Search Results (5)

N-acetyl para-aminophenol was suggested as a safer alternative to other drugs on the market for pain and fever in 1948. It was given the generic name “acetaminophen” in 1951 and the trade name “Tylenol” when it was put on the market in the USA in 1955 as a prescription drug to treat pediatric fever. It also received the generic name “paracetamol” in the UK where it was initially marketed in 1956 under the name “Panadol.” Toxicity from overdose of acetaminophen was reported in 1966. Research at the US National Institutes of Health uncovered the mechanisms of toxicity and proposed a treatment in a foundational series of papers in 1973 and 1974. A nomogram was developed in 1973 and published in 1975 to guide estimation of patient risk of hepatic toxicity. Rapid development followed utilizing acetylcysteine given both orally and intravenously. Various protocols and methods of administration have been employed over time with the primary use today of acetylcysteine intravenously as the therapeutic method. The nomogram has been revised over time to the current version, published in 2023, which allows stratification of patients to a high-risk group over 300 mg/L at 4 h and standard risk above 150 mg/L at 4 h, except in the UK where the standard risk is defined very conservatively with a line above 100 mg/L at 4 h. Adjunct therapy with fomepizole in patients with massive ingestions, delay until arrival in a health care facility or renal injury has been proposed. The mortality rate with treatment has been substantially reduced and recovery from hepatic injury is achieved in almost all patients. Full article

Methanol is a widely used industrial and household alcohol that poses significant health risks upon exposure. Despite its extensive use, methanol poisoning remains a critical public health concern globally, often resulting from accidental or intentional ingestion and outbreaks linked to contaminated beverages. Methanol toxicity stems from its metabolic conversion to formaldehyde and formic acid, leading to severe metabolic acidosis and multiorgan damage, including profound CNS effects and visual impairments. Epidemiological data underscore the widespread impact of methanol poisoning, with alarming case fatality rates reported in various countries. Comprehensive prevention and effective management strategies are urgently needed to address the significant morbidity and mortality associated with methanol poisoning. The clinical manifestations of methanol toxicity vary between adult and pediatric populations and between acute and chronic exposure. Adults typically present with gastrointestinal and neurological symptoms, whereas pediatric patients often exhibit more severe outcomes due to differences in metabolism and body weight. The diagnosis of methanol poisoning involves a combination of clinical evaluation, laboratory testing, and advanced diagnostic techniques. The identification of metabolic acidosis, elevated anion and osmolal gaps, and confirmation through methanol and formate levels are critical for accurate diagnosis. Timely intervention is crucial, and the management of methanol poisoning includes securing the airway, breathing, and circulation; addressing metabolic acidosis with sodium bicarbonate; administering antidotes such as fomepizole or ethanol; and administering hemodialysis, which plays a pivotal role in eliminating methanol and its toxic metabolites, especially in severe cases. The complexity of methanol poisoning necessitates a comprehensive approach encompassing early recognition, prompt intervention, and coordinated care among healthcare providers. Increased awareness, effective prevention strategies, and timely treatment protocols are essential to mitigate severe health consequences and improve patient survival and recovery. Full article

The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity—in contrast to the well-established mechanism of AAP hepatotoxicity. Subsequent “reverse translational” studies in the pre-clinical setting have identified novel mechanisms of action of high-dose AAP, including modulation of JAK-STAT signaling in both the tumor cell and the tumor immune microenvironment. Importantly, these effects are free-radical-independent and not reversed by concurrent administration of the established AAP rescue agents fomepizole and NAC. By administering high-dose AAP concurrently with fomepizole and NAC, 100-fold higher AAP levels than those of standard dosing can be achieved in mice without detected toxicity and with substantial anti-tumor efficacy against commonly used mouse models of lung and breast cancer that are resistant to standard first-line anti-cancer therapies. With these recent advances, additional clinical trials of high-dose AAP with concurrent NAC and fomepizole-based rescue are warranted. Full article

Methanol poisoning is a challenging issue due to its inducing acute multiple organ failures, and especially due to a lack of preparedness, available antidotes, and management protocols. The current study presents six cases of methanol poisoning that attended the emergency department of King Abdul Aziz Specialist Hospital, Taif, Saudi Arabia, between March and November 2022. All of the patients suffered from severe metabolic acidosis and visual impairment following the ingestion of homemade alcoholic beverages and colonia. Three patients were comatose, suffered from post-cardiac pulmonary arrest, and, finally, died, while the other three were non-comatose and discharged from the ICU after improvement. Management was based on clinical symptoms and other laboratory findings due to a shortage of methanol level measurement resources. The antidote, fomepizole, was not given to all of the cases due to its deficiency, and ethanol was given only to one patient due to difficulties in administering it without monitoring its concentration. Methanol poisoning and its outbreak provide insights into the dangers of hazardous homemade alcohol and other pharmaceutical preparations that might be adulterated with methanol, particularly to the shortage of suitable diagnostic testing and antidotes in addition to poor resources for management of intoxicated patients in some regions of Saudi Arabia. Full article

Silymarin is known for its hepatoprotective effects. Although there is solid evidence for its protective effects against Amanita phalloides intoxication, only inconclusive data are available for alcoholic liver damage. Since silymarin flavonolignans have metal-chelating activity, we hypothesized that silymarin may influence alcoholic liver damage by inhibiting zinc-containing alcohol dehydrogenase (ADH). Therefore, we tested the zinc-chelating activity of pure silymarin flavonolignans and their effect on yeast and equine ADH. The most active compounds were also tested on bovine glutamate dehydrogenase, an enzyme blocked by zinc ions. Of the six flavonolignans tested, only 2,3-dehydroderivatives (2,3-dehydrosilybin and 2,3-dehydrosilychristin) significantly chelated zinc ions. Their effect on yeast ADH was modest but stronger than that of the clinically used ADH inhibitor fomepizole. In contrast, fomepizole strongly blocked mammalian (equine) ADH. 2,3-Dehydrosilybin at low micromolar concentrations also partially inhibited this enzyme. These results were confirmed by in silico docking of active dehydroflavonolignans with equine ADH. Glutamate dehydrogenase activity was decreased by zinc ions in a concentration-dependent manner, and this inhibition was abolished by a standard zinc chelating agent. In contrast, 2,3-dehydroflavonolignans blocked the enzyme both in the absence and presence of zinc ions. Therefore, 2,3-dehydrosilybin might have a biologically relevant inhibitory effect on ADH and glutamate dehydrogenase. Full article