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| [PMID]: | 28778859 |
| [Au] Autor: | Miyazaki T; Choi IY; Rubas W; Anand NK; Ali C; Evans J; Gursahani H; Hennessy M; Kim G; McWeeney D; Pfeiffer J; Quach P; Gauvin D; Riley TA; Riggs JA; Gogas K; Zalevsky J; Doberstein SK |
| [Ad] Endereço: | Nektar Therapeutics, San Francisco, California (T.M., I.Y.C., W.R., N.K.A., C.A., J.E., H.G., M.H., G.K., D.M., J.P., P.Q., T.A.R., J.A.R., K.G., J.Z., S.K.D.); and MPI Research, Mattawan, Michigan (D.G.). |
| [Ti] Título: | NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential. |
| [So] Source: | J Pharmacol Exp Ther;363(1):104-113, 2017 Oct. | | [Is] ISSN: | 1521-0103 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics. |
| [Mh] Termos MeSH primário: |
Analgésicos Opioides/farmacologia
Morfinanos/farmacologia
Transtornos Relacionados ao Uso de Substâncias/prevenção & controle
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| [Mh] Termos MeSH secundário: |
Analgésicos Opioides/química
Analgésicos Opioides/metabolismo
Animais
Barreira Hematoencefálica/efeitos dos fármacos
Barreira Hematoencefálica/metabolismo
Células CACO-2
Relação Dose-Resposta a Droga
Composição de Medicamentos
Seres Humanos
Masculino
Morfinanos/química
Morfinanos/metabolismo
Permeabilidade
Ratos
Ratos Sprague-Dawley
Receptores Opioides mu/metabolismo
Fatores de Tempo
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Analgesics, Opioid); 0 (Morphinans); 0 (NKTR-181); 0 (Receptors, Opioid, mu) |
| [Em] Mês de entrada: | 1710 |
| [Cu] Atualização por classe: | 171009 |
[Lr] Data última revisão:
| 171009 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 170806 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1124/jpet.117.243030 |
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