Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 52
Filtrar
1.
J Med Chem ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34613725

RESUMO

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism. After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.

2.
Br J Anaesth ; 127(3): 405-414, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34229832

RESUMO

BACKGROUND: Allogeneic red blood cell (RBC) transfusion can induce immunosuppression, which can then increase the susceptibility to postoperative infection. However, studies in different types of surgery show conflicting results regarding this effect. METHODS: In this retrospective cohort study conducted in a tertiary referral centre, we included adult patients undergoing clean-contaminated surgery from 2014 to 2018. Patients who received allogeneic RBC transfusion from preoperative Day 30 to postoperative Day 30 were included into the transfusion group. The control group was matched for the type of surgery in a 1:1 ratio. The primary outcome was infection within 30 days after surgery, which was defined by healthcare-associated infection, and identified mainly based on antibiotic regimens, microbiology tests, and medical notes. RESULTS: Among the 8098 included patients, 1525 (18.8%) developed 1904 episodes of postoperative infection. Perioperative RBC transfusion was associated with an increased risk of postoperative infection after controlling for 27 confounders by multivariable regression analysis (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.39-1.84; P<0.001) and propensity score weighing (OR: 1.64; 95% CI: 1.45-1.85; P<0.001) and matching (OR: 1.70; 95% CI: 1.43-2.01; P<0.001), and a dose-response relationship was observed. The transfusion group also showed higher risks of surgical site infection, pneumonia, bloodstream infection, multiple infections, intensive care admission, unplanned reoperation, prolonged postoperative length of hospital stay, and all-cause death. CONCLUSIONS: Perioperative allogeneic RBC transfusion is associated with an increased risk of infection after clean-contaminated surgery in a dose-response manner. Close monitoring of infections and enhanced prophylactic strategies should be considered after transfusion.


Assuntos
Infecções Bacterianas/microbiologia , Transfusão de Eritrócitos/efeitos adversos , Hospedeiro Imunocomprometido , Assistência Perioperatória/efeitos adversos , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Antibacterianos/uso terapêutico , Bacteriemia/imunologia , Bacteriemia/microbiologia , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/imunologia , Infecções Bacterianas/mortalidade , Cuidados Críticos , Transfusão de Eritrócitos/mortalidade , Humanos , Tempo de Internação , Readmissão do Paciente , Assistência Perioperatória/mortalidade , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Procedimentos Cirúrgicos Operatórios/mortalidade , Infecção da Ferida Cirúrgica/imunologia , Infecção da Ferida Cirúrgica/microbiologia , Fatores de Tempo , Transplante Homólogo/efeitos adversos , Resultado do Tratamento
3.
BMC Genomics ; 22(1): 573, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34311701

RESUMO

BACKGROUND: Chinese indigenous rabbits have distinct characteristics, such as roughage resistance, stress resistance and environmental adaptability, which are of great significance to the sustainable development of the rabbit industry in China. Therefore, it is necessary to study the genetic diversity and population structure of this species and develop genomic resources. RESULTS: In this study, we used restriction site-associated DNA sequencing (RAD-seq) to obtain 1,006,496 SNP markers from six Chinese indigenous rabbit breeds and two imported rabbit breeds. Jiuyishan and Fujian Yellow rabbits showed the highest nucleotide diversity (π) and decay of linkage disequilibrium (LD), as well as higher observed heterozygosity (Ho) and expected heterozygosity (He), indicating higher genetic diversity than other rabbits. The inbreeding coefficient (FIS) of New Zealand rabbits and Belgian rabbits was higher than that of other rabbits. The neighbour-joining (NJ) tree, principal component analysis (PCA), and population structure analysis of autosomes and Y chromosomes showed that Belgian, New Zealand, Wanzai, Sichuan White, and Minxinan Black rabbits clustered separately, and Fujian Yellow, Yunnan Colourful, and Jiuyishan rabbits clustered together. Wanzai rabbits were clearly separated from other populations (K = 3), which was consistent with the population differentiation index (FST) analysis. The selection signature analysis was performed in two populations with contrasting coat colours. With Sichuan White and New Zealand rabbits as the reference populations and Minxinan Black and Wanzai rabbits as the target populations, 408, 454, 418, and 518 genes with a selection signature, respectively, were obtained. Gene Ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on the genes with a selection signature. The results showed that the genes with a selection signature were enriched in the melanogenesis pathway in all four sets of selection signature analyses. CONCLUSIONS: Our study provides the first insights into the genetics and genomics of Chinese indigenous rabbit breeds and serves as a valuable resource for the further effective utilization of the species.


