RESUMO
BACKGROUND: Irinotecan (CPT-11) is the key drug used in chemotherapy for many malignant tumors. CPT-11 has cholinergic activity and induces perspiration during intravenous administration. In this study, concentrations of CPT-11 and its active metabolite, SN-38, released during perspiration were measured and risk of exposure of these drugs was assessed. METHOD: Beads of sweat were collected using a dropper from four patients undergoing a chemotherapy regimen involving intravenous administration of CPT-11. The concentrations of CPT-11 and SN-38 in sweat were measured using liquid chromatography tandem mass spectrometry. RESULT: Chemotherapy regimens were capecitabine and irinotecan plus bevacizumab (n = 1), CPT-11 monotherapy (n = 1), and oxaliplatin-irinotecan-leucovorin-5-fluorouracil (n = 2). Uridine diphosphate-glucuronosyltransferase 1A1 phenotypes were *6 homo-type (n = 1), *6 hetero-type (n = 1), and wild type (n = 2). CPT-11 dose was 292.3 ± 75.5 mg/body weight (mean ± standard deviation). CPT-11 was detected in sweat secreted by all the four patients, and its mean (±standard deviation) concentration was 252.6 (±111.9) ng/ml. SN-38 was detected in only one of the patients who received oxaliplatin-irinotecan-leucovorin-5-fluorouracil treatment and who had the wild-type uridine diphosphate-glucuronosyltransferase 1A1 phenotype at a concentration of 74.37 ng/ml. CONCLUSION: CPT-11 and SN-38 are detected in sweat released during intravenous CPT-11 administration. Beads of sweat or linen clothes that absorb the sweat might be the source of CPT-11 and SN-38 exposure.
Assuntos
Irinotecano/efeitos adversos , Suor/efeitos dos fármacos , Inibidores da Topoisomerase I/efeitos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Glucuronosiltransferase/fisiologia , Humanos , Irinotecano/farmacocinética , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Suor/metabolismoRESUMO
PURPOSE: The purpose of the study was to evaluate the site of paronychia in patients with non-small cell lung cancer harboring an epidermal growth factor receptor (EGFR) gene activating mutation who were treated with EGFR tyrosine kinase inhibitors (EGFR TKIs). PATIENTS AND METHODS: The study included 55 patients with non-small-cell lung cancer who were treated with an EGFR TKIs. Resulting all toxicities were graded using the Common Terminology Criteria for Adverse Events version 4.0 system. Drug concentrations were determined with use of a quantum triple-quadrupole mass spectrometer and dried blood spots testing. RESULTS: Paronychia most commonly occurred in the thumb and the big toe. There was no correlation between the severity of paronychia and the drug concentration of each EGFR TKI at the site of paronychia. The mean penetration rates of the drug from plasma to the tip of the finger and toe were 74.1% (erlotinib), 82.2% (gefitinib), and 99.9% (afatinib). CONCLUSIONS: High concentrations of an EGFR TKI at the affected site did not play a role in the onset mechanism of paronychia. Therefore, educating patients about ways to avoid compression may be a better approach to managing this adverse event than reducing the dose of the EGFR-TKI or stopping treatment.
Assuntos
Paroniquia/induzido quimicamente , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Afatinib , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/administração & dosagem , Cloridrato de Erlotinib/efeitos adversos , Cloridrato de Erlotinib/sangue , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade , Paroniquia/sangue , Inibidores de Proteínas Quinases/sangue , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/sangueRESUMO
BACKGROUND: Nivolumab is a fully humanized IgG4 monoclonal antibody that targets the programmed death-1 (PD-1) receptor, disrupting PD-1-mediated signaling and restoring antitumor immunity. The objective of this study was to develop a nivolumab quantification method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and to evaluate its application in clinical therapeutic drug monitoring. METHODS: Nivolumab was purified from human plasma using rProtein A resin and then digested with trypsin. The ASGITFSNSGMHWVR peptide (multiple reaction monitoring transition: m/z 550.6â661.4) was detected as a surrogate peptide of nivolumab by triple quadrupole mass spectrometry. Plasma samples (126) were collected from 14 patients with non-small cell lung cancer who were undergoing clinical dosing regimen with nivolumab. The pharmacokinetic data were analyzed using Phoenix NLME software (Version 7.0, Certara, St. Louis, MO) based on a previously reported population pharmacokinetics (PPK) model of nivolumab. RESULTS: Nivolumab was selectively detected in human plasma and the linear range was 5-200 mcg/mL (R = 0.99). The accuracy and intraday and interday imprecision were within ±15% of the quality control values of 5 (lower limit of quantification), 10 (low), 80 (medium), and 160 (high) mcg/mL. The nivolumab concentrations measured using LC-MS/MS were consistent with those of previously reported PPK models, and the pharmacokinetic parameters could be adequately predicted from a single trough concentration using a Bayesian approach. CONCLUSIONS: An absolute quantification method for nivolumab using LC-MS/MS was successfully developed and validated. Combined with PPK analysis, this method should be useful for the therapeutic drug monitoring of nivolumab in clinical practice.
