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[PMID]:28966276
[Au] Autor:Ishikawa K; Karaki F; Tayama K; Higashi E; Hirayama S; Itoh K; Fujii H
[Ad] Endereço:Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University.
[Ti] Título:C-Homomorphinan Derivatives as Lead Compounds to Obtain Safer and More Clinically Useful Analgesics.
[So] Source:Chem Pharm Bull (Tokyo);65(10):920-929, 2017.
[Is] ISSN:1347-5223
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Buprenorphine shows strong analgesic effects on moderate to severe pain. Although buprenorphine can be used more safely than other opioid analgesics, it has room for improvement in clinical utility. Investigation of compounds structurally related to buprenorphine should be an approach to obtain novel analgesics with safer and improved profiles compared to buprenorphine. In the course of our previous studies, we observed that derivatives obtained by cyclizing C-homomorphinans were structurally related to buprenorphine. Hence, we synthesized cyclized C-homomorphinan derivatives with various oxygen functionalities on the side chains and evaluated their in vitro pharmacological profiles for the opioid receptors. Among the tested compounds, methyl ketone 2a with an N-methyl group showed full agonistic activities for the µ and the δ receptors and partial agonistic activity for the κ receptor. These properties were similar to those of norbuprenorphine, a major metabolite of buprenorphine, which reportedly contributes to the antinociceptive effect of buprenorphine. From these results, we concluded that cyclized C-homomorphinan would be a possible lead compound to obtain novel analgesics with buprenorphine-like properties.
[Mh] Termos MeSH primário: Analgésicos Opioides/química
Morfinanos/química
[Mh] Termos MeSH secundário: Analgésicos Opioides/síntese química
Animais
Buprenorfina/análogos & derivados
Buprenorfina/química
Células CHO
Cricetinae
Cricetulus
Ciclização
Seres Humanos
Cinética
Conformação Molecular
Morfinanos/síntese química
Ligação Proteica
Receptores Opioides/química
Receptores Opioides/genética
Receptores Opioides/metabolismo
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Morphinans); 0 (Receptors, Opioid); 0 (Recombinant Proteins); 40D3SCR4GZ (Buprenorphine); 7E53B4O073 (norbuprenorphine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE
[do] DOI:10.1248/cpb.c17-00385


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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
[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
[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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[PMID]:28739044
[Au] Autor:Yamamoto N; Ohrui S; Okada T; Yata M; Saitoh T; Kutsumura N; Nagumo Y; Irukayama-Tomobe Y; Ogawa Y; Ishikawa Y; Watanabe Y; Hayakawa D; Gouda H; Yanagisawa M; Nagase H
[Ad] Endereço:International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
[Ti] Título:Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor.
[So] Source:Bioorg Med Chem Lett;27(17):4176-4179, 2017 09 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The essential structure of the orexin 1 receptor (OX R) antagonist YNT-707 (2) was clarified, particularly the roles to OX R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6ß-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX R ligands.
[Mh] Termos MeSH primário: Compostos de Epóxi/farmacologia
Morfinanos/farmacologia
Antagonistas dos Receptores de Orexina/farmacologia
Receptores de Orexina/metabolismo
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Sítios de Ligação/efeitos dos fármacos
Relação Dose-Resposta a Droga
Compostos de Epóxi/química
Seres Humanos
Estrutura Molecular
Morfinanos/síntese química
Morfinanos/química
Antagonistas dos Receptores de Orexina/síntese química
Antagonistas dos Receptores de Orexina/química
Relação Estrutura-Atividade
Sulfonamidas/síntese química
Sulfonamidas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Epoxy Compounds); 0 (Morphinans); 0 (Orexin Receptor Antagonists); 0 (Orexin Receptors); 0 (Sulfonamides); 0 (YNT-707)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE


