[The chemical toxicological determination of isoniazid and metoclopramide in the objects used for animals poisoning and in biological fluids]. / Khimiko-toksikologicheskoe opredelenie izoniazida i metoklopramida v ob''ektakh, ispol'zuemykh dlia otravleniia zhivotnykh, i v biologicheskikh zhidkostiakh.

The number of mass casualty incidents among the dogs has significantly increased during a few recent years in the cities of this country; they are most frequently attributed to the activities of the so-called dog hunters. The dog hunters make use of a variety of chemical compounds for poisoning the dogs. Most of them are the multi-component substances, with their chemical composition being highly variable and continuously modified. The objective of the present study was to develop the method for the isolation and identification of isoniazid and metoclopramide introduced into the baits that are distributed by the dog hunters for the poisoning of the animals. The proposed method was tested with the use of biological fluids obtained from the laboratory animals. The effectiveness of isolation of the compounds of interest from these materials with the use of the liquid-liquid and fractional freezing extraction techniques was evaluated. In addition, the method for solid phase extraction with the use of the 'Oasis HLB' cartridges was developed.

Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes.

Some toxins cause their effects by affecting physiological processes that are fundamental to cell function or cause systemic effects as a result of cellular interaction. This review focuses on four examples, coumarin anticoagulants, isoniazid, methotrexate and thyroxine from the context of management of overdose as seen in acute general hospitals. The current basic clinical pharmacology of the toxin, the clinical features in overdose and evidence base for specific antidotes are discussed. The treatment for this group is based on an understanding of the toxic mechanism, but studies to determine the optimum dose of antidote are still required in all these toxins except thyroxine, where treatment dose is based on symptoms resulting from the overdose.

Near Fatal Poisoning by Isoniazid and Rifampicin.

Since six decades, Isoniazid and Rifampicin are used as first line drugs for treatment of tuberculosis. The minimum acute lethal or toxic dose of Rifampicin is not well established. However, non-fatal acute overdoses in adults have been reported with doses ranging from 9 to 12 gm and fatal acute overdoses with doses ranging from 14 to 60 gm. Isoniazid, if acutely ingested, even 1.5 to 2 gram may cause toxicity in adults. We report a case of Pott's spine on ATT, who took massive overdose of Rifampicin (>18 gm) and Isoniazid (>12 gm) and reported late (almost 36 hours) after ingestion. He was treated successfully with pyridoxine, hemodialysis and supportive care.

Fatal suicidal poisoning with antituberculosis agents with ST elevation and acute coronary syndrome symptoms--a case report.

A 19-years old, previously healthy male, ingested the higher amount of rifampicin, isoniazyd, pyrazinamide, ketoprofene and alcohol. Within less than 20 hours he developed dyspnoe, pruritus, red man syndrome, and ECG changes suggesting acute coronary syndrome appeared - ST interval elevation. In the next few hours chest pain appeared and troponin I concentration was elevated (13.54 ng/ml). The performed echocardiography revealed global hypokinesis with the decreased left ventricular ejection fraction (approx. 30%). There was no significant pathological changes in coronarography, except for slowed blood flow. Further patient developed cardiogenic shock, pulmonary oedema and died within 32 hours from medication overdose.

Extracorporeal treatments for isoniazid poisoning: Systematic review and recommendations from the EXTRIP workgroup.

Isoniazid toxicity from self-poisoning or dosing errors remains common in regions of the world where tuberculosis is prevalent. Although the treatment of isoniazid poisoning is centered on supportive care and pyridoxine administration, extracorporeal treatments (ECTRs), such as hemodialysis, have been advocated to enhance elimination of isoniazid. No systematic reviews or evidence-based recommendations currently exist on the benefit of ECTRs for isoniazid poisoning. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup systematically collected and rated the available evidence on the effect of and indications for ECTRs in cases of isoniazid poisoning. We conducted a systematic review of the literature, screened studies, extracted data on study characteristics, outcomes, and measurement characteristics, summarized findings, and formulated recommendations following published EXTRIP methods. Forty-three studies (two animal studies, 34 patient reports or patient series, and seven pharmacokinetic studies) met inclusion criteria. Toxicokinetic or pharmacokinetic analysis was available for 60 patients, most treated with hemodialysis (n = 38). The workgroup assessed isoniazid as "Moderately Dialyzable" by hemodialysis for patients with normal kidney function (quality of evidence = C) and "Dialyzable" by hemodialysis for patients with impaired kidney function (quality of evidence = A). Clinical data for ECTR in isoniazid poisoning were available for 40 patients. Mortality of the cohort was 12.5%. Historical controls who received modern standard care including appropriately dosed pyridoxine generally had excellent outcomes. No benefit could be extrapolated from ECTR, although there was evidence of added costs and harms related to the double lumen catheter insertion, the extracorporeal procedure itself, and the extracorporeal removal of pyridoxine. The EXTRIP workgroup suggests against performing ECTR in addition to standard care (weak recommendation, very low quality of evidence) in patients with isoniazid poisoning. If standard dose pyridoxine cannot be administered, we suggest performing ECTR only in patients with seizures refractory to GABAA receptor agonists (weak recommendation, very low quality of evidence).

