Improved Admixture Vaccine of Fentanyl and Heroin Hapten Immunoconjugates: Antinociceptive Evaluation of Fentanyl-Contaminated Heroin

Hwang, Candy S.; Smith, Lauren C.; Natori, Yoshihiro; Zhou, Bin; Janda, Kim D.

doi:10.1021/acsomega.8b01478

Cited by 31 publications

(43 citation statements)

References 26 publications

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“…Maximum antinociceptive potency shifts following vaccine administration were approximately 3-and 5-fold for IV and SC heroin, respectively and lasted for at least seven-toeight weeks. The present results are consistent with previous heroin conjugate vaccine studies in male and female mice (Bremer et al, 2017;Bremer et al, 2014;Hwang et al, 2018a;Hwang et al, 2018b;Hwang et al, 2018c;Jalah et al, 2015;Matyas et al, 2014;Sulima et al, 2017) and Schwienteck 15 male rats (Schlosburg et al, 2013;Stowe et al, 2011;Sulima et al, 2017). The present results extended these previous findings to the inclusion of female rats and no sex difference in vaccine effectiveness was observed.…”

Section: Schwienteck 14supporting

confidence: 93%

“…In addition, midpoint antibody titer levels in the present study were comparable to previous levels in mice (Bremer et al, 2017). The magnitude of heroin vaccineinduced potency shifts was similar to previous heroin-TT conjugate vaccine results using schedule-controlled responding in nonhuman primates (4-fold) and antinociceptive effects in female mice (5-7 fold) for heroin administered intramuscular (IM) and IP, respectively (Bremer et al, 2017;Hwang et al, 2018b;Hwang et al, 2018c). However, heroin potency shifts observed in the present study following heroin vaccine administration were less previously reported antinociceptive potency shifts (12-14 fold) in male mice administered heroin SC and IP (Bremer et al, 2017).…”

Section: Schwienteck 14supporting

confidence: 88%

“…Every two weeks after initial vaccination, rats were sedated under isoflurane anesthesia and tail-vein blood was collected in a volume of approximately 0.5 mL into microtainer tubes without additive (BD, Franklin Lakes, NJ). Tubes were immediately centrifuged at 1000g for 10 min and the serum supernatant was transferred Schwienteck 8 into a labeled storage tube and frozen at −80°C until analyzed for heroin mid-point titer levels as described previously (Bremer et al, 2017;Hwang et al, 2018a;Hwang et al, 2018c).…”

Section: Heroin Vaccine Experimentsmentioning

confidence: 99%

“…In addition, heroin has been reported to be contaminated with fentanyl or fentanyl analogs which would also mitigate vaccine effectiveness (Hibbs et al, 1991;Stogner, 2014). As a result, recent preclinical studies have examined the effectiveness of a combination heroin/fentanyl vaccine (Hwang et al, 2018b;Hwang et al, 2018c).…”

Section: Schwienteck 14mentioning

confidence: 99%

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Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone

Schwienteck

Blake

Bremer

et al. 2019

Preprint

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Background: One emerging strategy to address the opioid crisis includes opioid immunopharmacotherapies. This study compared effectiveness of a heroin-tetanus toxoid (TT) conjugate vaccine to antagonize heroin, 6-acetylmorphine (6-AM), morphine, and fentanyl antinociception in rats. Methods: Adult male and female Sprague Dawley rats received three doses of active or control vaccine at weeks 0, 2, and 4. Vaccine pharmacological selectivity was assessed by comparing opioid dose-effect curves in 50°C warm-water tail-withdrawal procedure before, during, and after active or control heroin-TT vaccine. Route of agonist administration [subcutaneous (SC) vs. intravenous [IV)] was also examined as a determinant of vaccine effectiveness. For comparison, continuous naltrexone treatment (0.0032-0.032 mg/kg/h) effects on heroin, 6-AM, and morphine antinociceptive potency was also determined. Results: The heroin-TT vaccine decreased potency of SC heroin (5-fold), IV heroin (3-fold), and IV 6-AM (3fold) for several weeks without affecting IV morphine or SC fentanyl potency. The control vaccine did not alter potency of any opioid. Naltrexone dose-dependently decreased antinociceptive potency of SC heroin, and treatment with 0.01 mg/kg/h naltrexone produced similar, approximately 8-fold decreases in potencies of SC and IV heroin, IV 6-AM, and IV morphine. The combination of naltrexone and active vaccine was more effective than naltrexone alone to antagonize SC heroin but not IV heroin. Conclusions: The heroin-TT vaccineformulation examined is less effective, but more selective, than chronic naltrexone to attenuate heroin antinociception in rats. The combination of naltrexone plus heroin-TT vaccine may be more effective than either treatment alone to block opioid effects under some conditions.

