improvement developed over 24 h and may have number of cases in which pyridoxine was successfully been unrelated to pyridoxine therapy; the patient used as an antidote for monomethylhydrazine-induced developed a severe sensory peripheral neuropathy lasting seizures or encephalopathy. There is no evidence that the for 6 months, one week after therapy [39]. Another acute liver toxicity or other toxic features may be treated patient suffered severe encephalopathy after 180 mg/day by pyridoxine [37]. of hydrazine sulphate ingestion for 2 weeks followed by 360 mg/day. Treatment consisted of mechanical ventila- As with INH, the initial management of patients tion with attendant supportive measures and high-dose presenting with seizures should focus on the ABCs and pyridoxine (5 g intravenously). The patient’s encephalo- the termination of the seizures with benzodiazepines. pathy resolved within 24 h after receiving pyridoxine [40]. The administration of pyridoxine may then be recom- A case of extensive burns associated with 1,1-dimethyl- mended; the common regimen consists of 25 mg/kg hydrazine toxicity in a 31-year-old man has also been intravenously over 15–30 min up to 5 g intravenously reported. Neurological symptoms dominated early devel- initially. The dose may be repeated for recurring seizures, opments. Specific treatment with pyridoxine, although up to 300 mg/kg per day if necessary, but should not begun late, effected a quite rapid resolution in the exceed 15–20 g/day. Some degree of synergism at the neurological symptoms [41]. GABA receptor level may be expected from the concommittant use of a benzodiazepine with pyridoxine. Crimidin toxicity Crimidin or 2-chloro-N,N,6-trimethyl-4-pyrimidinamine Hydrazine exposure is a rodenticide. Toxicity induced by this compound Monomethylhydrazine is also used as a propellant in the consists of CNS excitation: restlessness; apprehension; aerospace industry (rockets). Monomethylhydrazine and muscular stiffness; myoclonus; sensitivity to light, loud other hydrazines (1,1 and 1,2 dimethylhydrazine, phe- noises and contact; diaphoresis and convulsions [42,43]. nylhydrazine) are colourless highly reactive substances, The mechanism of action is not fully understood. widely used in industrial processes and easily absorbable Crimidin probably induces the production of an endo- through all routes: occupational intoxication through the genous GAD inhibitor by the liver [44,45], but could also percutaneous or inhalational route may occur in parti- directly decrease the activity of GAD, PPK or acetylcho- cular, but intentional ingestions have also been reported. line esterase [46,47]. The antidotal value of pyridoxine in crimidin toxicity has been evoked [48], but is not The toxicity that may be observed after exposure to these evidence based. Very few data are available about crimidin compounds is very similar to the monomethylhydrazine poisoning in humans, and only a few observations in syndrome. animals suggest that pyridoxine administration could have some effectiveness against crimidin-induced convulsions [49]. The efficacy of pyridoxine in hydrazine-induced toxicity has been evaluated in animal models. High-dose pyridoxine has been shown to prevent toxic effects and death Ethylene glycol toxicity caused by hydrazine administration in rats [38]. A single Pyridoxine (as well as thiamine) is a co-factor in the subcutaneous injection of each of five substituted metabolism of ethylene glycol in the presence of hydrazines, methylhydrazine, ethylhydrazine hydrochlor- magnesium. Therefore, supplementation with these ide, n-butylhydrazine hydrochloride, beta-N-[gamma- vitamins may be of theoretical benefit by shunting the L( + )-glutamyl]-4-hydroxymethylphenylhydrazine, and conversion of glyoxylate to glycine, a non-toxic metabolite MFH, were given alone and jointly with pyridoxine (pyridoxine) and to alpha-hydroxy-beta-ketoadipic acid hydrochloride to Swiss mice. The convulsive, toxic, and (thiamine), rather than to oxalate and formate (Figure 2) lethal effects of four compounds were successfully [50]. prevented by pyridoxine administered before and after injection. However, the toxic symptoms caused by MFH This approach is suggested by data obtained in animal were only slightly inhibited by pyridoxine [35]. A 10 models [51] and in studies in primary hyperoxaluria [52]. mg/kg dose intramuscularly was able to prevent the Such a supplement is inexpensive and safe. However, development of seizures induced by monomethylhydra- there are no scientific data to confirm the clinical zine 15 mg/kg in monkeys [36]. effectiveness of pyridoxine in ethylene glycol poisoning in humans. Only limited clinical experience related to the use of pyridoxine in hydrazine exposure has been reported. A Common recommendations consist of the administration 10 g dose of pyridoxine improved the mental status and of 50 mg pyridoxine intravenously, every 6–12 h [53,54],

or 1–2 mg/kg intravenously in the first 24–48 h of No adverse effects were observed with metadoxine treatment or until the acidosis has resolved or the therapy in such studies. These actions could be at least ethylene glycol level is no longer measurable [55]. Such partly related to the protection of the cellular redox state treatment is especially important in those patients against the free radical species and the reduced (e.g. alcoholic individuals) who may be deficient in this glutathione depletion generated by acute ethanol intox- vitamin. ication [60].