Assuntos
Genética Populacional , Polimorfismo de Nucleotídeo Único , Coelhos , Animais , Cruzamento , China , Genômica , Nova Zelândia , Análise de Sequência de DNA
4.
Molecules ; 26(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801899

RESUMO

Natural products are important sources for drug discovery, especially anti-tumor drugs. ß-Elemene, the prominent active ingredient extract from the rhizome of Curcuma wenyujin, is a representative natural product with broad anti-tumor activities. The main molecular mechanism of ß-elemene is to inhibit tumor growth and proliferation, induce apoptosis, inhibit tumor cell invasion and metastasis, enhance the sensitivity of chemoradiotherapy, regulate the immune system, and reverse multidrug resistance (MDR). Elemene oral emulsion and elemene injection were approved by the China Food and Drug Administration (CFDA) for the treatment of various cancers and bone metastasis in 1994. However, the lipophilicity and low bioavailability limit its application. To discover better ß-elemene-derived anti-tumor drugs with satisfying drug-like properties, researchers have modified its structure under the premise of not damaging the basic scaffold structure. In this review, we comprehensively discuss and summarize the potential anti-tumor mechanisms and the progress of structural modifications of ß-elemene.


Assuntos
Sesquiterpenos/química , Sesquiterpenos/metabolismo , Sesquiterpenos/farmacologia , Anticarcinógenos/metabolismo , Anticarcinógenos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , China , Curcuma/metabolismo , Humanos , Sesquiterpenos Monocíclicos/química , Sesquiterpenos Monocíclicos/metabolismo , Sesquiterpenos Monocíclicos/farmacologia , Rizoma/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
BMC Health Serv Res ; 21(1): 58, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33435985

RESUMO

BACKGROUND: Breast cancer costs were estimated at $16.5 billion in 2010 and were higher than other cancer costs. There are limited studies on breast cancer charges and costs by BRCA mutations and receptor status. We examined overall health care and breast cancer-related charges by BRCA status (BRCAm vs. BRCAwt), receptor status (HER2+ vs. HER2-), and treatment setting (neoadjuvant vs. adjuvant). METHODS: Retrospective cohort study of charge data from 1995-2014 in an academic medical center. Facilities, physician, pharmacy, and diagnosis-related charges were presented as mean and median charges with standard deviation (SD) and interquartile ranges (25%-75%). Wilcoxon rank-sum test was used to assess statistically significant differences in charges between comparators. RESULTS: Total median breast-cancer related charges were $65,414 for BRCAm and $54,635 for BRCAwt (p=0.19); however all-cause charges were higher for BRCAm patients ($145,066 vs. $119,119, p<0.001). HER2+ status was associated with higher median breast cancer charges ($152,159 vs. $44,087, p<0.0001) that was driven by the charges for biological agents. Patients initially seen in the neoadjuvant setting had higher mean breast cancer charges than in the adjuvant setting ($117,922 vs. $80,061, p<0.0001). CONCLUSION: BRCA mutation status was not associated with higher breast cancer charges but HER2+ status had significantly higher charges, due to charges for biological agents. Patients who initially received neoadjuvant treatment had significantly higher overall treatment charges than adjuvant therapy patients. With the advent of novel therapies for BRCAm, the economic impact of these treatments will be important to consider relative to their survival benefits.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Atenção à Saúde , Feminino , Humanos , Mutação , Estudos Retrospectivos
6.
Eur J Med Chem ; 213: 113165, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33454546