Assuntos
Monitoramento de Medicamentos/métodos , Nivolumabe/sangue , Plasma/química , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/sangue , Teorema de Bayes , Carcinoma Pulmonar de Células não Pequenas/sangue , Cromatografia Líquida/métodos , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem/métodosRESUMO
A series of N-benzoyl-2-methylindole-3-acetic acids were synthesized and biologically evaluated as prostaglandin (PG) D2 receptor antagonists. Some of the selected compounds significantly inhibited OVA-induced vascular permeability in guinea pig conjunctiva after oral dosing. Structure-activity relationship study is presented.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/metabolismo , Animais , Células CHO , Túnica Conjuntiva/irrigação sanguínea , Cricetinae , Cricetulus , Descoberta de Drogas , Cobaias , HumanosRESUMO
To identify new cost-effective prostaglandin D2 (DP) receptor antagonists, a series of novel 3-benzoylaminophenylacetic acids were synthesized and biologically evaluated. Among those tested, some representative compounds were found to be orally available. Receptor selectivity and rat PK profiles were also evaluated. The structure-activity relationship (SAR) study is presented.
Assuntos
Benzamidas/farmacologia , Desenho de Fármacos , Fenilacetatos/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Benzamidas/síntese química , Benzamidas/química , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Masculino , Conformação Molecular , Fenilacetatos/síntese química , Fenilacetatos/química , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D(2) (PGD(2)) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented. Optimized compounds were studied for their pharmacokinetics and in vivo potential. A structure-activity relationship study is also presented. Some of the test compounds were found to have in vivo efficacy towards the inhibition of PGD(2)-induced and OVA-induced vascular permeability in guinea pig conjunctiva.
Assuntos
Fenilacetatos/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Animais , Células CHO , Cricetinae , Cricetulus , Cobaias , Humanos , Modelos Moleculares , Fenilacetatos/química , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
Single electron transfer (SET)-photochemical decarboxylation of free carboxylic acids was performed in a polar solvent using several arenes such as phenanthrene, naphthalene, 1-methylnaphthalene, biphenyl, triphenylene, and chrysene in the presence of various electron acceptors such as 1,2-, 1,3-, and 1,4-dicyanobenzenes, methyl 4-cyanobenzoate, and 1,4-dicyanonaphthalene. The decarboxylation reaction was influenced by the arenes, electron acceptors, and solvent. The best result was achieved by the photoreaction using biphenyl and 1,4-dicyanonaphthalene in aqueous acetonitrile.
Assuntos
Ácidos Carboxílicos/química , Solventes/química , Acetonitrilas/química , Compostos de Bifenilo/química , Crisenos/química , Cianetos/química , Descarboxilação , Transporte de Elétrons , Naftalenos/química , Fenantrenos/química , Processos FotoquímicosRESUMO
AIM: To examine whether patterns of social participation vary in their associations with functional disability. METHODS: Data from 44 978 participants (22 750 men and 22 228 women) who participated in the 2010 Japan Gerontological Evaluation Study were analyzed; a study of those aged ≥65 years from 23 municipalities in eight prefectures. Social participation information was obtained at baseline with an eight-item questionnaire. Incidence of functional disability from 2010 to 2013 was defined as a new certification of eligibility for municipal public long-term care insurance. Social participation patterns were analyzed using exploratory factor analysis and participants were classified into quartiles of factor scores of social participation patterns. A competing risk model was used to calculate the hazard ratios and 95% confidence intervals for the incidence of functional disability in 3 years of follow-up. RESULTS: Two social patterns were identified: sports groups/clubs and hobby groups, and political groups/organizations and industry/trade associations. For both patterns, compared with participants in the lowest quartile, participants in the highest quartile were more likely to be male, college educated, high-income and current drinkers. Both patterns were associated with reduced incidence of functional disability (adjusted hazard ratios for top quartile of sports and hobby pattern: 0.66, 95% confidence interval: 0.59, 0.74; for political and industry/trade pattern: 0.81, 95% confidence interval: 0.72, 0.90; P for trend <0.001 for both). CONCLUSIONS: Those whose social participation patterns were characterized by frequent participation in sports groups/clubs and hobby groups or political groups/organizations and industry/trade associations were less likely to develop a functional disability. Geriatr Gerontol Int 2020; 20: 765-772.