Acute alcohol intoxication Clinical relevance Megadoses of pyridoxine have been proposed to protect Only the effect of pyridoxine on ethanol-induced from acute ethanol toxicity. lethality was evaluated in animals, and the antidotal value was not confirmed in humans when clinically Animal studies relevant parameters were observed. The results obtained In a rat model [56], pyridoxine 187.2 mg/kg. intramuscu- with metadoxine need further confirmation. larly resulted in a significant displacement of the ethanol lethality-dose curve towards the right (P < 0.005). The Some controversial or unresolved issues LD50 of ethanol significantly increased from 4.46 to Pyridoxine administration has been proposed as an 5.19 g/kg (P < 0.005). The intracerebroventricular admin- adjunct to d-penicillamine chelation therapy: a 10–25 istration of pyridoxine 1.1 mg resulted in a complete mg dose per day is suggested, because this chelating suppression of the mortality caused by an LD100 of agent has been shown to inhibit pyridoxine-dependent ethanol, and this effect was dose dependent. enzymes [61]. No data have actually supported this indication. Human studies Mardel et al. [57] have evaluated pyridoxine 1 g adminis- Zipeprol is an antitussive agent marketed in some tered intravenously as an agent for the reversal of ethanol- countries. The substance has an addictive capacity induced CNS depression in a randomized double-blind (opiate-like effects, hallucinations), and numerous cases placebo-controlled study of 108 patients with acute of toxicity have been reported. Some sources in France ethanol intoxication. The evolution of consciousness and textbooks recommend the use of pyridoxine in the and the mean fall in the blood alcohol level after 1 h treatment of convulsions related to zipeprol overdose were similar in both groups, suggesting the lack of an [62,63], although no data from a Medline review support antidotal value of pyridoxine in acute alcohol intoxication this indication. in humans. Theophylline therapy depresses plasma P5P levels, either More recently, metadoxine (pyridoxol L-2-pyrrolidone-5- by a direct theophylline effect or by P5P binding by carboxylate, 900 mg intravenously), a combination of ethylenediamine [64]. The depletion of P5P may pyridoxine and pyrrolidone carboxylate, was evaluated in decrease the GABA synthesis, thereby contributing to 58 patients of both sexes with acute ethanol intoxication difficult-to-treat seizures with substantial morbidity and in a double-blind, randomized, multicentre, placebo- mortality, as observed in theophylline intoxication. The controlled trial [58]. Metadoxine administation signifi- effect of pyridoxine on theophylline-induced CNS cantly decreased the blood ethanol half-life (from toxicity has been evaluated in various animal models, 6.70 ± 1.84 to 5.41 ± 1.99 h; P < 0.013). The faster rate and the results are equivocal: pyridoxine did not alter the of ethanol elimination was associated with a faster clinical frequency or time of onset of seizures or death in an improvement in the toxic symptoms. animal model of aminophylline poisoning in mice [65], whereas it was shown to improve the rate of seizures and In another open-label study [59], 52 acutely alcohol- deaths in mice and electroencephalogram abnormalities intoxicated patients were randomly assigned to one of in rabbits [66]. No consistent data are available in two groups: 300 mg metadoxine intravenously added to humans. standard treatment, compared with standard treatment alone. After 2 h, more patients receiving metadoxine had improved compared with those receiving standard treat- Pyridoxine toxicity ment alone (76.9 versus 42.3%, respectively). Metadox- Both acute toxicity and the delayed adverse effects of ine-treated patients