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[PMID]:28711625
[Au] Autor:Zhou H; Liu JX; Luo JF; Cheng CS; Leung EL; Li Y; Su XH; Liu ZQ; Chen TB; Duan FG; Dong Y; Zuo YH; Li C; Lio CK; Li T; Luo P; Xie Y; Yao XJ; Wang PX; Liu L
[Ad] Endereço:State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wailong, Taipa, Macau; Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wailong, Taipa, Macau; International Institute of Translation Chinese Medicine, Gu
[Ti] Título:Suppressing mPGES-1 expression by sinomenine ameliorates inflammation and arthritis.
[So] Source:Biochem Pharmacol;142:133-144, 2017 Oct 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Recently, microsomal prostaglandin E synthase 1 (mPGES-1) has attracted much attention from pharmacologists as a promising strategy and an attractive target for treating various types of diseases including rheumatoid arthritis (RA), which could preserve the anti-inflammatory effect while reducing the adverse effects often occur during administration of non-steroidal anti-inflammatory drugs (NSAIDs). Here, we report that sinomenine (SIN) decreased prostaglandin (PG)E levels without affecting prostacyclin (PG)I and thromboxane (TX)A synthesis via selective inhibiting mPGES-1 expression, a possible reason of low risk of cardiovascular event compared with NSAIDs. In addition, mPGES-1 protein expression was down-regulated by SIN treatment in the inflamed paw tissues both in carrageenan-induced edema model in rats and the collagen-II induced arthritis (CIA) model in DBA mice. More interestingly, SIN suppressed the last step of mPGES-1 gene expression by decreasing the DNA binding ability of NF-κB, paving a new way for drug discovery.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/uso terapêutico
Artrite Experimental/tratamento farmacológico
Edema/tratamento farmacológico
Expressão Gênica/efeitos dos fármacos
Morfinanos/uso terapêutico
Prostaglandina-E Sintases/genética
[Mh] Termos MeSH secundário: Células A549
Animais
Anti-Inflamatórios não Esteroides/efeitos adversos
Anti-Inflamatórios não Esteroides/isolamento & purificação
Anti-Inflamatórios não Esteroides/farmacologia
Artrite Experimental/imunologia
Técnicas de Cultura de Células
Sobrevivência Celular/efeitos dos fármacos
Edema/imunologia
Feminino
Macrófagos Peritoneais/efeitos dos fármacos
Masculino
Camundongos Endogâmicos DBA
Morfinanos/efeitos adversos
Morfinanos/isolamento & purificação
Morfinanos/farmacologia
Ratos Sprague-Dawley
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Morphinans); 63LT81K70N (sinomenine); EC 5.3.99.3 (Prostaglandin-E Synthases); EC 5.3.99.3 (Ptges protein, mouse); EC 5.3.99.3 (Ptges protein, rat)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170717
[St] Status:MEDLINE


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[PMID]:28708940
[Au] Autor:Soares JX; Alves EA; Silva AMN; de Figueiredo NG; Neves JF; Cravo SM; Rangel M; Netto ADP; Carvalho F; Dinis-Oliveira RJ; Afonso CM
[Ad] Endereço:LAQV, REQUIMTE, Department of Chemical Sciences, Laboratory of Applied Chemistry, Faculty of Pharmacy, University of Porto , José Viterbo Ferreira Street No. 228, 4050-313 Porto, Portugal.
[Ti] Título:Street-Like Synthesis of Krokodil Results in the Formation of an Enlarged Cluster of Known and New Morphinans.
[So] Source:Chem Res Toxicol;30(8):1609-1621, 2017 Aug 21.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:"Krokodil" is the street name for a homemade injectable drug that has been used as a cheap substitute for heroin. Codeine is the opioid starting material for krokodil synthesis, and desomorphine is claimed to be the main opioid of krokodil and the main component responsible for its addictive and psychoactive characteristics. However, due to its peculiar manufacture, using cheap raw materials, krokodil is composed of a large and complex mixture of different substances. In order to shed some light upon the chemical complexity of krokodil, its profiling was conducted by reverse phase high performance liquid chromatography coupled to a photodiode array detector (RP-HPLC-DAD) and by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-ESI-IT-Orbitrap-MS). Besides desomorphine, codeine, and morphine, profiting from the high resolution mass spectrometry (HRMS) data, an endeavor to study the morphinans content in krokodil was set for the first time. Considering codeine as the only morphinan precursor and the possible chemical transformations that can occur during krokodil synthesis, the morphinan chemical space was designed, and 95 compounds were defined. By making use of the morphinan chemical space in krokodil, the exact masses featured by HRMS, and the morphinan mass fragmentations patterns, a targeted identification approach was designed and implemented.The proposed 95 morphinans were searched using the full scan chromatogram of krokodil, and findings were validated by mass fragmentation of the correspondent precursor ions (MS spectra). Following this effort, a total of 54 morphinans were detected, highlighting the fact that these additional morphinans may contribute to the psychotropic effects of krokodil.
[Mh] Termos MeSH primário: Cromatografia Líquida de Alta Pressão
Codeína/análogos & derivados
Morfinanos/análise
Espectrometria de Massas em Tandem
[Mh] Termos MeSH secundário: Cromatografia de Fase Reversa
Codeína/análise
Codeína/síntese química
Morfina/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Morphinans); 76I7G6D29C (Morphine); 7OP86J5E33 (desomorphine); Q830PW7520 (Codeine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE
[do] DOI:10.1021/acs.chemrestox.7b00126