RESUMO

Inflammation is an adaptive response of the immune system to tissue malfunction or homeostatic imbalance. Corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently applied to treat varieties of inflammatory diseases but are associated with gastrointestinal, cardiovascular, and kidney side effects. Developing more effective and less toxic agents remain a challenge for pharmaceutical chemist due to the complexity of the different inflammatory processes. Alkaloids are widely distributed in plants with diverse anti-inflammatory activities, providing various potential lead compounds or candidates for the design and discovery of new anti-inflammatory drug candidates. Therefore, re-examining the anti-inflammatory alkaloid natural products is advisable, bringing more opportunities. In this review, we summarized and described the recent advances of natural alkaloids with anti-inflammatory activities and possible mechanisms in the period from 2009 to 2020. It is hoped that this review of anti-inflammatory alkaloids can provide new ideas for researchers engaged in the related fields and potential lead compounds for the discovery of anti-inflammatory drugs.


Assuntos
Alcaloides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Produtos Biológicos/uso terapêutico , Descoberta de Drogas , Inflamação/tratamento farmacológico , Alcaloides/síntese química , Alcaloides/química , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Humanos , Estrutura Molecular
7.
Breast Cancer Res Treat ; 186(3): 839-850, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33389410

RESUMO

MAIN PURPOSE: Germline BRCA mutations (BRCAm) strongly influence the risk of developing breast cancer. This study aimed to understand the role of BRCAm testing in affected individuals and to assess its impact on the outcome of BRCAm carriers compared to non-carriers (BRCAwt) with breast cancer. RESEARCH QUESTION: The research question is "Does standard of care testing for BRCAm improve survival outcomes of breast cancer patients?" METHODS: In a single institution observational cohort study, demographic and clinical characteristics were compared between breast cancer patients with and without BRCAm. Frequency of BRCA testing was assessed. Survival outcomes were assessed by initial treatment setting stratified by BRCA status. RESULTS: Of 5712 identified women with breast cancer, 14.6% (n = 835) were tested for a BRCA mutation and had a documented result. The total number and proportion of women tested for a BRCAm increased between 2000 and 2014, resulting in an increased number of BRCAm carriers identified. However, the proportion of women who underwent testing and had a BRCAm decreased during the study period from 27.5% in 2000-2004 to 13.3% in 2010-2014. Disease-free survival was similar in the adjuvant and neoadjuvant treatment settings between BRCAm and BRCAwt patients. Progression-free survival on first line treatment and overall survival for patients with metastatic disease was also similar between BRCAm and BRCAwt patients. CONCLUSIONS: The proportion of women tested and the number of BRCAm identified increased during the study period despite a decreasing proportion of positive results among women tested.


Assuntos
Neoplasias da Mama , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Mutação em Linhagem Germinativa , Humanos , Mutação
8.
Expert Opin Ther Pat ; 31(5): 435-452, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33347360

RESUMO

Introduction: DNA-dependent protein kinase (DNA-PK) plays a crucial role in the repair of DSBs via non-homologous end joining (NHEJ). Several DNA-PK inhibitors are being investigated for potential anticancer treatment in clinical trials.Area covered: This review aims to give an overview of patents published since 2010 by analyzing the patent space and structure features of scaffolds used in those patents. It also discusses the recent clinical developments and provides perspectives on future challenges and directions in this field.Expert opinion: As a key component of the DNA damage response (DDR) pathway, DNA-PK appears to be a viable drug target for anticancer therapy. The clinical investigation of a DNA-PK inhibitor employs both a monotherapy and a combination strategy. In the combination strategy, a DNA-PK inhibitor is typically combined with a DSB inducer, radiation, a chemotherapy agent, or a PARP inhibitor, etc. Patent analyses suggest that diverse structures comprising different scaffolds from mono-heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl are capable to achieve good DNA-PK inhibitory activity and good DNA-PK selectivity over other closely related enzymes. Several DNA-PK inhibitors are currently being evaluated in clinics, with the hope to get approval in the near future.