also exhibited a significantly pyridoxine have been reported. greater decrease in blood alcohol ( – 105.4 ± 61.5 versus – 60.1 ± 38.6 mg/dl, respectively). Finally, metadoxine Very high doses (2–6 g/kg) induce ataxia, incoordination, improved the clinical signs of acute alcohol intoxication, seizures, and are lethal in animal models. Massive an effect that appeared concurrent with but independent amounts of intravenous pyridoxine were well tolerated of the acceleration of alcohol clearance from the blood. in early pharmacological studies in humans [67], and very

high dosages were administered in INH overdose Conclusion patients without adverse effects (e.g. 357 mg/kg) [15]. The intravenous administration of high doses of pyridoxine is indicated to prevent (early phase) or to treat the However, excessive chronic administration (0.2–6 g a day) neurotoxicity, especially the convulsions and the impair- over months or years may occasionally result in the ment of consciousness, associated with INH, hydrazine or development of a peripheral sensory neuropathy asso- crimidine toxicity. The INH indication is supported by ciated with bilateral paraesthesia, hyperaesthesia, limb numerous isolated observations and short uncontrolled pains, ataxia, and incoordination. No motor deficit or series. Pyridoxine has no direct effects on the other CNS involvement is usually observed [68–71]. It usually aspects of the toxicity of these compounds, and is thus resolves within 6 months of pyridoxine withdrawal, but only a part of the management, so that other measures symptoms may, however, still persist for 3–6 weeks after (prevention of absorption, supportive care, including pyridoxine has been stopped. Experimental data in rats respiratory support) must be associated as needed. suggest that pharmacological doses of neurotrophic factor Morever, the initial management of the actively seizing NT-3 may be beneficial in the treatment of such large- patient should first focus on the ABCs, and the rapid fibre sensory neuropathies [72]. The peripheral neuro- termination of the seizure activity with benzodiazepines. toxicity of pyridoxine seems to be dose related [73], It is especially important because several surveys have although interindividual susceptibility has also been shown the absence of pyridoxine or the stocking of suggested [68,74]. Although pyridoxine-induced periph- insufficient doses in many emergency departments. eral neuropathies are most commonly observed as a result of a ‘megavitamin syndrome’ [75,76], lower doses taken Hydrazines and crimidine indications are only based on over a long period of time [77] may also result in theoretical concepts and anecdotal observations. neurotoxicity. Other indications of pyridoxine (at lower doses) in Albin et al. [78] reported on two patients treated with 132 clinical toxicology are less well documented, and could and 183 g intravenous pyridoxine (2 g/kg), respectively, include ethylene glycol toxicity, theophylline-induced over 3 days. They developed a severe sensory neuropathy seizures or acute alcohol intoxication. Promising results over several days, with transient autonomic dysfunction, have been obtained with metadoxine in various aspects of mild weakness, nystagmus, lethargy, and respiratory alcohol-related toxicity. Further studies are needed to depression. Both patients remained unable to walk at clarify these issues. the one year follow-up [79]. Besides the exceptionally high doses of pyridoxine, the preservative used in the Although the antidotal administration of pyridoxine is parenteral pyridoxine preparation may also play a role in usually well tolerated, adverse effects may result from the development of these adverse effects [80]. inappropriate dosages or too prolonged usage.

