4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes.

Liver injury due to acetaminophen (APAP) overdose is the major cause of acute liver failure in the United States. While treatment with N-acetylcysteine is the current standard of care for APAP overdose, anecdotal evidence suggests that administration of 4-methylpyrazole (4MP) may be beneficial in the clinic. The objective of the current study was to examine the protective effect of 4MP and its mechanism of action. Male C57BL/6J mice were co-treated with 300 mg/kg of APAP and 50 mg/kg of 4MP. The severe liver injury induced by APAP at 6 h as indicated by elevated plasma alanine aminotransferase activities, centrilobular necrosis, and nuclear DNA fragmentation was almost completely eliminated by 4MP. In addition, 4MP largely prevented APAP-induced activation of c-Jun N-terminal kinase (JNK), mitochondrial translocation of phospho-JNK and Bax, and the release of mitochondrial intermembrane proteins. Importantly, 4MP inhibited the generation of APAP protein adducts and formation of APAP-glutathione (GSH) conjugates and attenuated the depletion of the hepatic GSH content. These findings are relevant to humans because 4MP also prevented APAP-induced cell death in primary human hepatocytes. In conclusion, early treatment with 4MP can completely prevent liver injury after APAP overdose by inhibiting cytochrome P450 and preventing generation of the reactive metabolite.

A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning.

INTRODUCTION: Acetylcysteine prevents hepatic injury when administered soon after acetaminophen overdose. The most commonly used treatment protocols are a 72-hour oral and a 21-hour intravenous (IV) protocol. Between 1984 and 1994, 409 patients were enrolled in a study to describe the outcomes of patients who were treated using a 48-hour IV protocol. In 1991, an interim analysis reported the first 223 patients. The objective of this manuscript is to report the rates of hepatotoxicity and adverse events occurring during a 48-hour IV acetylcysteine protocol in the entire 409 patient cohort. METHODS: This was a multicenter, single-arm, open-label clinical trial enrolling patients who presented with a toxic serum acetaminophen concentration within 24 h of acute acetaminophen ingestion. Patients were treated with 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses. Serum aminotransferase activities were measured every 8 h during the protocol, and adverse events were recorded. The primary outcome was the percentage of subjects who developed hepatotoxicity defined as a peak serum aminotransferase greater than 1000 IU/L. RESULTS: Four hundred and nine patients were enrolled, and 309 met inclusion for the outcome analysis. The overall percentage of patients developing hepatotoxicity was 18.1%, and 3.4% of patients treated within 10 h developed hepatotoxicity. One acetaminophen-related death occurred in a patient treated at 22 h. Adverse events occurred in 28.9% of enrolled subjects; the most common adverse events were nausea, vomiting, and flushing, and no events were rated as serious by the investigator. CONCLUSIONS: Acetaminophen-overdosed patients treated with IV acetylcysteine administered as 140 mg/kg loading dose followed by 70 mg/kg every 4 h for 12 doses had a low rate of hepatotoxicity and few adverse events. This protocol delivers a higher dose of acetylcysteine which may be useful in selected cases involving very large overdoses.

Treatment of pain or fever with paracetamol (acetaminophen) in the alcoholic patient: a systematic review.

An unexpected clinical question has emerged in the treatment of pain or fever in the alcoholic patient: Is paracetamol a safe medication for the alcoholic patient? After decades of use in a variety of patients, sporadic reports suggest a relationship between liver injury and the use of paracetamol by alcoholic patients. We performed a systematic review of the medical literature to answer the question: Can administration of therapeutic doses of paracetamol cause hepatic injury in the alcoholic patient? After extensive data retrieval, each article in any language that involved the use of paracetamol by an alcoholic patient was abstracted and categorized for strength of evidence. Class I data (randomized, controlled trials) show that repeated ingestion of a therapeutic dose of paracetamol over 48 hours by patients with severe alcoholism did not produce an increase in hepatic aminotransferase enzyme levels nor any clinical manifestations compared with a placebo group. Class II data (prospective, nonrandomized trials) reveal that therapeutic doses of paracetamol have been administered to patients and an array of liver diseases (alcoholic, primary biliary, postnecrotic, or unspecified cirrhosis or alcoholic, acute viral, chronic active, or other infectious hepatitis) for periods up to 14 days without adverse effect. Finally, in several studies, a 1- to 2-g single dose of paracetamol was administered to alcoholic patients to study metabolism, again without adverse effect. In contrast, Class III data (retrospective case reviews and case reports) describe hepatic injury after repeated paracetamol ingestion with therapeutic intent, although usually not at therapeutic doses. Unfortunately, the information contained in Class III reports is often incomplete and contradictory. The history of ingestion is often unknown or contradicts other clinical information provided. For example, the history may indicate a therapeutic dose, but the serum paracetamol is elevated to levels only produced by ingestion much larger than the history indicates. In summary, all methodologically sound studies available indicate that therapeutic dosing of paracetamol to the alcoholic patient is not associated with hepatic injury. In fact, there is no change at all in hepatic aminotransferase enzymes, prothrombin time, or other biochemical parameters when compared with a placebo group in well-designed trials. Unless stronger evidence of a potentially dangerous interaction emerges, the use of paracetamol in the alcoholic patient is reasonable. During chronic treatment of pain, paracetamol may be preferred in the compliant alcoholic patients owing to the adverse effects associated with long-term use of nonsteroidal anti-inflammatory agents.

