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Toxicity tests in animals are grounded on two main assumptions: first, the effects observed in laboratory animals can be extrapolated to humans, especially when adjusted for body surface area; second, high-dose exposure in animals is essential to identify potential human hazards from lower doses. This is based on the quantal dose-response concept, which faces the challenge of extrapolating results from relatively few test animals to much larger human populations. For example, a 0.01% incidence...
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Treatment strategies for poisoning are a critical aspect of emergency medicine, focusing on preventing the absorption of toxins and enhancing their elimination. When a poisoning incident occurs, the first response is to halt exposure and decontaminate the patient, particularly through gastrointestinal (GI) methods if the poison was ingested.Gastrointestinal Decontamination Techniques:Activated charcoal is the cornerstone of GI decontamination. It works through adsorption, binding the toxin to...
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Drug toxicity quantifies the harm a compound causes to an organism, varying by dose and potentially impacting whole systems or specific organs like the liver. Toxic reactions may arise from venomous insect or spider bites, with effects ranging from mild symptoms to severe outcomes such as brain damage or death. Common forms of acute poisoning include ethanol intoxication and overdose of pain or fever medications, with substances like GHB and heroin being particularly lethal at doses close to...
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Ivermectin is generally safe, but can cause severe neurotoxicity, especially with high doses or in susceptible individuals. Understanding ivermectin toxicity requires considering drug interactions, genetics, and exposure levels.

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Area of Science:

  • Pharmacology
  • Toxicology
  • Neuroscience

Background:

  • Ivermectin, a macrocyclic lactone, is widely used for parasitic infections with a history of safety.
  • Emerging evidence suggests ivermectin can cause significant central nervous system toxicity.
  • The COVID-19 pandemic saw increased off-label use, raising concerns about ivermectin toxicity.

Purpose of the Study:

  • To comprehensively review the toxicological profile of ivermectin.
  • To identify factors contributing to ivermectin-induced neurotoxicity.
  • To characterize risks associated with ivermectin use, particularly during the COVID-19 pandemic.

Main Methods:

  • Integration of data from human clinical trials, pharmacovigilance, case reports, animal studies, and environmental investigations.
  • Analysis of P-glycoprotein (ABCB1/MDR1) function in blood-brain barrier transport.
  • Evaluation of species-, breed-, age-, dose-, and route-dependent susceptibility in animal models.

Main Results:

  • Controlled human trials show ivermectin is well-tolerated at therapeutic doses with mild adverse events.
  • Real-world data reveal rare but severe neurotoxic events (encephalopathy, seizures, coma) after supratherapeutic or standard-dose exposure in susceptible individuals.
  • Impaired blood-brain barrier efflux via P-glycoprotein dysfunction is a key mechanism of neurotoxicity.
  • Animal studies demonstrate significant variability in susceptibility based on genetics, age, and dosage.
  • Off-label use during the pandemic led to increased toxic exposures without proven benefit.

Conclusions:

  • Ivermectin neurotoxicity is a predictable outcome of pharmacokinetic and host-specific factors, not an inherent flaw.
  • Understanding transporter biology and exposure patterns is crucial for managing ivermectin toxicity risks.
  • While ivermectin has therapeutic value, its safety profile necessitates careful consideration of dose, individual susceptibility, and off-label use, especially in vulnerable populations.