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[PMID]: 26558897 [Au] Autor: Lassila T; Hokkanen J; Aatsinki SM; Mattila S; Turpeinen M; Tolonen A [Ad] Endereço: Department of Chemistry, University of Oulu , P.O. Box 3000, 90014 Oulu, Finland. [Ti] Título: Toxicity of Carboxylic Acid-Containing Drugs: The Role of Acyl Migration and CoA Conjugation Investigated. [So] Source: Chem Res Toxicol;28(12):2292-303, 2015 Dec 21. [Is] ISSN: 1520-5010 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Many carboxylic acid-containing drugs are associated with idiosyncratic drug toxicity (IDT), which may be caused by reactive acyl glucuronide metabolites. The rate of acyl migration has been earlier suggested as a predictor of acyl glucuronide reactivity. Additionally, acyl Coenzyme A (CoA) conjugates are known to be reactive. Here, 13 drugs with a carboxylic acid moiety were incubated with human liver microsomes to produce acyl glucuronide conjugates for the determination of acyl glucuronide half-lives by acyl migration and with HepaRG cells to monitor the formation of acyl CoA conjugates, their further conjugate metabolites, and trans-acylation products with glutathione. Additionally, in vitro cytotoxicity and mitochondrial toxicity experiments were performed with HepaRG cells to compare the predictability of toxicity. Clearly, longer acyl glucuronide half-lives were observed for safe drugs compared to drugs that can cause IDT. Correlation between half-lives and toxicity classification increased when "relative half-lives," taking into account the formation of isomeric AG-forms due to acyl migration and eliminating the effect of hydrolysis, were used instead of plain disappearance of the initial 1-O-ß-AG-form. Correlation was improved further when a daily dose of the drug was taken into account. CoA and related conjugates were detected primarily for the drugs that have the capability to cause IDT, although some exceptions to this were observed. Cytotoxicity and mitochondrial toxicity did not correlate to drug safety. On the basis of the results, the short relative half-life of the acyl glucuronide (high acyl migration rate), high daily dose and detection of acyl CoA conjugates, or further metabolites derived from acyl CoA together seem to indicate that carboxylic acid-containing drugs have a higher probability to cause drug-induced liver injury (DILI). [Mh] Termos MeSH primário: Acil Coenzima A/química Ácidos Carboxílicos/química Doença Hepática Induzida por Substâncias e Drogas Microssomos Hepáticos/efeitos dos fármacos [Mh] Termos MeSH secundário: Acetatos/química Acetatos/toxicidade Acilação Ácidos Carboxílicos/toxicidade Cromatografia Líquida Genfibrozila/química Genfibrozila/toxicidade Seres Humanos Espectrometria de Massas Estrutura Molecular Quinolinas/química Quinolinas/toxicidade Tolmetino/análogos & derivados Tolmetino/química Tolmetino/toxicidade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Acetates); 0 (Acyl Coenzyme A); 0 (Carboxylic Acids); 0 (Quinolines); 822G987U9J (zomepirac); D8K2JPN18B (Tolmetin); MHM278SD3E (montelukast); Q8X02027X3 (Gemfibrozil) [Em] Mês de entrada: 1608 [Cu] Atualização por classe: 161126 [Lr] Data última revisão: 161126 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151113 [St] Status: MEDLINE [do] DOI: 10.1021/acs.chemrestox.5b00315

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[PMID]: 26287512 [Au] Autor: Küçükgüzel SG; Koç D; Çikla-Süzgün P; Özsavci D; Bingöl-Özakpinar Ö; Mega-Tiber P; Orun O; Erzincan P; Sag-Erdem S; Sahin F [Ad] Endereço: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpasa, Istanbul, Turkey. [Ti] Título: Synthesis of Tolmetin Hydrazide-Hydrazones and Discovery of a Potent Apoptosis Inducer in Colon Cancer Cells. [So] Source: Arch Pharm (Weinheim);348(10):730-42, 2015 Oct. [Is] ISSN: 1521-4184 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Tolmetin hydrazide and a novel series of tolmetin hydrazide-hydrazones 4a-l were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, (1)H NMR) methods. N'-[(2,6-Dichlorophenyl)methylidene]-2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetohydrazide (4g) was evaluated in vitro using the MTT colorimetric method against the colon cancer cell lines HCT-116 (ATCC, CCL-247) and HT-29 (ATCC, HTB-38) to determine growth inhibition and cell viability at different doses. Compound 4g exhibited anti-cancer activity with an IC50 value of 76 µM against colon cancer line HT-29 (ATCC, HTB-38) and did not display cytotoxicity toward control NIH3T3 mouse embryonic fibroblast cells compared to tolmetin. In addition, this compound was evaluated for caspase-3, caspase-8, caspase-9, and annexin-V activation in the apoptotic pathway, which plays a key role in the treatment of cancer. We demonstrated that the anti-cancer activity of this compound was due to the activation of caspase-8 and caspase-9 involved in the apoptotic pathway. In addition, in this study, we investigated the catalytical effect of COX on the HT-29 cancer line, the apoptotic mechanism, and the moleculer binding of tolmetin and compound 4g on the COX enzyme active site. [Mh] Termos MeSH primário: Antineoplásicos/síntese química Antineoplásicos/farmacologia Apoptose/efeitos dos fármacos Neoplasias do Colo/tratamento farmacológico Hidrazonas/síntese química Hidrazonas/farmacologia Tolmetino/síntese química Tolmetino/farmacologia [Mh] Termos MeSH secundário: Antineoplásicos/metabolismo Caspase 8/metabolismo Caspase 9/metabolismo Proliferação Celular/efeitos dos fármacos Sobrevivência Celular/efeitos dos fármacos Neoplasias do Colo/enzimologia Neoplasias do Colo/patologia Ciclo-Oxigenase 1/química Ciclo-Oxigenase 1/metabolismo Inibidores de Ciclo-Oxigenase/síntese química Inibidores de Ciclo-Oxigenase/farmacologia Relação Dose-Resposta a Droga Desenho de Drogas Ativação Enzimática Células HCT116 Células HT29 Seres Humanos Hidrazonas/metabolismo Células MCF-7 Simulação de Acoplamento Molecular Conformação Proteica Transdução de Sinais/efeitos dos fármacos Relação Estrutura-Atividade Tolmetino/análogos & derivados Tolmetino/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Cyclooxygenase Inhibitors); 0 (Hydrazones); D8K2JPN18B (Tolmetin); EC 1.14.99.1 (Cyclooxygenase 1); EC 1.14.99.1 (PTGS1 protein, human); EC 3.4.22.- (CASP8 protein, human); EC 3.4.22.- (CASP9 protein, human); EC 3.4.22.- (Caspase 8); EC 3.4.22.- (Caspase 9) [Em] Mês de entrada: 1610 [Cu] Atualização por classe: 161230 [Lr] Data última revisão: 161230 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150820 [St] Status: MEDLINE [do] DOI: 10.1002/ardp.201500178

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[PMID]: 25212638 [Au] Autor: Boersen N; Carvajal MT; Morris KR; Peck GE; Pinal R [Ad] Endereço: a Department of Industrial and Physical Pharmacy and. [Ti] Título: The influence of API concentration on the roller compaction process: modeling and prediction of the post compacted ribbon, granule and tablet properties using multivariate data analysis. [So] Source: Drug Dev Ind Pharm;41(9):1470-8, 2015. [Is] ISSN: 1520-5762 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: OBJECTIVE: While previous research has demonstrated roller compaction operating parameters strongly influence the properties of the final product, a greater emphasis might be placed on the raw material attributes of the formulation. There were two main objectives to this study. First, to assess the effects of different process variables on the properties of the obtained ribbons and downstream granules produced from the rolled compacted ribbons. Second, was to establish if models obtained with formulations of one active pharmaceutical ingredient (API) could predict the properties of similar formulations in terms of the excipients used, but with a different API. MATERIALS AND METHODS: Tolmetin and acetaminophen, chosen for their different compaction properties, were roller compacted on Fitzpatrick roller compactor using the same formulation. Models created using tolmetin and tested using acetaminophen. The physical properties of the blends, ribbon, granule and tablet were characterized. Multivariate analysis using partial least squares was used to analyze all data. RESULTS: Multivariate models showed that the operating parameters and raw material attributes were essential in the prediction of ribbon porosity and post-milled particle size. The post compacted ribbon and granule attributes also significantly contributed to the prediction of the