Isoniazid-induced status epilepticus in a pediatric patient after inadequate pyridoxine therapy.

BACKGROUND: Isoniazid (INH) is an effective treatment for tuberculosis and among the most common causes of drug-induced seizures in the United States. Isoniazid intoxication produces a characteristic clinical syndrome including seizures, metabolic acidosis, and, in severe cases, respiratory depression and coma. CASE: A 10-month-old male infant was presented after being found with his father's INH. The patient was brought to a local hospital where he had a witnessed generalized seizure and was given 650 mg pyridoxine intravenously, which was based on a 70 mg/kg recommendation. Five hours after the time of ingestion, the patient developed recurrent generalized seizures. He was given diazepam and then loaded with phenobarbital 20 mg/kg, while awaiting more pyridoxine from the pharmacy. He received an additional 2 g pyridoxine for a suspected ingestion of approximately 2.7 g INH (290 mg/kg total dose), and his seizures subsequently resolved. DISCUSSION: Treatment of INH toxicity must address correction of gamma-aminobutyric acid deficiency with pyridoxine replacement and management of life-threatening events. For poisonings in which the amount of INH ingested is known, pyridoxine is dosed on a gram-for-gram basis. Several reference textbooks recommend pyridoxine dosing in children to be 70 mg/kg. This was the justification for the initial pyridoxine dose administered in our case. However, after review of the referenced literature, the rationale supporting this recommendation remains unclear. Benzodiazepines should also be given with pyridoxine as they have been shown to have a synergistic effect in terminating seizures in animal models. CONCLUSIONS: As soon as possible after INH overdose is suspected or diagnosed, pyridoxine should be administered in a dose approximately equal to the estimated amount of INH ingested regardless of the age of the patient.

Liver transplantation for acute liver failure due to toxic agent ingestion in children.

ALF is characterized by sudden onset, impaired liver function, jaundice and encephalopathy, without previous liver disease. We analyzed the patients who underwent LT due to toxic agent induced ALF to raise community awareness about preventing the toxic agent induced ALF. Five children (three boys, two girls) underwent LT due to toxic agent ingestion. Toxic agents were mushroom poisoning (n = 2), Datura stramonium (n = 1), yellow phosphorous (n = 1) and INH (n = 1). On admission, one patient had stage IV, two had stage III and two had stage II hepatic encephalopathy but worsened during the follow-up. One patient had renal failure, and three patients required mechanical ventilation. Three patients underwent LRLT and others from a DD. Post-operative complications were managed by supportive managements successfully, and overall all the patients are alive (100% survival) without any organ sequelae. Although outcome of these patients are excellent, ALF may be prevented in these cases by educating the public about consuming mushrooms and toxic effects of wild plants, prohibiting fireworks and serial liver enzyme measurements after initiating INH.

Suicidal Isoniazid poisoning.

Accidental or intentional Isoniazid poisoning may manifest within half to three hours as intractable seizure, acidosis, and coma. Single high dose of pyridoxine was used as an antidote with good response as reported earlier. Ingestion of more than 80 mg/kg body weight produces severe central nervous system symptoms and a dose of 125 mg/kg is potentially lethal if not promptly treated. We report a case of suicidal attempt with use of Isoniazid, who developed grand mal seizures and was controlled with diazepam and symptomatic treatment.

Coma caused by isoniazid poisoning in a patient treated with pyridoxine and hemodialysis.

Isoniazid is widely used to treat tuberculosis. In populations with a high prevalence rate of tuberculosis, acute ingestion of isoniazid has been reported as a potential cause of coma. In this study, we present the diagnosis and treatment of isoniazid poisoning in a case with acute coma as the major clinical presentation.A 32-year-old male who ingested 12 g isoniazid (2 hours prior to medical attention) was brought to the emergency department while in a coma and experiencing frequent seizures. Initial treatment with large doses of pyridoxine (for 6 hours) failed to awaken this patient. The patient was then given hemodialysis and pyridoxine; after 3 days he awoke from coma, with no further reported seizures.Isoniazid poisoning should be suspected in patients whose major symptoms are coma and seizure, especially those who have access to isoniazid. Monitoring the blood level of isoniazid will establish the diagnosis and help clinical management. A combination of hemodialysis and pyridoxine is effective in treating isoniazid poisoning.