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[PMID]:28688957
[Au] Autor:Suzuki S; Sugawara Y; Tsuji R; Tanimura R; Kaneko C; Yuzawa N; Yagi M; Kawai K
[Ad] Endereço:Pharmaceutical Research Laboratories, Toray Industries, Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Shinya_Suzuki@nta.toray.co.jp.
[Ti] Título:Discovery of highly selective κ-opioid receptor agonists: 10α-Hydroxy TRK-820 derivatives.
[So] Source:Bioorg Med Chem Lett;27(16):3920-3924, 2017 08 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:κ-Opioid receptor agonists with high selectivity over the µ-opioid receptor are attractive targets in the development of drugs for pain and pruritus. We previously reported the synthesis of 10α-hydroxy TRK-820 (1). In this study, we elucidated the biological properties of 1 and optimized its 6-acyl unit by modifying our synthetic route. Among the 10α-hydroxy TRK-820 derivatives prepared, 26 showed the most potent κ-opioid agonist activity (EC =0.00466nM) and excellent selectivity and 22 was the most κ-selective agonist.
[Mh] Termos MeSH primário: Analgésicos/farmacologia
Descoberta de Drogas
Morfinanos/farmacologia
Neuralgia/tratamento farmacológico
Receptores Opioides kappa/agonistas
Compostos de Espiro/farmacologia
[Mh] Termos MeSH secundário: Analgésicos/administração & dosagem
Analgésicos/química
Animais
Comportamento Animal/efeitos dos fármacos
Relação Dose-Resposta a Droga
Seres Humanos
Camundongos
Estrutura Molecular
Morfinanos/administração & dosagem
Morfinanos/química
Ratos
Compostos de Espiro/administração & dosagem
Compostos de Espiro/química
Relação Estrutura-Atividade
Substância P/administração & dosagem
Substância P/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Morphinans); 0 (Receptors, Opioid, kappa); 0 (Spiro Compounds); 0 (TRK 820); 33507-63-0 (Substance P)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170710
[St] Status:MEDLINE


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[PMID]:28604788
[Au] Autor:Kamimura K; Yokoo T; Kamimura H; Sakamaki A; Abe S; Tsuchiya A; Takamura M; Kawai H; Yamagiwa S; Terai S
[Ad] Endereço:Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Asahimachido-ri, Chuo-ku, Niigata, Niigata, Japan.
[Ti] Título:Long-term efficacy and safety of nalfurafine hydrochloride on pruritus in chronic liver disease patients: Patient-reported outcome based analyses.
[So] Source:PLoS One;12(6):e0178991, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND AIM: Among various symptoms accompanied with chronic liver disease, pruritus affects the quality of life of patients, causing physical and mental stress, and worsens hepatic function. Recently, κ-opioid receptor agonist, nalfurafine hydrochloride was approved to treat central pruritus in patients with liver disease in Japan. This study aimed to assess the long-term efficacy and safety of nalfurafine hydrochloride on pruritus in chronic liver disease patients. METHODS: A patient-reported outcome using questionnaire-based methods was used for 41 liver disease patients with or without pruritus symptoms. Nalfurafine hydrochloride (2.5 µg/day) was orally administered to 18 patients suffering from pruritus symptoms and whose current treatment was not effective. The same questionnaires and visual analogue scales (VAS) were repeatedly followed up for the patients for the entire follow-up period, and biochemical analyses were performed to evaluate the safety of the treatment. RESULTS: Pruritus completely disappeared in seven of 18 cases, and VAS scores showed a decreasing trend over time from the start of nalfurafine hydrochloride administration in all patients who received the medication. Among 11 patients who were followed up for more than 12 weeks, nine patients showed continuous improvement of symptoms, and this progress was still apparent at ≥20 weeks after starting administration (p < 0.0001). The medication was discontinued in four patients because of progression of primary disease, high cost, oral dryness, and anemia. No significant toxicity was observed on the serum biochemical analyses. CONCLUSIONS: Nalfurafine hydrochloride contributed to long-term suppression of pruritus without significant safety problems.
[Mh] Termos MeSH primário: Antipruriginosos/uso terapêutico
Hepatopatias/complicações
Morfinanos/uso terapêutico
Prurido/tratamento farmacológico
Prurido/etiologia
Compostos de Espiro/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Antipruriginosos/administração & dosagem
Antipruriginosos/efeitos adversos
Doença Crônica
Feminino
Seres Humanos
Hepatopatias/diagnóstico
Hepatopatias/etiologia
Masculino
Meia-Idade
Morfinanos/administração & dosagem
Morfinanos/efeitos adversos
Medidas de Resultados Relatados pelo Paciente
Qualidade de Vida
Compostos de Espiro/administração & dosagem
Compostos de Espiro/efeitos adversos
Inquéritos e Questionários
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antipruritics); 0 (Morphinans); 0 (Spiro Compounds); 0 (TRK 820)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178991