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Section: Schwienteck 14supporting

confidence: 93%

Section: Schwienteck 14supporting

confidence: 88%

Section: Heroin Vaccine Experimentsmentioning

confidence: 99%

Section: Schwienteck 14mentioning

confidence: 99%

See 2 more Smart Citations

Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone

Schwienteck

Blake

Bremer

et al. 2019

Preprint

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show abstract

“…Yet, this same fentanyl vaccine elicited antibodies displaying very weak affinity towards structurally dissimilar opioids such as heroin (Bremer et al, 2016;Hwang et al, 2018a). Recent preclinical research has explored the development of combination immunopharmacotherapy approaches directed at multiple, structurally dissimilar abused opioids (e.g., fentanyl and heroin) (Hwang et al, 2018b;Hwang et al, 2018c). In conclusion, opioid-targeted vaccines may provide for a unique clinically effective option for OUD treatment.…”

Section: Fentanyl Vaccine In Nhps 16mentioning

confidence: 99%

Vaccine blunts fentanyl potency in male rhesus monkeys

Tenney

Blake

Bremer

et al. 2019

Preprint

Self Cite

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KDJ) Fentanyl vaccine in NHPs 2 Highlights • Vaccine blunted fentanyl rate-suppression potency ~ 10-fold • Vaccine blunted fentanyl antinociceptive potency ~25-fold • Fentanyl vaccine was as effective as acute 0.032 mg/kg naltrexone • Vaccine was selective for fentanyl and not oxycodone • Antibody immune response ~ 3 nM affinity for fentanyl AcknowledgementsWe appreciate the technical assistance of Stacie Havens for the pharmacokinetic experiments. AbstractOne proposed factor contributing to the increased opioid overdose deaths is the increased frequency of synthetic opioids, including fentanyl and fentanyl analogs. A treatment strategy currently under development to address the ongoing opioid crisis is immunopharmacotherapies or opioid-targeted vaccines. The present study determined the effectiveness and selectivity of a fentanyl-tetanus toxoid conjugate vaccine to alter the behavioral effects of fentanyl and a structurally dissimilar mu-opioid agonist oxycodone in male rhesus monkeys (n=3-4). Fentanyl and oxycodone produced dose-dependent suppression of behavior in an assay of schedulecontrolled responding and antinociception in an assay of thermal nociception (50°C). Acute naltrexone (0.032 mg/kg) produced an approximate 10-fold potency shift for fentanyl to decrease operant responding. The fentanyl vaccine was administered at weeks 0, 2, 4, 9, 19, and 44 and fentanyl or oxycodone potencies in both behavioral assays were redetermined over the course of 49 weeks. The vaccine significantly and selectively shifted fentanyl potency at least 10-fold in both assays at several time points over the entire experimental period. Mid-point titer levels were significantly correlated with fentanyl antinociceptive potency shifts. Antibody affinity for fentanyl as measured by a competitive binding assay increased over time to around 3-4 nM. The fentanyl vaccine also significantly increased fentanyl plasma levels approximately 6-fold consistent with the hypothesis that the vaccine sequesters fentanyl in the blood. Overall, these results support the continued development and evaluation of this fentanyl vaccine to address the ongoing opioid crisis.

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The M3-TT Vaccine Decreases the Antinociceptive Effects of Morphine and Heroin in Mice

Barbosa-Méndez

Matus-Ortega

Miramontes

et al. 2021

Int J Ment Health Addiction

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Improved Admixture Vaccine of Fentanyl and Heroin Hapten Immunoconjugates: Antinociceptive Evaluation of Fentanyl-Contaminated Heroin

Cited by 31 publications

References 26 publications

Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone

Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone

Vaccine blunts fentanyl potency in male rhesus monkeys

The M3-TT Vaccine Decreases the Antinociceptive Effects of Morphine and Heroin in Mice

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