Assuntos
Proteína Quinase Ativada por DNA/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Dano ao DNA/efeitos dos fármacos , Desenvolvimento de Medicamentos , Humanos , Neoplasias/genética , Patentes como Assunto
9.
Biochem Pharmacol ; 182: 114224, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32956642

RESUMO

Epigenetic enzymes histone deacetylases (HDACs) are clinically validated anticancer drug targets which have been studied intensively in the past few decades. Although several drugs have been approved in this field, they are still limited to a subset of hematological malignancies (in particular T-cell lymphomas), with therapeutic potential not fully realized and the drug-resistance occurred after a certain period of use. To maximize the therapeutic potential of these classes of anticancer drugs, and to extend their application to solid tumors, numerous combination therapies containing an HDACi and an anticancer agent from other mechanisms are currently ongoing in clinical trials. Recently, dual targeting strategy comprising the HDACs component has emerged as an alternative approach for combination therapies. In this perspective, we intend to gather all HDACs-containing dual inhibitors related to cancer therapy published in literature since 2015, classify them into five categories based on targets' biological functions, and discuss the rationale why dual acting agents should work better than combinatorial therapies using two separate drugs. The article discusses the pharmacological aspects of these dual inhibitors, including in vitro biological activities, pharmacokinetic studies, in vivo efficacy studies, as well as available clinical trials. The review of the current status and advances should provide better analysis for future opportunities and challenges of this field.


Assuntos
Antineoplásicos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Antineoplásicos/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Humanos
10.
R Soc Open Sci ; 7(5): 200038, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32537215

RESUMO

Herein, we report the first access of ß-elemene derivatives through the SeO2-mediated oxidation reaction. Several new compounds were isolated through such a one-step reaction, and their structures were elucidated using various 2D-NMR techniques. This method provides easy access to multiple oxidative ß-elemene derivatives in one single step and represents the first modifications on cyclohexyl ring of ß-elemene. It is expected to open up the opportunity for future derivatization on cyclohexyl ring of ß-elemene. The new compounds obtained above showed better anti-proliferation activities than ß-elemene itself on several cancer cell lines. Among them, compound 17 shows the best activity in antiproliferation assays of A549 and U-87MG cell lines.

11.
Int J Med Inform ; 139: 104122, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32339929

RESUMO

BACKGROUND: In ambulatory care settings, physicians largely rely on clinical guidelines and guideline-based clinical decision support (CDS) systems to make decisions on hypertension treatment. However, current clinical evidence, which is the knowledge base of clinical guidelines, is insufficient to support definitive optimal treatment. OBJECTIVE: The goal of this study is to test the feasibility of using deep learning predictive models to identify optimal hypertension treatment pathways for individual patients, based on empirical data available from an electronic health record database. MATERIALS AND METHODS: This study used data on 245,499 unique patients who were initially diagnosed with essential hypertension and received anti-hypertensive treatment from January 1, 2001 to December 31, 2010 in ambulatory care settings. We used recurrent neural networks (RNN), including long short-term memory (LSTM) and bi-directional LSTM, to create risk-adapted models to predict the probability of reaching the BP control targets associated with different BP treatment regimens. The ratios for the training set, the validation set, and the test set were 6:2:2. The samples for each set were independently randomly drawn from individual years with corresponding proportions. RESULTS: The LSTM models achieved high accuracy when predicting individual probability of reaching BP goals on different treatments: for systolic BP (<140 mmHg), diastolic BP (<90 mmHg), and both systolic BP and diastolic BP (<140/90 mmHg), F1-scores were 0.928, 0.960, and 0.913, respectively. CONCLUSIONS: The results demonstrated the potential of using predictive models to select optimal hypertension treatment pathways. Along with clinical guidelines and guideline-based CDS systems, the LSTM models could be used as a powerful decision-support tool to form risk-adapted, personalized strategies for hypertension treatment plans, especially for difficult-to-treat patients.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/diagnóstico , Redes Neurais de Computação , Planejamento de Assistência ao Paciente/normas , Guias de Prática Clínica como Assunto/normas , Determinação da Pressão Arterial , Bases de Dados Factuais , Registros Eletrônicos de Saúde , Estudos de Viabilidade , Humanos , Hipertensão/tratamento farmacológico , Monitorização Fisiológica
12.
Bioorg Med Chem Lett ; 30(10): 127109, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32201021