Another potential adverse effect of the rapid infusion of References large dose of pyridoxine in poisoned patients is a transient 1 Boyer EW. Antituberculous agents. In: Goldfrank LR, Flomenbaum NE, worsening of metabolic acidosis frequently present in Lewin NA, Howland MA, Neslon LS, editors. Goldfrank’s toxicologic emergencies, 7th ed. New York: McGraw Hill; 2002. pp. 655–670. patients with seizures. A 100 mg/ml solution of pyridoxine 2 Alvarez FG, Guntupalli KK. Isoniazid overdose: four case reports and hydrochloride has a pH of less than 3. In a randomized, review of the literature. Intens Care Med 1995; 21:641–644. controlled crossover trial in five human volunteers, Lo 3 Watkins RC, Hambrick EL, Benjamin G, Chavda SN. Isoniazid toxicity presenting as seizures and metabolic acidosis. J Natl Med Assoc 1990; Vecchio et al. [81] demonstrated that a 5 min infusion of 82:62–64. pyridoxine (5 g in 50 ml saline versus 50 ml normal saline 4 Shannon MW. Isoniazid. In: Haddad LM, Shannon MW, Winchester JF, solution) induced a significant but transient increase in editors. Clinical management of poisoning and drug overdose, 3rd ed. Philadelphia: WB Saunders Co.; 1998. pp. 721–726. the base deficit of 2.74 mEq/l. 5 Brown CV. Acute isoniazid poisoning. Am Rev Respir Dis 1972; 105: 206–216. 6 Temmerman W, Dhondt A, Vandewoude K. Acute isoniazid intoxication: seizures, acidosis and coma. Acta Clin Belg 1999; 54:211–216. Pyridoxine availability 7 Salkind AR, Hewitt CC. Coma from long-term overingestion of isoniazid. Parenteral pyridoxine is a relatively inexpensive antidote Arch Intern Med 1997; 157:2518–2520. h 8 Chin L, Sievers ML, Herrier RN, Picchioni AL. Potentiation of pyridoxine (10 g costs approximately US$40 or 40), may prevent or by depressants and anticonvulsants in the treatment of acute isoniazid correct life-threatening toxicity and obviate the need for intoxication in dogs. Toxicol Appl Pharmacol 1981; 58:504–509. more expensive and invasive procedures such as haemo- 9 Chin L, Sievers ML, Laird HE, Herrier RN, Picchioni AL. Evaluation of diazepam and pyridoxine as antidotes to isoniazid intoxication in rats and dialysis. However, several surveys have indicated than dogs. Toxicol Appl Pharmacol 1978; 45:713–722. many emergency departments are ill-equipped to handle 10 Starke H, Williams S. Acute poisoning from overdose of isoniazid: a case acute INH-induced neurotoxicity because of the poor report. Lancet 1963; 83:406–408. 11 Blanchard PD, Yao JD, McAlpine DE, Hurt R. Isoniazid overdose in the availability of pyridoxine or inadequate dose stocking Cambodian population of Olmsted County, Minnesota. JAMA 1986; (less than 5–10 g) to treat at least one patient [82–86]. 256:3131–3133.

12 Romero JA, Kuczler FJ. Isoniazid overdose; recognition and management. 42 US Environmental Protection Agency. Rodenticides. In: Reigart JR, Am Family Phys 1998; 57:749–752. Roberts JR, editors. Recognition and management of pesticide poisonings, 13 Miller J, Robinson A, Percy AK. Acute isoniazid poisoning in childhood. Am J 5th ed., chapter 17. 1999. Available at: http://www.epa.gov/oppfod01/ Dis Child 1980; 134:290–292. safety/healthcare/handbook/Chap17.pdf. Accessed: 5 February 2005. 14 Bredemann JA, Krechel SW, Eggers GW Jr. Treatment of refractory seizures 43 TELETOX: Base de donne´es des produits phytosanitaires. Universite´ in massive isoniazid overdose. Anesth Analg 1990; 71:554–557. Virtuelle Me´dicale Francophone. Universite´ Virtuelle Paris 5 Rene´ Descartes. 15 Wason S, Lacouture PG, Lovejoy FH Jr. Single high dose pyridoxine Available at: http://www.uvp5.univ-paris5.fr/TELETOX/SelDci/ treatment for isoniazide poisoning. JAMA 1981; 246:1102–1104. DciAff.asp?DciCle = 470. Accessed: 3 January 2005. 16 Brent J, Vo N, Kulig K, Rumack BH. Reversal of prolonged isoniazid-induced 44 Hansen KL. The effect of castrix (crimidin) on pyridoxal-50-phosphate and the coma by pyridoxine. Arch Intern Med 1990; 150:1751–1753. activity of pyridoxal kinase. Acta Vet Scand 1973; 14:495–500. 