tablet tensile strength. CONCLUSIONS: Models derived using tolmetin could reasonably predict the ribbon porosity of a second API. After further processing, the post-milled ribbon and granules properties, rather than the physical attributes of the formulation were needed to predict downstream tablet properties. An understanding of the percolation threshold of the formulation significantly improved the predictive ability of the models. [Mh] Termos MeSH primário: Acetaminofen/administração & dosagem Excipientes/química Modelos Químicos Tolmetino/administração & dosagem [Mh] Termos MeSH secundário: Acetaminofen/química Química Farmacêutica/métodos Composição de Medicamentos/métodos Análise dos Mínimos Quadrados Análise Multivariada Tamanho da Partícula Porosidade Comprimidos Resistência à Tração Tolmetino/química [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Excipients); 0 (Tablets); 362O9ITL9D (Acetaminophen); D8K2JPN18B (Tolmetin) [Em] Mês de entrada: 1606 [Cu] Atualização por classe: 150825 [Lr] Data última revisão: 150825 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140913 [St] Status: MEDLINE [do] DOI: 10.3109/03639045.2014.958754

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[PMID]: 24809893 [Au] Autor: Sentellas S; Morales-Ibanez O; Zanuy M; Albertí JJ [Ad] Endereço: Preclinical Development, Almirall, S.A, Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: sonia.sentellas@almirall.com. [Ti] Título: GSSG/GSH ratios in cryopreserved rat and human hepatocytes as a biomarker for drug induced oxidative stress. [So] Source: Toxicol In Vitro;28(5):1006-15, 2014 Aug. [Is] ISSN: 1879-3177 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The formation of reactive oxygen species (ROS) could cause cellular damage and eventually lead to apoptosis and necrosis. The ratio between oxidized glutathione and reduced glutathione (GSSG-to-GSH ratio) has been used as an important in vitro and in vivo biomarker of the redox balance in the cell and consequently of cellular oxidative stress. This paper optimizes a LC-MS/MS method for the simultaneous determination of GSH and GSSG. The proposed method is based on the derivatization of reduced GSH using iodoacetic acid (IAA) in order to prevent its rapid oxidation to GSSG during sample preparation. The optimized analytical method was applied to evaluate the effect of different pharmaceutical agents on GSSG-to-GSH ratio in cryopreserved rat and human hepatocytes in culture. Hepatocyte viabilities were also determined at the same time by using the WST-1 assay as a direct measurement of cell mitochondrial respiration. The results obtained demonstrate that cryopreserved rat and human hepatocytes in culture are reliable in vitro models for the evaluation of cellular oxidative stress. In addition, the GSSG-to-GSH ratio measurements could be a biomarker of hepatotoxicity providing similar results to those of cytotoxicity assay. [Mh] Termos MeSH primário: Criopreservação Dissulfeto de Glutationa/metabolismo Glutationa/metabolismo Hepatócitos [Mh] Termos MeSH secundário: Aminopirina/toxicidade Animais Biomarcadores/metabolismo Células Cultivadas Ciclosporina/toxicidade Flutamida/toxicidade Seres Humanos Masculino Estresse Oxidativo Ratos Sprague-Dawley Tolmetino/análogos & derivados Tolmetino/toxicidade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers); 01704YP3MO (Aminopyrine); 76W6J0943E (Flutamide); 822G987U9J (zomepirac); 83HN0GTJ6D (Cyclosporine); D8K2JPN18B (Tolmetin); GAN16C9B8O (Glutathione); ULW86O013H (Glutathione Disulfide) [Em] Mês de entrada: 1501 [Cu] Atualização por classe: 151119 [Lr] Data última revisão: 151119 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 140510 [St] Status: MEDLINE