RESUMO

Histone lysine specific demethylase 1 (LSD1 or KDM1A) is a potential therapeutic target in oncology due to its overexpression in various human tumors. We report herein a new class of benzofuran acylhydrazones as potent LSD1 inhibitors. Among the 31 compounds prepared, 14 compounds exhibited excellent LSD1 inhibitory activity with IC50 values ranging from 7.2 to 68.8 nM. In cellular assays, several compounds inhibited the proliferations of various cancer cell lines, including PC-3, MCG-803, U87 MG, PANC-1, HT-29 and MCF-7. This opens up the opportunity for further optimization and investigation of this class compounds for potential cancer treatment.


Assuntos
Benzofuranos/química , Inibidores Enzimáticos/química , Histona Desmetilases/antagonistas & inibidores , Hidrazonas/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/metabolismo , Humanos , Hidrazonas/metabolismo , Hidrazonas/farmacologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
13.
Artigo em Inglês | MEDLINE | ID: mdl-32065106

RESUMO

BACKGROUND: Many human diseases are associated with dysregulation of HDACs. HDAC6 exhibits deacetylase activity not only to histone protein but also to non-histone proteins such as α- tubulin, HSP90, cortactin, and peroxiredoxin. These unique functions of HDAC6 have gained significant attention in the medicinal chemistry community in recent years. Thus a great deal of effort has devoted to developing selective HDAC6 inhibitors for therapy with the hope to minimize the side effects caused by pan-HDAC inhibition. OBJECTIVE: The review intends to analyze the structural feature of the scaffolds, to provide useful information for those who are interested in this field, as well as to spark the future design of the new inhibitors. METHODS: The primary tool used for patent searching is SciFinder. All patents are retrieved from the following websites: the World Intellectual Property Organization (WIPO®), the United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. The years of patents covered in this review are between 2016 and 2019. RESULTS: Thirty-six patents from seventeen companies/academic institutes were classified into three categories based on the structure of ZBG: hydroxamic acid, 1,3,4-oxadiazole, and 1,2,4-oxadiazole. ZBG connects to the cap group through a linker. The cap group can tolerate different functional groups, including amide, urea, sulfonamide, sulfamide, etc. The cap group appears to modulate the selectivity of HDAC6 over other HDAC subtypes. CONCLUSION: Selectively targeting HDAC6 over other subtypes represents two fold advantages: it maximizes the pharmacological effects and minimizes the side effects seen in pan-HDAC inhibitors. Many small molecule selective HDAC6 inhibitors have advanced to clinical studies in recent years. We anticipate the approval of selective HDAC6 inhibitors as therapeutic agents in the near future.


Assuntos
Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Patentes como Assunto , Desenvolvimento de Medicamentos , Desacetilase 6 de Histona/fisiologia , Inibidores de Histona Desacetilases/efeitos adversos , Humanos
14.
J Reconstr Microsurg ; 35(8): 594-601, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31075801