17 Brown A, Maillet M, Fiser D, Arnold WC. Acute isoniazid intoxication: 45 Hansen KL. The influence of crimidin metabolized by liver on brain glutamic reversal of CNS symptoms with large dose of pyridoxine. Pediatr Pharmacol acid decarboxylase in vitro. Acta Pharmacol Toxicol (Copenhagen) 1976; 1984; 4:199–202. 39:53–57. 18 Adler M, Girsh-Solomonovich Z, Raikhlin-Eisenkraft B. Pyridoxine for severe 46 Murakami Y, Murakami K, Makino K. On the convulsive action of castrix. metabolic acidosis and seizures due to isoniazid overdose. Harefuah 1993; Biochem Pharmacol 1972; 21:277–280. 124:616–618. 47 Murakami Y, Makino K. On the convulsive action of castrix. Biochem 19 Chin L, Sievers ML, Herrier HE, Picchioni AL. Convulsions as the etiology of Pharmacol 1973; 22:2247–2252. lactic acidosis in acute isoniazid toxicity in dogs. Toxicol Appl Pharmacol 48 Baud FJ, Brouard A. Vitamine B6. In: Baud F, Barriot P, Riou B, editors. Les 1979; 49:377–384. antidotes. Paris: Masson; 1992. pp. 261–264. 20 Sharma S. Lactic acidosis. eMedicine, Instant access to the minds of 49 Lumeij JT, Schotman AJ, de Vries HW. Crimidine (2-chloro-4- medicine. Available at: eMedicine.com, Inc:2004: http:// (dimethylamino)-6-methylpyrimidine) poisoning in a dog due to ingestion of www.emedicine.com/med/topic1253.htm. Accessed: 3 January 2005. the rodenticide Castrix. Vet Q 1983; 5:107–111. 21 Borron SW, Megarbane B. Lactic acidosis. eMedicine, Instant access to the 50 Goldfrank LR, Flomenbaum NE. Toxin alcohols. In: Goldfrank’s toxicologic minds of medicine. Available at: eMedicine.com, Inc:2001: http:// emergencies, 6th ed. Stamford, Connecticut: Appelton and Lange; 1998. www.emedicine.com/emerg/topic291.htm. Accessed: 3 January 2005. pp. 1049–1060. 22 Vale JA. Position statement: gastric lavage. American Academy of Clinical 51 Durand A, Auzepy P, Hebert JL, Trieu T. A study of mortality and urinary Toxicology; European Association of Poisons Centres and Clinical excretion of oxalate in male rats following acute experimental intoxication Toxicologists. J Toxicol Clin Toxicol 1997; 35:711–719. with diethylene-glycol. Preliminary report. Eur J Intens Care Med 1976; 23 Chyka PA, Seger D. Position statement: single-dose activated charcoal. 2:143–146. American Academy of Clinical Toxicology; European Association of Poisons 52 Nath R, Thind SK, Murthy MS, Farooqui S, Gupta R, Koul HK. Role of Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1997; 35:721–741. pyridoxine in oxalate metabolism. Ann NY Acad Sci 1990; 585:274–284. 24 Siefkin AD, Albertson TE, Corbett MG. Isoniazid overdose: 53 Ellenhorn MJ, Barceloux DG. Medical toxicology. Diagnosis and treatment of pharmacokinetics and effects of oral charcoal in treatment. Hum Toxicol human poisoning. New York: Elsevier; 1988. 1987; 6:497–501. 54 Olson KR. Poisoning and drug overdose. East Norwalk: Appleton and 25 Orlowski JP, Paganini EP, Pippenger CE. Treatment of a potentially lethal Lange; 1990. dose isoniazid ingestion. Ann Emerg Med 1988; 17:73–76. 55 Keyes DC. Toxicity, ethylene glycol. eMedicine, Instant access to the minds 26 Cash JM, Zawada ET Jr. Isoniazid overdose. Successful treatment with of medicine. Available at: http://www.emedicine.com/emerg/ pyridoxine and hemodialysis. West J Med 1991; 155:644–666. topic177.htm:2002. Accessed: 3 January 2005. 27 Ellenhorn MJ. Isoniazid. In: Ellenhorn MJ, Schonwald S, Ordog G, 56 Gonzalez LE, Parada MA, Hernandez L. Pyridoxine acts in the brain to Wasserberger J, editors. Ellenhorn’s medical toxicology: diagnosis and reduce ethanol toxicity in rats. Alcohol 1992; 9:519–522. treatment of human poisoning, 2nd ed. Baltimore: Williams and Wilkins; 57 Mardel S, Phair I, O’Dwyer F, Henry JA. Intravenous pyridoxine in acute 1997. pp. 240–243. ethanol intoxication. Hum Exp Toxicol 1994; 13:321–323. 28 Blowey DL, Johnson D, Verjee Z. Isoniazid-associated rhabdomyolysis. 