Carfentanil toxicity in the African green monkey: Therapeutic efficacy of naloxone

Langston, Jeffrey L.; Moffett, Mark C.; Makar, Jennifer R.; Burgan, Bradley M.; Myers, Todd M.

doi:10.1016/j.toxlet.2020.02.008

Cited by 9 publications

(4 citation statements)

References 22 publications

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“…This estimate well fitted the experimental data available on carfentanil in other laboratory non-human primate studies. In female rhesus monkeys, respiratory depression was produced at IV doses of 0.6 and 1.0 μg/kg [ 37 ]. In Rocky Mountain wapiti ( Cervus elaphus nelsoni ), a regimen combining IM 10 mg/kg carfentanil and 0.1 mg/kg xylazine (administered for anesthesia) decreased the RR, with complete reversion using naloxone administered 10 min later [ 38 ].…”

Section: Specificities Of the Main Fentanyl Analogsmentioning

confidence: 99%

Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs—Lessons from Animal Studies

et al. 2023

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In 2020, fentanyl and its analogs contributed to ~65% of drug-attributed fatalities in the USA, with a threatening increasing trend during the last ten years. These synthetic opioids used as potent analgesics in human and veterinary medicine have been diverted to recreational aims, illegally produced and sold. Like all opioids, central nervous system depression resulting from overdose or misuse of fentanyl analogs is characterized clinically by the onset of consciousness impairment, pinpoint miosis and bradypnea. However, contrasting with what observed with most opioids, thoracic rigidity may occur rapidly with fentanyl analogs, contributing to increasing the risk of death in the absence of immediate life support. Various mechanisms have been proposed to explain this particularity associated with fentanyl analogs, including the activation of noradrenergic and glutamatergic coerulospinal neurons and dopaminergic basal ganglia neurons. Due to the high affinities to the mu-opioid receptor, the need for more elevated naloxone doses than usually required in morphine overdose to reverse the neurorespiratory depression induced by fentanyl analogs has been questioned. This review on the neurorespiratory toxicity of fentanyl and analogs highlights the need for specific research focused on these agents to better understand the involved mechanisms of toxicity and develop dedicated strategies to limit the resulting fatalities.

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Section: Specificities Of the Main Fentanyl Analogsmentioning

confidence: 99%

Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs—Lessons from Animal Studies

et al. 2023

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“…As such, the goal of Dr. Myer's laboratory is to first define the progression of opioid (carfentanil) intoxication, which would then inform the selection of a 'trigger' treat and finally evaluation of dose-specific MCM (naloxone) efficacy and safety. Based on subcutaneously-administered carfentanil studies, where bradypnea was used as the primary endpoint, the probability of incapacitation (ED 50 values) at 1x and 1.6x were determined to be 0.71 and 1.15 μg/kg, respectively [65]. The clinical signs of intoxication were found to be reliable, though the time to onset of symptoms was variable.…”

Section: The African Green Monkey (Agm) As a Laboratory Model For Pharmaceutical-based Agent Characterization And Medical Countermeasuresmentioning

confidence: 99%

“…Recovery to "normal functioning" occurred between 10 and 40 minutes after treatment. Lower naloxone doses often produced only transient recovery, necessitating readministration of the MCM [65]. Dr. Myers then discussed redirection of the project to quantify toxicity, MCM efficacy and safety via an automated operant behavioral testing approach instead.…”

Section: The African Green Monkey (Agm) As a Laboratory Model For Pharmaceutical-based Agent Characterization And Medical Countermeasuresmentioning

confidence: 99%

National Institutes of Health (NIH) Executive Meeting Summary: Developing Medical Countermeasures to Rescue Opioid-Induced Respiratory Depression (a Trans-Agency Scientific Meeting)—August 6/7, 2019