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[PMID]: 23600654 [Au] Autor: Yag G; Calis S; Arica-Yegin B [Ad] Endereço: Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University , Sihhiye-Ankara , Turkey. [Ti] Título: The effect of inorganic salt type and concentration on hydrophilic drug loading into microspheres using the emulsion/solvent diffusion method. [So] Source: Drug Dev Ind Pharm;40(3):390-7, 2014 Mar. [Is] ISSN: 1520-5762 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: AIM: In order to avoid gastric irritation caused by tolmetin sodium (TS), gastro resistant Eudragit® S 100 microsphere formulations were prepared with the emulsion/solvent diffusion method. MATERIALS: Considering the high water solubility of the TS molecule, the effects of the presence of inorganic salt (NaCl, NaBr and KH2PO4; 0.1 M and 1.0 M) in external phase and external phase pH on the encapsulation efficiency were evaluated. RESULTS: Percentage yield value was found to vary between 55.8% and 72.1%. Improvement in encapsulation efficiency was determined by increasing concentrations of NaCl, NaBr and KH2PO4. The microspheres were observed to have a spherical shape and the measured particle size values varied between 52.1 and 81.5 µm. The released amounts of the drug were found to be low as the inorganic salt concentrations increased. CONCLUSION: Conclusively, drug release in stomach pH was significantly prevented by the microspheres prepared using Eudragit® S 100 polymer, and these formulations are considered to be a model for other orally administered drugs with similar problems. [Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/administração & dosagem Microesferas Ácidos Polimetacrílicos/química Tolmetino/administração & dosagem [Mh] Termos MeSH secundário: Anti-Inflamatórios não Esteroides/efeitos adversos Anti-Inflamatórios não Esteroides/química Química Farmacêutica Difusão Emulsões Concentração de Íons de Hidrogênio Interações Hidrofóbicas e Hidrofílicas Tamanho da Partícula Sais/química Solubilidade Solventes/química Tolmetino/efeitos adversos Tolmetino/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Emulsions); 0 (Polymethacrylic Acids); 0 (Salts); 0 (Solvents); 25086-15-1 (methylmethacrylate-methacrylic acid copolymer); D8K2JPN18B (Tolmetin) [Em] Mês de entrada: 1410 [Cu] Atualização por classe: 140212 [Lr] Data última revisão: 140212 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130423 [St] Status: MEDLINE [do] DOI: 10.3109/03639045.2012.763139

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[PMID]: 23973633 [Au] Autor: Neamtu S; Tosa N; Bogdan M [Ad] Endereço: Department of Molecular and Biomolecular Physics, National Institute of Isotopic and Molecular Technology, 400293 Cluj-Napoca, Romania. silvia.neamtu@itim-cj.ro [Ti] Título: Spectroscopic investigation of tolmetin interaction with human serum albumin. [So] Source: J Pharm Biomed Anal;85:277-82, 2013 Nov. [Is] ISSN: 1873-264X [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The interaction of tolmetin (TOL) with human serum albumin (HSA) in physiological buffer solution (pH 7.4) was studied by fluorescence and UV-vis absorption spectroscopy at different temperatures, combined with time-resolved fluorescence measurements. The experimental results showed that there was a strong fluorescence quenching of HSA by tolmetin. Using the continuous variation method, a single class of binding sites for TOL on HSA was put in evidence. The binding constants Ka were calculated at different temperatures, using a nonlinear fit to the experimental data, and the thermodynamic parameters ΔH(0), ΔS(0) and ΔG(0) were given. The obtained thermodynamic signature suggests that at least van der Waals and electrostatic type interactions are present. Quenching efficiency calculations, based on steady state and time-resolved spectroscopy, indicate that both static and dynamic quenching mechanisms are present. [Mh] Termos MeSH primário: Albumina Sérica/química Tolmetino/química [Mh] Termos MeSH secundário: Sítios de Ligação Seres Humanos Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Serum Albumin); D8K2JPN18B (Tolmetin) [Em] Mês de entrada: 1405 [Cu] Atualização por classe: 130909 [Lr] Data última revisão: 130909 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130827 [St] Status: MEDLINE