Assuntos
Pessoas com Deficiência/estatística & dados numéricos , Passatempos/psicologia , Participação Social/psicologia , Esportes/psicologia , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Avaliação da Deficiência , Feminino , Avaliação Geriátrica , Humanos , Incidência , Japão/epidemiologia , Masculino , Modelos de Riscos Proporcionais , Inquéritos e QuestionáriosRESUMO
Aim: The transitivity of osimertinib to cerebrospinal fluid (CSF) is of clinical concern. A quantitative LC-MS/MS method for the determination of osimertinib in human plasma and CSF was developed to evaluate its transitivity. Results: The calibration range was 40-1000 nM in plasma and 0.8-100 nM in CSF. Accuracy and precision were within 15%. Osimertinib in the CSF but not in plasma strongly adsorbed onto the storage container. The mean adsorbed loss of osimertinib was 45.5% in CSF. Nonspecific binding in CSF was decreased by protein addition (mean loss = 5.8%). Conclusion: A robust validated method was developed for the quantification of osimertinib in human plasma and CSF.
Assuntos
Acrilamidas/sangue , Acrilamidas/líquido cefalorraquidiano , Compostos de Anilina/sangue , Compostos de Anilina/líquido cefalorraquidiano , Análise Química do Sangue/métodos , Acrilamidas/química , Adsorção , Compostos de Anilina/química , Calibragem , Cromatografia Líquida , Humanos , Limite de Detecção , Espectrometria de Massas em TandemRESUMO
A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of gefitinib in dried blood spots (DBSs). Gefitinib was extracted with methanol from DBS of 3â¯mm in diameter and detected using a triple quadrupole mass spectrometer. The method was validated by evaluating its precision, accuracy, selectivity, carryover, matrix effect, recovery, and stability. For clinical validation, paired finger-prick DBS and plasma concentrations were compared for 10 patients with non-small cell lung cancer (NSCLC) taking gefitinib. The calibration linear range was 37.5-2400â¯ng/mL (coefficient of determination [R2]â¯=â¯0.99), encompassing the therapeutic concentrations of gefitinib. The accuracy and precision were within 15% of the quality control (QC) concentrations of 80, 200, and 2000â¯ng/mL. The lower limit of quantification was determined to be 40â¯ng/mL. Gefitinib was stable in DBSs for up to 5â¯months at room temperature and -20⯰C, and at 40⯰C for 24â¯h. A good correlation was observed between the gefitinib levels measured by the DBS method and plasma concentrations (R2â¯=â¯0.99). This method provides a simple, fast, and accurate approach to the quantitative analysis of gefitinib in finger-prick DBSs. The method would be useful for minimally invasive evaluation of the clinical gefitinib blood concentration.
Assuntos
Antineoplásicos/sangue , Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco/métodos , Quinazolinas/sangue , Espectrometria de Massas em Tandem/métodos , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Coleta de Amostras Sanguíneas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Feminino , Gefitinibe , Humanos , Modelos Lineares , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Quinazolinas/uso terapêutico , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Vancomycin is a commonly used antimicrobial agent for patients undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Vancomycin has large inter- and intraindividual pharmacokinetic variability, which is mainly described by renal function; various studies have indicated that vancomycin pharmacokinetics are altered in special populations. However, little is known regarding vancomycin pharmacokinetics in patients undergoing allo-HSCT. Therefore, we aimed to develop a population pharmacokinetic (PopPK) model of vancomycin in patients undergoing allo-HSCT for effective and safe antimicrobial therapy and to develop a vancomycin dosing nomogram for a vancomycin optimal-dosing strategy. In total, 285 observations from 95 patients undergoing allo-HSCT were available. The final PopPK parameter estimates were central volume of distribution (V1, L), 39.2; clearance (L/h), 4.25; peripheral volume of distribution (V2, L), 56.1; and intercompartmental clearance (L/h), 1.95. The developed vancomycin model revealed an increase in V1 and V2 compared with those in the general population that consisted of patients with methicillin-resistant Staphylococcus aureus. Moreover, serum creatinine was reduced because of an increase in the plasma fraction because of destruction of hematopoietic stem cells accompanying allo-HSCT pretreatment, suggesting that the Cockcroft-Gault equation-based creatinine clearance value was overestimated. To our knowledge, this is the first PopPK study to develop a dosing nomogram for vancomycin in patients undergoing allo-HSCT and was proven to be useful in optimizing the dosage and dosing interval of vancomycin in these patients. This strategy will provide more useful information for vancomycin therapy with an evidence-based dose adjustment.