RESUMO

BACKGROUND: Bilateral mastectomy rates are increasing in the United States. The abdomen is the most common harvest site for autologous reconstruction. Nationwide data were examined to determine differences in hospital charges, length of stay (LOS), and early postoperative complications following immediate bilateral pedicled transverse rectus abdominis myocutaneous (pTRAM), free TRAM (fTRAM), deep inferior epigastric perforator (DIEP), and superficial inferior epigastric artery (SIEA) perforator flaps and were compared with unilateral reconstruction. METHODS: Patients who underwent immediate bilateral breast reconstruction using a single method of abdominally based reconstruction were identified using the 2009 to 2014 Nationwide Inpatient Sample Database. Outcomes included total hospital charges, LOS, and immediate postoperative complications. RESULTS: We identified 13,348 cases of bilateral mastectomy with a single type of immediate bilateral autologous flap reconstruction. The majority were bilateral DIEP flaps. Mean total cost for bilateral pTRAM, fTRAM, DIEP, and SIEA flaps was US $21,886.80, US $28,839.40, US $30,051.30, and US $33,784.90, respectively (p < 0.0001). Mean LOS for bilateral pTRAM, fTRAM, DIEP, and SIEA was 4.3, 4.9, 4.5, and 5.4 days, respectively (p = 0.0002), and hematoma rates were 1.93, 2.61, 3.68, and 16.59%, respectively, (p = 0.0001), whereas return to the operating room for vascular anastomosis revision was 0, 1.63, 1.99, and 19.07%, respectively (p < 0.0001). Cost is less for unilateral pTRAM, fTRAM, and DIEP flaps (p < 0.0001). LOS is shorter for unilateral fTRAM versus bilateral (p < 0.0001). No differences were appreciated between unilateral and bilateral hematoma and reoperation rates for any reconstruction (p > 0.1). CONCLUSION: Immediate complication rates were higher in bilateral free flaps compared with bilateral pedicled flaps. pTRAM and fTRAM flap reconstructions are still performed frequently with acceptable immediate results without considering long-term morbidity, aesthetics, and abdominal muscle function. Bilateral SIEA free flaps were associated with significantly higher total cost, LOS, and complication rates compared with other groups. Complications were similar between unilateral and bilateral reconstruction procedures. While cost is significantly greater for bilateral procedures compared with unilateral pTRAM, fTRAM, and DIEP flaps, it is not doubled.


Assuntos
Neoplasias da Mama/cirurgia , Mamoplastia/métodos , Retalho Miocutâneo/transplante , Reto do Abdome/transplante , Estudos Transversais , Feminino , Preços Hospitalares/estatística & dados numéricos , Humanos , Tempo de Internação/estatística & dados numéricos , Mastectomia , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Retrospectivos , Transplante Autólogo , Estados Unidos
15.
Expert Opin Ther Pat ; 29(2): 137-149, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30621465

RESUMO

INTRODUCTION: Tyrosine kinase 2 (Tyk2) is a non-receptor tyrosine-protein kinase, an enzyme that in humans is encoded by the TYK2 gene. Tyk2, together with three other family subtypes, namely, Jak1, Jak2, and Jak3, belong to the JAK family. Before 2014, far more publications and patents appeared in public domain attributing to the development of selective Jak2 and Jak3 inhibitors than those for selective Tyk2 and Jak1 inhibitors. AREAS COVERED: This review sought to give an overview of patents related to small molecule selective Tyk2 inhibitors published from 2015 to 2018. The article also covers clinical activities of small molecule selective Tyk2 inhibitors in recent years. EXPERT OPINION: As a key component of the JAK-STAT signaling pathway, Tyk2 regulates INFα, IL12, and IL23. Selective inhibition of Tyk2 can provide pharmacological benefits in the treatment of many diseases such as psoriasis, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cancer, and diabetes. The selectivity against other Jak family subtypes (such as Jak2) is crucial in order to minimize the potential side effects and to maximize the desired pharmacological effects. In this context, this review of recent selective Tyk2 inhibitor patents may prove valid, interesting, and promising within the therapeutic paradigm.


Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Animais , Humanos , Janus Quinases/metabolismo , Patentes como Assunto , Inibidores de Proteínas Quinases/efeitos adversos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , TYK2 Quinase/genética
16.
J Manag Care Spec Pharm ; 25(1): 18-27, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30589633