Thoracic spine compression fracture during isoniazid-induced seizures: case report.

We report here an 11-year-old previously healthy girl with isoniazid intoxication who sustained a seizure-induced thoracic compression fracture. The following might be the first such case reported in the medical literature. Isoniazid toxicity should be suspected in any patient who comes to the emergency department with refractory seizures and metabolic acidosis. Forceful muscle contractions during a convulsive seizure can result in vertebral compression fracture, especially in the midthoracic region. A complaint of back pain after isoniazid-induced seizures in patients raises a strong suspicion of vertebral fracture and should be evaluated radiologically.

Oral pyridoxine can substitute for intravenous pyridoxine in managing patients with severe poisoning with isoniazid and rifampicin fixed dose combination tablets: a case report.

BACKGROUND: Fixed drug combination of isoniazid and rifampicin is a rare cause of poisoning even in endemic countries for tuberculosis infection. Severe poisoning can cause severe morbidity and mortality if not treated promptly. Though intravenous pyridoxine is the preferred antidote for severe standard isoniazid poisoning it is not freely available even in best of care centers. We describe a case of severe poisoning with fixed drug combination of isoniazid and rifampicin successfully managed with oral pyridoxine at national hospital of Sri Lanka. CASE PRESENTATION: A 22 year old, Sri Lankan female presented to a local hospital 1 h after self-ingestion of 28 tablets of fixed drug combination of isoniazid and rifampicin which contained 4.2 g of standard isoniazid and 7.2 g of rifampicin. One and half hours after ingestion she developed generalized tonic-clonic seizure with loss of consciousness. She was given intravenous diazepam 5 mg immediately and transferred to national hospital of Sri Lanka, for further care. Upon arrival to tertiary care hospital in 3.5 h of poisoning she had persistent vomiting, dizziness and headache. On examination, she was drowsy but arousable, orange-red discoloration of the body was noted even with the dark skin complexion. She also had orange-red colour urine and vomitus. Pulse rate was 104 beats/min, blood pressure 130/80 mmHg, respiratory rate was 20 breaths/min. The arterial blood gas analysis revealed compensated metabolic acidosis and mildly elevated lactic acid level. Considering the clinical presentation with neurological toxicity and the large amount of isoniazid dose ingested, crushed oral tablets of pyridoxine 4.2 g (equal to standard isoniazid dose ingested) administered immediately via a nasogastric tube since intravenous preparation was not available in the hospital. Simultaneously forced diuresis using intravenous 0.9% saline was commenced in order to enhance excretion of toxic metabolites via kidneys. She had no recurrence of seizures but had acute liver injury subsequently which gradually improved with supportive care. Her liver functions found to be completely normal 1 week after the discharge. CONCLUSIONS: Poisoning with fixed drug combination of isoniazid and rifampicin tablets is rare but can cause severe morbidity and mortality if not treated promptly. Oral pyridoxine can substitute for intravenous pyridoxine with almost similar efficacy at a low cost in managing patients with acute severe standard isoniazid poisoning in resource poor setting.

Acute isoniazid toxicity and the need for adequate pyridoxine supplies.

A 25-year-old, 54-kg Hispanic man who had recently started multidrug therapy for pulmonary tuberculosis presented in status epilepticus after ingesting 9 g of isoniazid in a suicide attempt. Successful management of this patient required collaboration between several institutions to provide the large amount of necessary intravenous pyridoxine. Ultimately, this single overdose depleted the supply of intravenous pyridoxine for a significant region of the state of Nebraska. Isoniazid is commonly used to treat tuberculosis, but it is encountered relatively infrequently as the cause of an acute overdose. Severe isoniazid overdoses may present as seizure activity that is refractory to conventional antiepileptic therapy. Although intravenous pyridoxine is an effective antidote for isoniazid overdoses in patients presenting with status epilepticus, this agent has few indications and is typically stocked in limited quantities. In regions with large populations of patients who receive antituberculosis therapy, collaborative networks must be created to ensure that adequate supplies of intravenous pyridoxine (> or = 20 g) are available for effective treatment of isoniazid poisonings.

Reversal of prolonged isoniazid-induced coma by pyridoxine.

Isoniazid overdose is known to result in the rapid onset of seizures, metabolic acidosis, and prolonged obtundation. Pyridoxine has been reported to be effective in treating isoniazid-induced seizures. We report three cases of obtundation secondary to isoniazid overdose that was immediately reversed by intravenous pyridoxine. In two of these cases, status seizures were stopped by intravenous pyridoxine administration, but the patients remained comatose for prolonged periods. The comas were immediately reversed by the administration of additional pyridoxine. In the third case, the patient's lethargy was treated by intravenous pyridoxine on presentation and was followed by immediate awakening. Pyridoxine is effective in treating not only isoniazid-induced seizures, but also the mental status changes associated with this overdose. The dose required to induce awakening may be higher than that required to control seizures.