58 Shpilenya LS, Muzychenko AP, Gasbarrini G, Addolorato G. Metadoxine in Am J Emerg Med 1995; 13:543–544. acute alcohol intoxication: a double-blind, randomized, placebo-controlled 29 Brozen R, Hampers M. Toxicity, mushroom – Gyromitra toxin. eMedicine, study. Alcohol Clin Exp Res 2002; 26:340–346. Instant access to the minds of medicine. Available at: http:// 59 Diaz Martinez MC, Diaz Martinez A, Villamil Salcedo V, Cruz Fuentes C. www.emedicine.com/emerg/topic459.htm:2001. Accessed: 3 January Efficacy of metadoxine in the management of acute alcohol intoxication. JInt 2005. Med Res 2002; 30:44–51. 30 Habal R, Martinez JA. Toxicity, mushrooms. eMedicine, Instant access to the 60 Calabrese V, Calderone A, Ragusa N, Rizza V. Effects of metadoxine minds of medicine. Available at: http://www.emedicine.com/med/ on cellular status of glutathione and of enzymatic defence system topic1527.htm:2002. Accessed: 3 January 2005. following acute ethanol intoxication in rats. Drugs Exp Clin Res 1996; 22: 31 Michelot D, Toth B. Poisoning by Gyromitra esculenta – a review. J Appl 17–24. Toxicol 1991; 11:235–243. 61 Seelig MS. Auto-immune complications of D-penicillamine, a possible result 32 Trestrail JH. Monomethylhydrazine-containing mushrooms. In: Spoerke DG, of zinc and magnesium depletion and of pyridoxine inactivation. JAmColl Rumack BH, editors. Handbook of mushroom poisoning: diagnosis and Nutr 1982; 1:207–214. treatment. Boca Raton, FL: CRC Press; 1994. pp. 279–287. 62 Pyridoxine. In: Tox-In – paracelse, base de connaissance sur les 33 George ME, Pinkerton MK, Back KC. Therapeutics of monomethylhydrazine intoxications humaines aigues. Available at: http://www.egora.fr/tox-in/ intoxication. Toxicol Appl Pharmacol 1982; 63:201–208. paracels.htm. Accessed: 5 February 2005. 34 Shouse MN. Acute effects of pyridoxine hydrochloride on 63 Ellenhorn MJ. Respiratory drugs. In: Ellenhorn MJ, Schonwald S, Ordog G, monomethylhydrazine seizure latency and amygdaloid kindled seizure Wasserberger J, editors. Ellenhorn’s medical toxicology: diagnosis and thresholds in cats. Exp Neurol 1982; 75:79–88. treatment of human poisoning, 2nd ed. Baltimore: Williams and Wilkins; 35 Toth B, Erickson J. Reversal of the toxicity of hydrazine and analogues by 1997. pp. 808–839. pyridoxine hydrochloride. Toxicology 1977; 7:31–36. 64 Weir MR, Keniston RC, Enriquez JI, McNamee GA. Depression of vitamin 36 Sterman MB, Kovalevsky RA. Anticonvulsants – effects of restraint B6 levels due to theophylline. Ann Allergy 1990; 65:59–62. and pyridoxine on hydrazine seizures in the monkey. Exp Neurol 1979; 65 Bonner AB, Peterson SL, Weir MR. Seizures induced by theophylline and 65:78–86. isoniazid in mice. Vet Hum Toxicol 1999; 41:175–177. 37 Braun R, Greeff U, Netter KJ. Liver injury by the false morel poison gyromitrin. 66 Glenn GM, Krober MS, Kelly P, McCarty J, Weir M. Pyridoxine as therapy in Toxicology 1979; 12:155–163. theophylline-induced seizures. Vet Hum Toxicol 1995; 37:342–345. 38 Cornish HH. The role of vitamin B in the toxicity of hydrazines. Am NY Acad 67 Unna JC. Studies of the toxicity an pharmacology of vitamin B6 (2-methyl-3- Sci 1969; 166:136–145. hydroxy-4,5-bis-[hydroxymethyl]-pyridine). J Pharmacol Exp Ther 1940; 39 Harati Y, Niakan E. Hydrazine toxicity, pyridoxine therapy, and peripheral 70:400–407. neuropathy. Ann Intern Med 1986; 104:728–729. 68 Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, 40 Nagappan R, Riddell T. Pyridoxine therapy in a patient with severe hydrazine Brown MJ. Sensory neuropathy from pyridoxine abuse. A new megavitamin sulfate toxicity. Crit Care Med 2000; 28:2116–2118. syndrome. N Engl J Med 1983; 309:445–448. 41 Dhennin C, Vesin L, Feauveaux J. Burns and the toxic effects of a derivative 69 Berger A, Schaumburg HH. More on neuropathy from pyridoxine abuse. of hydrazine. Burns Incl Therm Inj 1988; 14:130–134. N Engl J Med 1984; 311:986–987.