Assuntos
Antibacterianos/farmacocinética , Transplante de Células-Tronco Hematopoéticas , Vancomicina/farmacocinética , Adolescente , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Infecções Bacterianas/prevenção & controle , Feminino , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Vancomicina/administração & dosagem , Vancomicina/uso terapêutico , Adulto JovemRESUMO
A series of N-(p-alkoxy)benzoyl-5-methoxy-2-methylindole-3-acetic acids and N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid were discovered as new chemical leads for a prostaglandin D2 (PGD2) receptor antagonist. Most of them exhibited PGD2 receptor binding and blocked cyclic adenosine 3',5'-monophosphate (cAMP) formation in vitro. In particular, 2-methylindole-4-acetic acid analog 1 showed markedly increased receptor affinity and cAMP antagonist activity. Chemistry and structure activity relationship (SAR) data are also presented.
Assuntos
Ácidos Indolacéticos/síntese química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Área Sob a Curva , Ligação Competitiva/fisiologia , Células CHO , Cricetinae , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/metabolismo , Meia-Vida , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacocinética , Indometacina/análogos & derivados , Indometacina/química , Indometacina/farmacocinética , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Relação Estrutura-AtividadeRESUMO
Th1 cell activation and cytokine production shift the balance between Th1 and Th2, favoring the upregulation of proinflammatory activity that leads to destruction of allogeneic hepatocytes following transplantation. Th2-type cytokines. such as IL-10, have immune regulatory function. The aim of this study was to determine the antirejection efficacy of allogeneic hepatocytes with spheroidal shape (spheroids) genetically modified with viral IL-10 (vIL-10). Allogeneic hepatocyte spheroids, transferred vIL-10 gene by using adenovirus as the vector, were transplanted into the spleen of Nagase's analbuminemic rats (NAR). NAR transplanted with vIL-10-transfected hepatocytes showed an abrupt rise in serum albumin levels that peaked on day 7 and remained at high levels up to day 21 after transplantation. The peak level of albumin on day 7 in vIL-10-transfected NAR was eminently higher than that in nontransfected NAR. Histopathological analysis revealed that in nontransfected NAR hepatocyte spheroids were more or less rejected on day 4, and, in contrast, vIL-10-transfected spheroids were still not rejected on day 14. This protective effect correlated with sustained high vIL-10 level in the splenic vein in NAR transplanted with vIL-10-transfected hepatocyte spheroids, suggesting that vIL-10 secreted from the transplanted hepatocytes induced an active suppression of allogeneic response. This study provides evidence to support the possibility of using vIL-10 gene therapy to prevent allogeneic response in hepatocyte transplantation.