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[PMID]: 23333829 [Au] Autor: Rong Z; Xu Y; Zhang C; Xiang D; Li X; Liu D [Ad] Endereço: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China. [Ti] Título: Evaluation of intestinal absorption of amtolmetin guacyl in rats: breast cancer resistant protein as a primary barrier of oral bioavailability. [So] Source: Life Sci;92(3):245-51, 2013 Feb 27. [Is] ISSN: 1879-0631 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: AIMS: The purpose of the present study was to investigate the role of efflux transporters on the intestinal absorption of amtolmetin guacyl (MED-15). MAIN METHODS: The effects of P-glycoprotein (P-gp), multiple resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) inhibitors on intestinal absorption amount of MED-5 (tolmetin-glycine amide derivative), the metabolite formed from MED-15 in the intestinal epithelial cells were studied in the in vitro everted gut sac experiments. Moreover, the in situ single-pass intestine perfusion was adopted to clarify the role of efflux transporters in excreting MED-5 in knockout mice. The plasma concentration of MED-5 and tolmetin, the metabolite formed from MED-5 was determined in Bcrp1 knockout mice and wild-type mice. KEY FINDINGS: BCRP inhibitor Ko143 (50 µM and 100 µM) significantly increased the intestinal absorption amount in jejunum, ileum and colon (p<0.05). However, no effect was observed in the presence of P-gp inhibitor verapamil and MRP2 inhibitor MK571 in each intestinal segment. Furthermore, the plasma concentration MED-5 and tolmetin, metabolites of MED-15, increased 2-fold and 4-fold, respectively, in Bcrp1 knockout mice compared with wild-type mice after the single-pass perfusion of small intestine with MED-15. SIGNIFICANCE: It may be concluded that BCRP plays an important role in the intestinal efflux of MED-5 and limits the bioavailability after oral administration of MED-15. [Mh] Termos MeSH primário: Transportadores de Cassetes de Ligação de ATP/metabolismo Anti-Inflamatórios não Esteroides/farmacocinética Glicina/análogos & derivados Absorção Intestinal/efeitos dos fármacos Intestinos/metabolismo Pirróis/farmacocinética [Mh] Termos MeSH secundário: Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores Transportadores de Cassetes de Ligação de ATP/genética Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo Adenosina/análogos & derivados Adenosina/farmacologia Administração Oral Animais Anti-Inflamatórios não Esteroides/farmacologia Disponibilidade Biológica Dicetopiperazinas Glicina/farmacocinética Glicina/farmacologia Compostos Heterocíclicos de 4 ou mais Anéis Absorção Intestinal/genética Antagonistas de Leucotrienos/farmacologia Masculino Camundongos Camundongos Knockout Propionatos/farmacologia Pirróis/farmacologia Quinolinas/farmacologia Ratos Ratos Sprague-Dawley Tolmetino/análogos & derivados Tolmetino/farmacologia Vasodilatadores/farmacologia Verapamil/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 2); 0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Abcc2 protein, rat); 0 (Abcg2 protein, mouse); 0 (Abcg2 protein, rat); 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Diketopiperazines); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (Leukotriene Antagonists); 0 (Propionates); 0 (Pyrroles); 0 (Quinolines); 0 (Vasodilator Agents); 104076-16-6 (ST 679); 5Q9O54P0H7 (verlukast); 87344-05-6 (tolmetin glycinamide); CJ0O37KU29 (Verapamil); D8K2JPN18B (Tolmetin); K72T3FS567 (Adenosine); TE7660XO1C (Glycine) [Em] Mês de entrada: 1303 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130122 [St] Status: MEDLINE

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[PMID]: 23179562 [Au] Autor: Kulo A; Hendrickx S; de Hoon J; Mulabegovic N; van Calsteren K; Verbesselt R; Allegaert K [Ad] Endereço: Center for Clinical Pharmacology, University Hospitals Leuven, Leuven, Belgium. [Ti] Título: The impact of pregnancy on urinary ketorolac metabolites after single intravenous bolus. [So] Source: Eur J Drug Metab Pharmacokinet;38(1):1-4, 2013 Mar. [Is] ISSN: 0378-7966 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: Compared to female volunteers or postpartum, ketorolac clearance is higher at delivery. To explore the alterations that explain this higher clearance, urinary ketorolac metabolites collected at delivery (n = 40) were compared to female volunteers (unpaired, n = 8) or postpartum (paired, n = 8) following intravenous administration of 30 mg ketorolac tromethamine. A mean 38 (SD 9) % of the ketorolac dose was retrieved in 8-h urine collections. This was based on mean portions of 56 (20), 10 (14) and 33 (12) % for free ketorolac, ketorolac-glucuronide and