70 Parry GJ, Bredesen DE. Sensory neuropathy with low-dose pyridoxine. 78 Albin R, Albers J, Greenberg HS, Townsend JB, Lynn RB, Burke JM Jr, Neurology 1985; 35:1466–1468. Alessi AG. Acute sensory neuropathy-neuronopathy from pyridoxine 71 Cohen M, Bendich A. Safety of pyridoxine: a review of human and animal overdose. Neurology 1987; 37:1729–1732. studies. Toxicol Lett 1986; 34:129–139. 79 Albin R, Albers J. Long-term follow-up of pyridoxine-induced acute sensory 72 Helgren ME, Cliffer KD, Torrento K, Cavnor C, Curtis R, DiStefano PS, neuropathy-neuronopathy. Neurology 1990; 40:1319. et al. Neurotrophin-3 administration attenuates deficits of pyridoxine- 80 Burda AM, Sigg T, Wahl M. Possible adverse reactions to preservatives in induced large-fiber sensory neuropathy. J Neurosci 1997; 17: high-dose pyridoxine hydrochloride i.v. injection. Am J Health Syst Pharm 372–382. 2002; 59:1886–1887. 73 Berger AR, Schaumburg HH, Schroeder C, Apfel S, Reynolds R. Dose 81 Lo Vecchio F, Curry SC, Graeme KA, Wallace KL, Suchard J. Intravenous response, coasting, and differential fiber vulnerability in human toxic pyridoxine-induced metabolic acidosis. Ann Emerg Med 2001; 38:62–64. neuropathy: a prospective study of pyridoxine neurotoxicity. Neurology 82 Dart RC, Stark Y, Fulton B, Koziol-McLain J, Lowenstein SR. Insufficient 1992; 42:1367–1370. stocking of poisoning antidotes in hospital pharmacies. JAMA 1996; 74 Bendich A, Cohen M. Vitamin B6 safety issues. Ann NY Acad Sci 1990; 276:1508–1510. 585:321–330. 83 Santucci KA, Shah BR, Linakis JG. Acute isoniazid exposures and antidote 75 Morra M, Philipszoon HD, D’Andrea G, Cananzi AR, L’Erario R, Milone FF. availability. Pediatr Emerg Care 1999; 15:99–101. Sensory and motor neuropathy caused by excessive ingestion of vitamin B6: 84 McGuigan MA, Yamada J. The geographic distribution of tuberculosis and a case report. Funct Neurol 1993; 8:429–432. pyridoxine supply in Ontario. Can J Hosp Pharm 1995; 48:348–351. 76 Dordain G, Deffond D. Neuropathies a` la pyridoxine. Revue de la litte´rature. 85 Woolf AD, Chrisanthus K. On-site availability of selected antidotes: results of The´rapie 1994; 49:333–337. a survey of Massachusetts hospitals. Am J Emerg Med 1997; 15:62–66. 77 Dalton K, Dalton MJ. Characteristics of pyridoxine overdose neuropathy 86 Scharman EJ, Rosencrane JG. Isoniazid toxicity: a survey of pyridoxine syndrome. Acta Neurol Scand 1987; 76:8–11. availability. Am J Emerg Med 1994; 12:386–388.