Assuntos
Rejeição de Enxerto/prevenção & controle , Hepatócitos/imunologia , Hepatócitos/transplante , Terapia de Imunossupressão/métodos , Interleucina-10/genética , Tolerância ao Transplante/imunologia , Adenoviridae/genética , Animais , Galactosídeos/genética , Técnicas de Transferência de Genes , Genes Reporter/genética , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Hepatócitos/metabolismo , Indóis , Interleucina-10/biossíntese , Interleucina-10/uso terapêutico , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Ratos , Ratos Endogâmicos , Albumina Sérica/biossíntese , Albumina Sérica/metabolismo , Esferoides Celulares/imunologia , Esferoides Celulares/transplante , Células Th1/imunologia , Células Th2/imunologia , Transplante Homólogo/imunologia , Transplante Homólogo/métodosRESUMO
The Japanese Antarctic Research Expedition (JARE) has had a presence in Antarctica since 1956. The Syowa station is 15,000 km from Japan and evacuation of patients is impossible during the winter months. From 1956 to 2003, a total of 4932 telemedical consultations were undertaken, i.e. every member of the station needed an average of 4 medical consultations each winter. Forty five percent of the consultations were surgical or orthopaedic cases, 23% were for internal medicine and 12% were for dental problems. In the early 1980s, satellite radio-telephony was found to be useful for consultations, but did not have the ability to transmit medical pictures. Email was transmitted by the International Mobile Satellite Organization (INMARSAT) but the connection was only available every 2 hours and the maximum message size was 100 kByte. In 2004, the International Telecommunications Satellite (INTELSAT) system made a connection constantly available, and increased the maximum message size to 10 MByte. Transmission of still and moving pictures became possible. Scheduled consultations are performed monthly. A doctor in Japan can ask the patient questions and perform a proxy examination with the assistance of the Antarctic doctor. Real-time telemedicine is very effective in orthopaedic and surgical cases, skin, eye and dental troubles. Still pictures are more effective for understanding in detail skin and eye problems. Emergency consultations are effective if adequate consulting staff are available.
Assuntos
Consulta Remota/tendências , Telemedicina/tendências , Regiões Antárticas/epidemiologia , Correio Eletrônico/estatística & dados numéricos , História do Século XX , História do Século XXI , Humanos , Japão , Consulta Remota/estatística & dados numéricos , Telemedicina/história , Comunicação por Videoconferência/estatística & dados numéricosRESUMO
Deuterium exchange of a carboxy group was achieved by photochemical decarboxylation of free carboxylic acids in the presence of thiol and a small amount of D(2)O, and a deuterated product with excellent deuterium content was obtained; this reaction is a practical means of synthesizing regioselective deuterium-labelled compounds under mild reaction conditions.
Assuntos
Ácidos Carboxílicos/química , Deutério/química , Catálise , Descarboxilação , Transporte de Elétrons , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Processos Fotoquímicos , Estereoisomerismo , Compostos de Sulfidrila/químicaRESUMO
A series of Indomethacin analogs were synthesized and biologically evaluated. Among the compounds tested, N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid 2 was discovered as a new chemical lead for a prostaglandin D2 (PGD2) receptor antagonist. Structure-activity relationship data are also presented.
Assuntos
Antagonistas de Prostaglandina/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Camundongos , Antagonistas de Prostaglandina/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMO
The process of discovery for highly potent prostaglandin D(2) (PGD(2)) receptor antagonists is reported. A series of N-(p-alkoxy)benzoyl-2-methylindole-4-acetic acids were synthesized and identified as a new class of selective PGD(2) receptor antagonists. Most of them exhibited strong PGD(2) receptor antagonism in binding studies and the cAMP formation assay. The structure-activity relationships (SAR), including subtype selectivity of the synthesized compounds, are also discussed.
Assuntos
Antialérgicos/farmacologia , Ácidos Indolacéticos/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Antialérgicos/síntese química , Sítios de Ligação , AMP Cíclico/metabolismo , Desenho de Fármacos , Ácidos Indolacéticos/química , Relação Estrutura-AtividadeRESUMO
The process of discovering a series of N-(p-alkoxy)benzoyl-2-methylindole-4-acetic acid analogs is presented since these compounds represent a new class of potent, selective, and orally active prostaglandin D2 (PGD2) receptor antagonists. Most of these compounds exhibit strong PGD2 receptor binding and PGD2 receptor antagonism in cAMP formation assays. When given orally, these new antagonists dramatically suppress allergic inflammatory responses, such as the PGD2-induced or OVA-induced increase of vascular permeability. Structure-activity relationship (SAR) data are also discussed.
Assuntos
Antialérgicos/química , Antialérgicos/farmacologia , Ácidos Indolacéticos/química , Ácidos Indolacéticos/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Animais , Antialérgicos/administração & dosagem , Cobaias , Humanos , Ácidos Indolacéticos/administração & dosagem , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMO
A series of N-(p-alkoxy)benzoyl-2-methylindole-4-acetic acids were synthesized and evaluated for prostaglandin D(2) (DP) receptor affinity and antagonist activity. Some of them exhibited strong receptor binding and were potent in the cAMP formation assays. These antagonists also suppressed allergic inflammatory responses such as the PGD(2)-induced increase of microvascular permeability. Structure-activity relationship (SAR) data are presented.