p-hydroxy-ketorolac, respectively. The mean ketorolac-glucuronide portion at delivery (5 %) was lower compared to female volunteers (21 %) or postpartum (21 %) (p = 0.003 and p = 0.002, respectively). Similarly, there was a difference in mean portion of free urinary ketorolac at delivery when compared to healthy female volunteers (60-45 %, p = 0.046). Using paired statistics, the mean portion of total urinary ketorolac was lower (62-73 %, p = 0.015) while the portion retrieved as p-hydroxy-ketorolac was significantly higher at delivery compared to postpartum (38-28 %, p = 0.031). The differences in urine metabolites suggest that the increased ketorolac clearance at delivery is in part explained by increased metabolic clearance to p-hydroxy-ketorolac, reflecting increased oxidation activity. [Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/urina Cetorolaco de Trometamina/urina [Mh] Termos MeSH secundário: Adulto Anti-Inflamatórios não Esteroides/administração & dosagem Anti-Inflamatórios não Esteroides/farmacocinética Bélgica Biotransformação Estudos de Casos e Controles Parto Obstétrico Feminino Glucuronídeos/urina Seres Humanos Hidroxilação Injeções Intravenosas Cetorolaco de Trometamina/administração & dosagem Cetorolaco de Trometamina/farmacocinética Taxa de Depuração Metabólica Período Pós-Parto/urina Gravidez Tolmetino/análogos & derivados Tolmetino/urina [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Glucuronides); 111930-01-9 (4-hydroxyketorolac); 4EVE5946BQ (Ketorolac Tromethamine); D8K2JPN18B (Tolmetin) [Em] Mês de entrada: 1306 [Cu] Atualização por classe: 171111 [Lr] Data última revisão: 171111 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 121127 [Cl] Clinical Trial: ClinicalTrial [St] Status: MEDLINE [do] DOI: 10.1007/s13318-012-0108-7

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[PMID]: 23388474 [Au] Autor: Krowicki ZK [Ad] Endereço: Department of Pharmacology and Experimental Therapeutics, Louisiana State University Medical Center, New Orleans, USA. z.krowicki@sccs.pl [Ti] Título: Involvement of hindbrain and peripheral prostanoids in gastric motor and cardiovascular responses to delta-9-tetrahydrocannabinol in the rat. [So] Source: J Physiol Pharmacol;63(6):581-8, 2012 Dec. [Is] ISSN: 1899-1505 [Cp] País de publicação: Poland [La] Idioma: eng [Ab] Resumo: We previously reported that delta-9-tetrahydrocannabinol (delta-9-THC), the primary psychoactive constituent of Cannabis sativa, inhibited gastric motor activity and evoked bradycardia and hypotension upon its parenteral administration in the rat. As prostanoids are important mediators of the actions of cannabinoids, we hypothesized that the inhibitory gastric motor and cardiovascular effects of delta-9-THC could depend on cyclooxygenase (COX) activation in the hindbrain and/or in the periphery. To test this hypothesis, vehicle or delta-9-THC (0.2 mg/kg, i.v.) were administered before and 15-min after the COX inhibitor tolmetin (50 mg/kg, i.v.) or 15 min after topical application of tolmetin to the surface of the dorsal medulla (0.5 mg/rat) in chloralose-anesthetized rats. Delta-9-THC-evoked gastric motor inhibition and bradycardia were abolished by parenteral and were attenuated by hindbrain administration of tolmetin. Moreover, administration of delta-9-THC after parenteral tolmetin evoked marked and long-lasting hypertension. We concluded that the inhibitory gastric motor and cardiovascular effects of systemically administered delta-9-THC depend on the hindbrain and peripheral activation of COX. [Mh] Termos MeSH primário: Dronabinol/farmacologia Motilidade Gastrointestinal/efeitos dos fármacos Hemodinâmica/efeitos dos fármacos Prostaglandinas/metabolismo Psicotrópicos/farmacologia Rombencéfalo/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Pressão Arterial/efeitos dos fármacos Inibidores de Ciclo-Oxigenase/farmacologia Dronabinol/administração & dosagem Frequência Cardíaca/efeitos dos fármacos Injeções Intravenosas Masculino Psicotrópicos/administração & dosagem Ratos Ratos Sprague-Dawley Rombencéfalo/metabolismo Tolmetino/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Cyclooxygenase Inhibitors); 0 (Prostaglandins); 0 (Psychotropic Drugs); 7J8897W37S (Dronabinol); D8K2JPN18B (Tolmetin) [Em] Mês de entrada: 1308 [Cu] Atualização por classe: 131121 [Lr] Data última revisão: 131121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 130208 [St] Status: MEDLINE