Pyridoxine in clinical toxicology: a review.

Pyridoxine (vitamin B6) is a co-factor in many enzymatic pathways involved in amino acid metabolism: the main biologically active form is pyridoxal 5-phosphate. Pyridoxine has been used as an antidote in acute intoxications, including isoniazid overdose, Gyromitra mushroom or false morrel (monomethylhydrazine) poisoning and hydrazine exposure. It is also recommended as a co-factor to improve the conversion of glyoxylic acid into glycine in ethylene glycol poisoning. Other indications are recommended by some sources (for example crimidine poisoning, zipeprol and theophylline-induced seizures, adjunct to d-penicillamine chelation), without significant supporting data. The value of pyridoxine or its congener metadoxine as an agent for hastening ethanol metabolism or improving vigilance in acute alcohol intoxication is controversial. This paper reviews the various indications of pyridoxine in clinical toxicology and the supporting literature. The potential adverse effects of excessive pyridoxine dosage will also be summarized.

Intentional isoniazid overdosage among southwestern American Indians.

A 30-month study explored the degree to which self-destructive behavior compromised tuberculosis therapy and prophylaxis among southwestern American Indians. The frequency of isoniazid (INH) overdosage paralleled the extent of INH usage in each tribe and the entent to which INH was perscribed for each tuberculosis category. The authors recommend the careful selection of patients for INH prophylaxis, the dispensing of small amounts at short intervals, the close monitoring of patient compliance with the prescribed drug regimen, and, possiblly, the dispensing of individually wrapped tablets to inhibit the impulsive ingestion of massive amounts of the drug.

Acute isoniazid neurotoxicity in an urban hospital.

OBJECTIVES: To describe the presentation and treatment of acute isoniazid (INH) neurotoxicity appearing at an inner-city municipal hospital. DESIGN: Case series. PARTICIPANTS: Seven patients (eight patient visits) with an age range of 5 days to 14.9 years. RESULTS: At our institution, no children appeared with acute INH neurotoxicity in the period 1985 through 1990, whereas seven patients were treated from 1991 through 1993. This paralleled the rise in the number of children with tuberculous infection and disease seen at our institution, from an average 96 per year to 213 per year during these two time periods. All seven patients were receiving INH daily for tuberculosis (TB) prophylaxis. Accidental ingestion (five episodes) and suicidal attempts (three episodes) accounted for these visits. The total amount ingested range from 14.3 to 99.3 mg/kg (mean, 54 mg/kg). All but one patient presented with afebrile seizures. One patient presented twice with seizures. Acute INH neurotoxicity was not suspected on the first admission; however, when readmitted 4 weeks later with another seizure, the diagnosis of acute INH neurotoxicity was made. INTERVENTION: Intravenous pyridoxine was used in five episodes. Because it was not a stocked item in our pediatric emergency cart (as well as at another hospital, necessitating a transfer of a patient with refractory seizures to our hospital), the average delay was 5.8 hours (range, 1.3 to 13 hours) before it was given. Two patients with refractory seizures failed to respond to anticonvulsants, and their seizures were controlled only after parenteral pyridoxine. CONCLUSIONS: We have seen an increased incidence of acute INH neurotoxicity because of the resurgence of TB in New York City. Others as well may see a similar rise based on local trends in TB infection and disease. Acute INH toxicity should be suspected in children presenting with seizures with or without fever. In patients with a known access to INH, seizures should be considered to be caused by INH toxicity unless proved otherwise. Parenteral pyridoxine, the specific antidote for INH-induced refractory seizures, should be readily available in every emergency department in the areas similarly experiencing increasing trends of TB.

Intentional isoniazid overdosage in young Southeast Asian refugee women.

During a two-year period, from January 1984 through December 1985, six cases of intentional overdosage with isoniazid were reported in young Southeast Asian refugee women. The patients were aged 14 to 23 years, had all immigrated within one year and were receiving isoniazid preventive therapy for tuberculosis infection without disease. Clinically, all patients experienced generalized seizures, and three sustained moderate metabolic acidosis. All recovered uneventfully. Psychiatric evaluations revealed that two patients had major depression; two, adjustment disorders with depressed mood; and two, no psychiatric illness. The latter two patients and two others ingested an excessive amount of isoniazid immediately following an argument with a family member. Because tuberculosis infection is prevalent in refugees immigrating from Southeast Asia, isoniazid, given for six months to one year as preventive therapy, is one of the most frequently prescribed drugs during the early resettlement period. There may be an increased risk of intentional isoniazid overdosage during preventive therapy of young refugee women.