et al. 2019

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On August 6th, 2019, a two-day trans-agency scientific meeting was convened by the United States (U.S.) National Institute of Allergy and Infectious Diseases (NIAID/NIH) on the research and development of medical countermeasures (MCMs) and treatment strategies to mitigate synthetic opioid-induced toxicities. This trans-agency meeting was an initiative of the Chemical Countermeasures Research Program (CCRP) and organized by the NIAID in collaboration with the National Institute of Drug Abuse (NIDA), the Biomedical Advanced Research and Development Authority (BARDA), the Food and Drug Administration (FDA), and the Defense Threat Reduction Agency (DTRA). The CCRP is part of the larger NIH biodefense research program coordinated by NIAID, which also includes MCM research and development programs against biological, radiological, and nuclear threats. Its overarching goal is to integrate cutting-edge research and technological advances in science and medicine to enhance the nation's medical response capabilities during and after a public health emergency involving the deliberate or accidental release of toxic chemicals. The potential of a mass casualty public health event involving synthetic opioids is a rapidly growing concern. As such, the overall goals of this trans-agency meeting are to better understand opioidinduced toxicities and advance the development of MCMs to mitigate and reverse opioid-induced respiratory depression (OIRD) to prevent consequential mortality. The primary objectives of the meeting were (1) highlight the latest research on mechanisms of OIRD and related toxicities, animal models, diagnostics, delivery technologies, and emerging new treatment options to prevent lethality; (2) identify current knowledge gaps to advance medical countermeasure development; (3) hear from the U.S. FDA on regulatory considerations to support new technology and treatment approaches; and (4) provide a forum for networking and collaborative partnerships. To accomplish this, a diverse group of almost 200 US domestic and international subject matter experts spanning fundamental and translational research from academia, industry, and government came together in-person to share their collective expertise and experience in this important field. This report briefly summarizes the information presented throughout the meeting, which was also webcast live in its entirety to registered remote attendees.Keywords Opioids . Medical countermeasures . Respiratory depression . NIAID Synthetic opioids such as fentanyl, carfentanil, and their congeners are currently of the utmost public health concern to the US government. This concern stems from multiple factors to include their extremely high potency, wide pharmaceutical and illicit availability, and the potential of large-scale intentional as well as accidental release that could result in mass poisonings and casualties. Consequently, these compounds are not only considered public health risks under the ongoing "opioid epidemic," but also chemical threats by both civilian and militar...

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“…7 Both fentanyl and carfentanil were placed in Schedule II of the Controlled Substances Act, meaning that they have "high potential for abuse" and are "considered dangerous". 8 Carfentanil-induced toxicity is reported in nonhuman primates at a dose of 0.8 μg/kg, 9 which would translate to a dose of only 56 μg (approximately the mass of a grain of salt) in an average-sized human. Carfentanil's only approved clinical use is in veterinary medicine as a large-animal tranquilizer; 7 however, illicitly manufactured carfentanil has been found in street mixtures intended for recreational use by humans.…”

mentioning

confidence: 99%

Efficacy and Selectivity of Monovalent and Bivalent Vaccination Strategies to Protect against Exposure to Carfentanil, Fentanyl, and Their Mixtures in Rats

Crouse

Gradinati

et al. 2022

ACS Pharmacol. Transl. Sci.

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Drug-related fatal overdoses have significantly increased in the past decade due to the widespread availability of illicit fentanyl and other potent synthetic opioids such as carfentanil. Deliberate or accidental consumption or exposure to carfentanil, fentanyl, and their mixture induces respiratory depression and bradycardia that can be difficult to reverse with the opioid receptor antagonist naloxone. Vaccines offer a promising strategy to reduce the incidence of fatalities associated with fentanyl-related substances, as well as treatment for opioid use disorder (OUD). This study reports monovalent and bivalent vaccination strategies that elicit polyclonal antibody responses effective in protecting against the pharmacological actions of carfentanil, fentanyl, or carfentanil/fentanyl mixtures. Rats were prophylactically immunized with individual conjugate vaccines containing either carfentanil- or fentanyl-based haptens, or their combination in bivalent vaccine formulations, and then challenged with carfentanil, fentanyl, or their mixture. First, these studies identified a lead vaccine protective against carfentanil-induced antinociception, respiratory depression, and bradycardia. Then, efficacy against both carfentanil and fentanyl was achieved through bivalent vaccination strategies that combined lead anti-carfentanil and anti-fentanyl vaccines via either heterologous prime/boost or co-administration immunization regimens. These preclinical data support the development of vaccines as a viable strategy to prevent toxicity from exposure to excessive doses of carfentanil, fentanyl, or their mixtures.

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Carfentanil toxicity in the African green monkey: Therapeutic efficacy of naloxone

Cited by 9 publications

References 22 publications

Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs—Lessons from Animal Studies

Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs—Lessons from Animal Studies

National Institutes of Health (NIH) Executive Meeting Summary: Developing Medical Countermeasures to Rescue Opioid-Induced Respiratory Depression (a Trans-Agency Scientific Meeting)—August 6/7, 2019

Efficacy and Selectivity of Monovalent and Bivalent Vaccination Strategies to Protect against Exposure to Carfentanil, Fentanyl, and Their Mixtures in Rats

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