Hydrogen sulfide poisoning: an antidotal role for sodium nitrite?

In 2 separate incidents, 6 patients were poisoned with hydrogen sulfide (H2S) in sewer gas. In the first incident, mixing acid- and sodium hydroxide-based drain cleaners in a confined space resulted in 4 poisonings and 2 deaths. Three would-be rescuers were seriously poisoned and 1 died. Two survivors had neurological sequelae. Sodium nitrite appeared to have some clinical efficacy in 1 case. The second incident involved 2 patients working on a pump in a sewage pond. A patient lying on a raft close to the pond surface was seriously poisoned; sodium nitrite was clinically efficacious and this patient survived without developing neurological sequelae. Sodium nitrite deserves further clinical study as a potential H2S antidote.

Cimetidine as adjunctive treatment for acetaminophen overdose.

The aim of this study was to determine if cimetidine in addition to N-acetylcysteine and standard supportive care provide additional hepatoprotection following acute acetaminophen poisoning. It was designed as a prospective study with alternate month treatment protocol, and the work was carried out at a regional certified poison information centre. For a 2-year period, consultations received by the Rocky Mountain Poison Center involving acute acetaminophen overdose patients with a serum level above the nomogram line, but who would not receive N-acetylcystine therapy until at least 8 h postingestion, were prospectively evaluated for adjunctive treatment with cimetidine. All patients received standard supportive therapy and N-acetylcysteine treatment. During odd numbered months, cimetidine 300 mg was administered intravenously every 6 h for the duration of N-acetylcysteine therapy. Forty-one cimetidine treated patients were compared to 66 patients in the control group. The peak measured AST levels (+/- s.e.) were 1259+/-330 and 1301+/-451 for the control and cimetidine treatment groups, respectively (P = 0.94). Fourteen of 64 patients (21%) in the control group and 8/41 patients (20%) in the cimetidine group developed an AST > 1000 IUL-1. There were no statistical differences between the cimetidine-treated and control groups when classified by AST < 100 IUL-1, 100-1000 IUL-1, or > 1000 IUL-1. The addition of cimetidine therapy to standard N-acetylcysteine treatment did not provide additional hepatoprotection in acutely acetaminophen poisoned patients when treatment was started later than 8 h post overdose.(ABSTRACT TRUNCATED AT 250 WORDS)

Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers.

The safety, efficacy and pharmacokinetic parameters of 5 g of hydroxocobalamin given intravenously, alone or in combination with 12.5 g of sodium thiosulfate, were evaluated in healthy adult men who were heavy smokers. Sodium thiosulfate caused nausea, vomiting, and localized burning, muscle cramping, or twitching at the infusion site. Hydroxocobalamin was associated with a transient reddish discoloration of the skin, mucous membranes, and urine, and when administered alone produced mean elevations of 13.6% in systolic and 25.9% in diastolic blood pressure, with a concomitant 16.3% decrease in heart rate. No other clinically significant adverse effects were noted. Hydroxocobalamin alone decreased whole blood cyanide levels by 59% and increased urinary cyanide excretion. Pharmacokinetic parameters of hydroxocobalamin were best defined in the group who received both antidotes: t1/2 (alpha), 0.52 h; t1/2 (beta), 2.83 h; Vd (beta), 0.24 L/kg; and mean peak serum concentration 753 mcg/mL (560 mumol/L) at 0-50 minutes after completion of infusion. Hydroxocobalamin is safe when administered in a 5 gram intravenous dose, and effectively decreases the low whole blood cyanide levels found in heavy smokers.

Exchange transfusion and multidose activated charcoal following vancomycin overdose.

The inadvertent administration of a concentrated vancomycin solution to a 47 day-old premature male twin resulted in extremely high vancomycin levels and altered renal function. A 1.5 volume exchange transfusion did not change the measured vancomycin level. Multiple doses of oral activated charcoal, 1 g/kg, were administered beginning 5 h after the exchange transfusion. A calculated half-life of vancomycin before the exchange transfusion was 35 h. The half-life after the exchange transfusion and during charcoal administration was calculated to be 12 h. The only apparent adverse effect of this vancomycin overdose was reversible nephrotoxicity. The infant's hearing, tested by brainstem auditory responses, was normal. The higher volume of distribution of vancomycin in infants may preclude removing significant amounts of this drug by exchange transfusion. Gastrointestinal dialysis with activated charcoal warrants consideration in cases of vancomycin overdose in neonates.

Ibuprofen overdose in adults.