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[PMID]:28554659
[Au] Autor:Andersson H; Mitchard T; Johnson N; Floettmann E
[Ad] Endereço:Department of Pathology, Drug Safety & Metabolism, Innovative Medicines and Early Development, AstraZeneca, Gothenburg, Sweden. Electronic address: bhanderssonx@gmail.com.
[Ti] Título:Naloxegol, an opioid antagonist with reduced CNS penetration: Mode-of-action and human relevance for rat testicular tumours.
[So] Source:Toxicol Appl Pharmacol;329:85-95, 2017 Aug 15.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Naloxegol is an opioid antagonist which has been developed for the treatment of patients with opioid induced constipation. In the nonclinical safety program naloxegol was shown to have a very benign toxicity profile. In the rat, but not the mouse, 2-year carcinogenicity study a change in tumour pattern with an increase in testicular Leydig cell tumours (LCT) was observed after dosing at high (supra-pharmacological) concentrations. To establish the basis of the increase in LCT and to assess its potential relevance to humans, studies to exclude and potentially identify mode-of-action (MoA) were performed. A genotoxic mechanism was ruled out following negative results in the Ames, mouse lymphoma, and micronucleus assays. An effect on androgen metabolism was excluded since the treatment of rats with naloxegol for 14days did not result in any induction of CYP protein levels. It was demonstrated that administration of centrally restricted opioid antagonists naloxegol or methylnaltrexone at high doses induced an increase in LH release with no clear increase in testosterone, in contrast to the centrally acting opioid antagonist naloxone, which showed marked increases in both LH and testosterone. LCT due to increased LH stimulation is common in rats but not documented in humans. Collectively, the lack of genotoxicity signal, the lack of androgen effect, the increase in LH secretion in rats, which is no considered to be relevant for LCT formation in humans, and high margins to clinical exposures, the observed increase in LCT in the rat is not expected to be clinically relevant.
[Mh] Termos MeSH primário: Barreira Hematoencefálica/metabolismo
Tumor de Células de Leydig/induzido quimicamente
Hormônio Luteinizante/sangue
Morfinanos/toxicidade
Antagonistas de Entorpecentes/toxicidade
Polietilenoglicóis/toxicidade
Neoplasias Testiculares/induzido quimicamente
[Mh] Termos MeSH secundário: Animais
Biomarcadores/sangue
Permeabilidade Capilar
Cães
Feminino
Seres Humanos
Tumor de Células de Leydig/patologia
Masculino
Camundongos
Morfinanos/metabolismo
Naltrexona/análogos & derivados
Naltrexona/metabolismo
Naltrexona/toxicidade
Antagonistas de Entorpecentes/metabolismo
Polietilenoglicóis/metabolismo
Compostos de Amônio Quaternário/metabolismo
Compostos de Amônio Quaternário/toxicidade
Coelhos
Ratos Sprague-Dawley
Medição de Risco
Especificidade da Espécie
Neoplasias Testiculares/patologia
Testosterona/sangue
Fatores de Tempo
Testes de Toxicidade/métodos
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Morphinans); 0 (Narcotic Antagonists); 0 (Quaternary Ammonium Compounds); 0RK7M7IABE (methylnaltrexone); 30IQX730WE (Polyethylene Glycols); 3XMK78S47O (Testosterone); 44T7335BKE (naloxegol); 5S6W795CQM (Naltrexone); 9002-67-9 (Luteinizing Hormone)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170531
[St] Status:MEDLINE


