Case-Control Study

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Avermectin Poisoning
Chen-Chang Yang, MD, MPH, DrPH Department of
Environmental Occupational Medicine, National
Yang-Ming University Division of Clinical
Toxicology, Taipei VGH Medical Center, Taipei,
Taiwan EAPCCT, May 6-9, 2008
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Outline

• Introduction
• Pharmacology/Toxicology
• Pharmacokinetics/Toxicokinetics
• Animal Toxicity
• Human Toxicity
• Management
• Conclusions

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Introduction

• A family of macrocyclic lactones with a novel
  mode of action against parasites
• Effective in as low as 10 mg/kg
• First isolated from Streptomyces avermitilis at
  the Kitasato Institute in Japan
• 8 natural avermectin components, namely A1a, A1b,
  A2a, A2b, B1a, B1b, B2a, and B2b, were
  discovered. Compounds of the B series were found
  to be extremely effective
• Ivermectin (22, 23-dihydro-avermectin B1) was
  released for use in animals and humans in 1981

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Vet Parasitol 199559139-56.
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Introduction

• Ivermectin (Mectizan) has become a popular drug
  in the treatment of many animal and human
  parasite infestations, such as onchocerciasis
  (river blindness) because of its
• High tolerability
• Prolonged post-treatment effect
• Broad spectrum of anti-parasitic activity
• Other avermectins, e.g. abamectin, doramectin,
  and emamectin, were subsequently used as
  agricultural insecticides and miticides in animal
  health and/or crop protection

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http//www.vacunasaep.org/imagen/mapa_oncocerca.jp
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Vet Parasitol 199559139-56.
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Pharmacology/Toxicology

• Various avermectin components differ in their
  potency and safety
• All avermectins are believed to share common
  pharmacologic/toxicologic mechanisms
• Activation of glutamate-gated chloride channel
  present in the invertebrate nerve and muscle
  cells and/or through the effect on GABA receptors
  ? paralysis and death of parasites

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J Pharmacol Exp Ther 20002951051-60.
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Pharmacology/Toxicology

• In vertebrates, avermectins produce GABA-mimetic
  effects by acting as an agonist at GABAA
  receptor, stimulating the release of GABA, or
  through other mechanisms
• Mammals are less susceptible to the toxic effects
  of avermectins because GABA-mediated nerves occur
  only in the CNS and avermectins do not readily
  cross the BBB ? wide margin of safety
• May induce hypotension through an increase in
  serum NO levels
• Potential toxicity of solvents/additives (e.g.
  hexanol, butylated hydroxytoluene, propylene
  glycol) in pesticides

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J Pharmacol Exp Ther 20002951051-60.
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Hum Exp Toxicol 200322433-7.
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Pharmacokinetics/Toxicokinetics

• Absorbed orally, parenterally, and dermally
• Maximum serum concentrations (ivermectin)
  appeared 2.7 to 5h after oral dosing, and
  elimination half-life was 28?10h among healthy
  volunteers and treated subjects
• Largely excreted into the bile and feces
• Urinary excretion 0.5-2.0
• No relevant information in poisoned subjects

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Animal Toxicity

• High doses of avermectins do cause neurotoxicity
• Manifestations mydriasis, emesis, anorexia,
  diarrhea, drooling, depression, ataxia, stupor,
  coma, tremors, blindness, and death
• Cattle injected s.c. with 30X the recommended
  dose of ivermectin (i.e. 6 mg/kg) no signs of
  toxicity
• Higher (40X) dose toxicity and death
• Dogs (beagles) showed no toxic effects at 2 mg/kg
• Mydriasis and tremors were seen at 5 mg/kg (gt
  200X the therapeutic dose) of ivermectin and
  more pronounced toxic signs at 10 mg/kg
• Dose-related toxicity was also found in chickens

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Regul Toxicol Pharmacol 200747257-60.
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Animal Toxicity

• Young animals are more sensitive. For example, a
  kitten exhibited toxicosis after receiving s.c.
  administration of 0.3 mg/kg of ivermectin
• Animals deficient in p-glycoprotein, a component
  of the BBB, are also more sensitive (gt50X) than
  animals with normal p-glycoprotein levels
• Findings in abamectin-sensitive CF-1 mice
• Collies allow more avermectins into the CNS
  because of mdr1 gene mutation
• Ivermectin a potent inhibitor of
  p-glycoprotein?
• Possible drug (toxin)-drug (toxin)
  interactions?

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Filaria J 20032(S1)S8
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Figure 1. CF-1 mouse insensitive to abamectin
(0.8 mg/kg) demonstrating moderate
p-glycoprotein expression in capillary
endothelial cells
Figure 3. CF-1 mouse sensitive to abamectin
demonstrating no p-glycoprotein expression
Figure 2. CD-1 mouse insensitive to abamectin
demonstrating slight to moderate p-glycoprotein
expression Toxicol Appl Pharmacol
1997143357-65.
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Toxicol Appl Pharmacol 1997143357-65.
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Human Toxicity

• Adverse effects of ivermectin therapy are not
  uncommon and most of them appear within 48h of
  initiating therapy ?
• myalgia, pruritus, painful skin edema,
  hypotension, and dyspnea (Mazzotti-type reaction)
• Little data concerning human avermectin poisoning
• Two children had vomiting, somnolence,
  tachycardia, hypotension, and mydriasis after
  ivermectin overdose
• A 46-year-old man developed marked drowsiness,
  unconsciousness, weakness, ataxia, and visual
  changes after iatrogenic overdose by 200 mg of
  ivermectin

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Human Toxicity

• Chung et al (1999) reported 19 patients with
  agricultural avermectin poisoning. Most patients
  had certain CNS and GI effects after mild
  poisoning and showed hypotension and coma
  following severe poisoning
• Sriapha et al (2006) reported 49 cases with
  abamectin poisoning. Most patients were
  asymptomatic or had mild symptoms
• 16 cases (34) had serious symptoms,
  manifesting coma, hypotension, and metabolic
  acidosis 5 died
• Emamectin poisoning in a 67-year-old man GI
  upset, mild CNS depression, and aspiration

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Management

• Prompt GI decontamination followed by activated
  charcoal therapy may be helpful
• Picrotoxin, a GABA antagonist, has been proposed
  as an antidote in treating ivermectin toxicosis
  in animals. However, its use is not recommended
  because of its seizure activity and narrow margin
  of safety
• Neostigmine in a dose of 25-150 mg showed some
  effects in the treatment of ivermectin toxicosis
  in cats

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Management

• Physostigmine in a dose of 1-2 mg was shown to
  temporarily reverse CNS depression and reduce
  seizure-like behaviors in the management of
  comatose animals (collies)
• Avermectins do not regulate cholinergic nerve
  transmissions and both neostigmine and
  physostigmine are unlikely to be effective
• Flumazenil probably ineffective
• Conclusions no effective antidote

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Conclusions

• Avermectins are newer pesticides with a wide
  margin of safety
• Human avermectin poisonings are uncommon
• Avermectins can produce dose-related toxicity
  primarily through their effects on GABAergic
  neurons
• Severely poisoned patients may develop coma,
  hypotension, metabolic acidosis, and even death
• The prognosis of avermectin poisoned patients is
  generally favorable unless complicated with
  severe hypotension or aspiration

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