A prospective study of 63 ibuprofen overdose cases in adults (14 years or older) reported to the Rocky Mountain Poison and Drug Center between March 1987 and February 1988 was done to determine the incidence of renal injury and utility of timed plasma levels. No serious toxicity was noted. No CNS or other significant toxicity was seen with ingestion of less than 3 g. Two patients with normal serum creatinines had minor elevations of the blood urea nitrogen after ingesting 4 and 4.8 g. Timed plasma levels (125 total) from patients without coingestants from this study (48) and previously published reports (77) were compared with a previously described nomogram. The resulting nomogram revision may be useful in determining which initially asymptomatic patients are likely to remain so. Renal function tests are not routinely required for patients ingesting less than 6 g. Four h of observation is sufficient for asymptomatic patients not requiring psychiatric admission. Plasma ibuprofen levels are not required for proper patient management.

Fluoride ingestion in children: a review of 87 cases.

All cases of fluoride ingestion in children younger than 12 years old reported to the Rocky Mountain Poison Center between January 1 and December 31, 1986, were retrospectively reviewed. Eighty-seven cases were identified. Eighty-four cases involved accidental ingestion of dental fluoride products in the home (tablets, drops, rinses) in children 8 months to 6 years old. Two older children (8 and 9 years old) became symptomatic after fluoride treatment by a dentist. A 13-month-old child died after ingesting an unknown amount of sodium fluoride insecticide, the only insecticide exposure in our series. Postmortem total serum calcium value was 4.8 mg/dL (normal 8.8 to 10.3). No other patients had serious symptoms or sequelae. Twenty-six (30%) of 87 became symptomatic, with gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain) in 25 patients and drowsiness in 1. Only 3 patients became symptomatic later than 1 hour after ingestion. Analysis of data from 70 cases with sufficient information revealed that as the amount of fluoride ingested increased, the percentage of patients with symptoms increased. Not including the fatal case, 6 patients had serum calcium levels measured, and all were normal. Children who ingested up to 8.4 mg/kg of elemental fluoride in dental products had mild and self-limited symptoms, mostly gastrointestinal.

Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol.

STUDY OBJECTIVE: To determine the safety and efficacy of a 48-hour IV N-acetylcysteine (IV NAC) treatment protocol for acute acetaminophen overdose. DESIGN: Nonrandomized trial open to all eligible patients. SETTING: Multicenter; hospitals included moderate- and high-volume private, university, and municipal hospitals in urban and suburban settings. TYPE OF PARTICIPANTS: Two hundred twenty-three patients were entered. Of these, 179 met inclusion criteria: acute acetaminophen overdose, plasma acetaminophen concentration above the treatment nomogram line, treatment with IV NAC according to the protocol, and sufficient data to determine outcome. INTERVENTIONS: IV NAC treatment consisted of a loading dose of 140 mg/kg followed by 12 doses of 70 mg/kg every four hours. MEASUREMENTS AND MAIN RESULTS: Patients were grouped for analysis according to risk group based on the initial plasma acetaminophen concentration. Hepatotoxicity (aspartate aminotransferase or alanine aminotransferase of more than 1,000 IU/L) developed in 10% (five of 50) of patients at "probable risk" when IV NAC was started within ten hours of acetaminophen ingestion and in 27.1% (23 of 85) when therapy was begun after ten to 24 hours. Among "high-risk" patients first treated 16 to 24 hours after overdose, hepatotoxicity occurred in 57.9% (11 of 19). There were two deaths (two of 179, 1.1%). Adverse reactions resulting from NAC occurred in 32 of 223 cases (14.3%), consisting in 29 of 32 patients (91% of reactions) of transient, patchy, skin erythema or mild urticaria during the loading dose that did not require discontinuation of therapy. CONCLUSION: This 48-hour IV NAC protocol is safe and effective antidotal therapy for acetaminophen overdose. Based on available data, it is equal to 72-hour oral and 20-hour IV treatment protocols when started early and superior to the 20-hour IV regimen when treatment is delayed. Further study will be required to determine its relative efficacy in the high-risk patient treated very late.

Hyperbaric oxygen treatment for carbon tetrachloride poisoning.

Carbon tetrachloride (CCl4) undergoes hepatic reductive metabolism to trichloromethyl (.CCl3) and peroxytrichloromethyl (CCl3OO.) free radicals, toxic intermediates which may initiate hepatocellular damage. Recent investigations have demonstrated a potential role for hyperoxia and hyperbaric oxygen as therapeutic interventions for CCl4 poisoning. Elevated oxygen concentrations in vitro and in vivo reduce lipid peroxidation and hepatotoxicity. In vivo studies of hyperbaric oxygen following administration of CCl4 in a rat model have shown improved survival and decreased hepatotoxicity. Case reports of human poisoning, with potentially lethal ingested doses of CCl4, also suggest a potential role for treatment with hyperbaric oxygen. Hyperoxia may act by altering the metabolism of CCl4. These studies and case reports support the recommendation that 100% normobaric and hyperbaric oxygen should be treatment considerations for CCl4 poisoning.

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.