  9 / 2833 MEDLINE  
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[PMID]:28548207
[Au] Autor:Al-Huniti N; Zhou D; Xu H; Aksenov S; Bui KH; Fox R; Helmlinger G; Stanski D
[Ad] Endereço:Quantitative Clinical Pharmacology, AstraZeneca LP, Waltham, Massachusetts, USA.
[Ti] Título:Pharmacometric Modeling of Naloxegol Efficacy and Safety: Impact on Dose and Label.
[So] Source:Clin Pharmacol Ther;102(5):741-744, 2017 Nov.
[Is] ISSN:1532-6535
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Naloxegol is a peripherally acting µ-opioid receptor antagonist that was developed for the treatment of opioid-induced constipation. Modeling and simulation of naloxegol efficacy and tolerability informed selection of doses for phase III studies and provided comprehensive dosage recommendations for the naloxegol US package insert.
[Mh] Termos MeSH primário: Rotulagem de Medicamentos/métodos
Modelos Biológicos
Morfinanos/farmacocinética
Antagonistas de Entorpecentes/farmacocinética
Polietilenoglicóis/farmacocinética
[Mh] Termos MeSH secundário: Analgésicos Opioides/efeitos adversos
Animais
Constipação Intestinal/induzido quimicamente
Constipação Intestinal/tratamento farmacológico
Constipação Intestinal/metabolismo
Relação Dose-Resposta a Droga
Rotulagem de Medicamentos/legislação & jurisprudência
Rotulagem de Medicamentos/normas
Seres Humanos
Morfinanos/normas
Morfinanos/uso terapêutico
Antagonistas de Entorpecentes/normas
Antagonistas de Entorpecentes/uso terapêutico
Polietilenoglicóis/normas
Polietilenoglicóis/uso terapêutico
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Morphinans); 0 (Narcotic Antagonists); 30IQX730WE (Polyethylene Glycols); 44T7335BKE (naloxegol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170527
[St] Status:MEDLINE
[do] DOI:10.1002/cpt.719


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[PMID]:28504549
[Au] Autor:Li Y; Hoffmann M; Severin P
[Ad] Endereço:Clinical Sample Science, Early Clinical Development, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, USA.
[Ti] Título:Determination of naloxegol in human biological matrices.
[So] Source:Bioanalysis;9(8):609-619, 2017 Apr.
[Is] ISSN:1757-6199
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIM: Naloxegol is an oral peripherally acting µ-opioid receptor antagonist approved for the treatment of opioid-induced constipation. Sensitive, robust, bioanalytical methods were required to quantitate naloxegol in human biological matrices as part of the clinical development program. METHODOLOGY/RESULTS: Analytical plasma samples were prepared using Solid Phase Extraction (SPE) coupled with concentration. The method's linearity was established at 0.1-50 ng/ml with up to 100-fold dilution. Urine samples were analyzed directly postdilution; dialysate samples were extracted by supported liquid extraction. Sensitive liquid chromatography/mass spectrometry (LC-MS/MS) assays were developed and validated, and demonstrated acceptable precision, accuracy and selectivity for naloxegol in the appropriate matrices. CONCLUSION: Methods for quantifying naloxegol in human biological matrices have been successfully validated.
[Mh] Termos MeSH primário: Cromatografia Líquida/métodos
Morfinanos/sangue
Morfinanos/urina
Antagonistas de Entorpecentes/sangue
Antagonistas de Entorpecentes/urina
Extração em Fase Sólida/métodos
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Analgésicos Opioides/efeitos adversos
Constipação Intestinal/induzido quimicamente
Constipação Intestinal/tratamento farmacológico
Seres Humanos
Limite de Detecção
Polietilenoglicóis
Receptores Opioides mu/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Morphinans); 0 (Narcotic Antagonists); 0 (Receptors, Opioid, mu); 30IQX730WE (Polyethylene Glycols); 44T7335BKE (naloxegol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170516
[St] Status:MEDLINE
[do] DOI:10.4155/bio-2016-0253



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