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[PMID]: 22937138 [Au] Autor: Flanagan JU; Yosaatmadja Y; Teague RM; Chai MZ; Turnbull AP; Squire CJ [Ad] Endereço: Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand. [Ti] Título: Crystal structures of three classes of non-steroidal anti-inflammatory drugs in complex with aldo-keto reductase 1C3. [So] Source: PLoS One;7(8):e43965, 2012. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Aldo-keto reductase 1C3 (AKR1C3) catalyses the NADPH dependent reduction of carbonyl groups in a number of important steroid and prostanoid molecules. The enzyme is also over-expressed in prostate and breast cancer and its expression is correlated with the aggressiveness of the disease. The steroid products of AKR1C3 catalysis are important in proliferative signalling of hormone-responsive cells, while the prostanoid products promote prostaglandin-dependent proliferative pathways. In these ways, AKR1C3 contributes to tumour development and maintenance, and suggest that inhibition of AKR1C3 activity is an attractive target for the development of new anti-cancer therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) are one well-known class of compounds that inhibits AKR1C3, yet crystal structures have only been determined for this enzyme with flufenamic acid, indomethacin, and closely related analogues bound. While the flufenamic acid and indomethacin structures have been used to design novel inhibitors, they provide only limited coverage of the NSAIDs that inhibit AKR1C3 and that may be used for the development of new AKR1C3 targeted drugs. To understand how other NSAIDs bind to AKR1C3, we have determined ten crystal structures of AKR1C3 complexes that cover three different classes of NSAID, N-phenylanthranilic acids (meclofenamic acid, mefenamic acid), arylpropionic acids (flurbiprofen, ibuprofen, naproxen), and indomethacin analogues (indomethacin, sulindac, zomepirac). The N-phenylanthranilic and arylpropionic acids bind to common sites including the enzyme catalytic centre and a constitutive active site pocket, with the arylpropionic acids probing the constitutive pocket more effectively. By contrast, indomethacin and the indomethacin analogues sulindac and zomepirac, display three distinctly different binding modes that explain their relative inhibition of the AKR1C family members. This new data from ten crystal structures greatly broadens the base of structures available for future structure-guided drug discovery efforts. [Mh] Termos MeSH primário: 3-Hidroxiesteroide Desidrogenases/química Anti-Inflamatórios não Esteroides/química Hidroxiprostaglandina Desidrogenases/química [Mh] Termos MeSH secundário: 3-Hidroxiesteroide Desidrogenases/metabolismo Membro C3 da Família 1 de alfa-Ceto Redutase Anti-Inflamatórios não Esteroides/metabolismo Ácido Flufenâmico/química Ácido Flufenâmico/metabolismo Flurbiprofeno/química Flurbiprofeno/metabolismo Hidroxiprostaglandina Desidrogenases/metabolismo Ibuprofeno/química Ibuprofeno/metabolismo Indometacina/química Indometacina/metabolismo Ácido Meclofenâmico/química Ácido Meclofenâmico/metabolismo Ácido Mefenâmico/química Ácido Mefenâmico/metabolismo Naproxeno/química Naproxeno/metabolismo Sulindaco/química Sulindaco/metabolismo Tolmetino/análogos & derivados Tolmetino/química Tolmetino/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Anti-Inflammatory Agents, Non-Steroidal); 184SNS8VUH (Sulindac); 367589PJ2C (Mefenamic Acid); 48I5LU4ZWD (Meclofenamic Acid); 57Y76R9ATQ (Naproxen); 5GRO578KLP (Flurbiprofen); 60GCX7Y6BH (Flufenamic Acid); 822G987U9J (zomepirac); D8K2JPN18B (Tolmetin); EC 1.1.- (3-Hydroxysteroid Dehydrogenases); EC 1.1.1.- (Hydroxyprostaglandin Dehydrogenases); EC 1.1.1.357 (AKR1C3 protein, human); EC 1.1.1.357 (Aldo-Keto Reductase Family 1 Member C3); WK2XYI10QM (Ibuprofen); XXE1CET956 (Indomethacin) [Em] Mês de entrada: 1302 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 120901 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0043965

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