RESUMO

BACKGROUND: Reliance on prescription opioids to manage pain has been associated with increases in diversion, overdose, and addiction. Prevalence of misuse and abuse has been shown to be higher among government-insured populations than commercially insured populations. However, the prevalence and costs of misuse/abuse among the Medicare fee-for-service (FFS) population has not been studied. OBJECTIVES: To (a) determine the prevalence and costs of prescription opioid misuse/abuse and (b) evaluate the prevalence and costs associated with those identified as at risk for opioid misuse/abuse in Medicare FFS beneficiaries. METHODS: This retrospective case-control study used Medicare claims data for the calendar years of 2010 and 2011 and included Medicare beneficiaries aged at least 18 years. The index date was the date of first diagnosed misuse/abuse or at risk for abuse and had to occur between July 1, 2010, and June 30, 2011, and beneficiaries had to have at least 6 months continuous eligibility before and after the index date. Matching (1:1) was used for comparing opioid misusers/abusers with nonabuser controls, as well as comparing patients at risk for opioid abuse with controls not at risk for abuse. Controls were matched to cases by gender, age, disability, and geographic region. The index date of the control patient was set equal to the index date of the matched case. RESULTS: Prevalence of misuse/abuse in the Medicare FFS population was 13.1 per 1,000 persons, with the majority among patients receiving Medicare based on disability (76.2%). The prevalence of at risk for misuse/abuse was 117.4 per 1,000 persons. Approximately half of the Medicare FFS patients used an opioid. Overall total annual unadjusted mean costs of health care resources were significantly greater for abusers than for matched controls ($46,194 vs. $21,964; P < 0.0001), with a mean annual excess cost of $24,230. The overall total adjusted 6-month post-index mean costs of health care resources for abusers was significantly greater than that of matched controls ($33,942 vs. $10,754; P < 0.0001), with a mean excess cost of $23,188. CONCLUSIONS: The prevalence of diagnosed abuse among Medicare FFS population (13.1 per 1,000 persons) was higher than other payer groups studied using similar ICD-9-CM codes, and the majority of abuse was among those receiving Medicare based on disability (76.2%). The prevalence of at-risk abuse was 9 times higher than the prevalence of diagnosed abuse. As with other studies, health care resource utilization and costs were significantly greater for diagnosed abuse than matched controls. DISCLOSURES: This study was sponsored by Pfizer. Roland is a Pfizer employee and stockholder and was involved in all aspects of the study as part of a mid-career fellowship in pharmacoeconomics with the University of Utah. Ye and Stevens are employees of University of Utah, and Oderda was an employee of University of Utah, which received financial support from Pfizer in connection with the development of this manuscript. Oderda also reports consulting fees from Pfizer, Trevena, and Pacira, unrelated to this study. The results of this study were presented at the Academy of Managed Care Pharmacy Nexus 2015; October 26-29, 2015; Orlando, FL, and the AMCP Managed Care & Specialty Pharmacy Annual Meeting 2016; April 19-22, 2016; San Francisco, CA.


Assuntos
Analgésicos Opioides/efeitos adversos , Overdose de Drogas/epidemiologia , Medicare/economia , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Uso Indevido de Medicamentos sob Prescrição/economia , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/economia , Estudos de Casos e Controles , Overdose de Drogas/economia , Overdose de Drogas/etiologia , Planos de Pagamento por Serviço Prestado/economia , Planos de Pagamento por Serviço Prestado/estatística & dados numéricos , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Masculino , Medicare/estatística & dados numéricos , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/economia , Transtornos Relacionados ao Uso de Opioides/etiologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Prevalência , Estudos Retrospectivos , Estados Unidos , Adulto Jovem
17.
J Reconstr Microsurg ; 35(1): 74-82, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30085346

RESUMO

BACKGROUND: The abdomen is the most common area from which tissue is harvested for autologous breast reconstruction. We sought to examine national data to determine the differences in total hospital charges, length of stay (LOS), and early postoperative complications following pedicled transverse rectus abdominis myocutaneous flap (pTRAM), free TRAM (fTRAM), deep-inferior epigastric perforator (DIEP), and superficial inferior epigastric artery perforator (SIEA) flaps. METHODS: The 2009-2013 Nationwide Inpatient Sample Database was used to identify patients who underwent a unilateral mastectomy and only one type of abdominally based autologous flap (pTRAM, fTRAM, DIEP, and SIEA) during the same hospital admission. Outcomes of interest included total charges, LOS, and complications including revision of vascular anastomosis and hematoma. RESULTS: A total of 3,310 cases were identified, corresponding to 15,991 abdominally based unilateral immediate breast reconstructions after standard weighting was applied; 5,079 (31.8%) were pTRAM flaps, 4,461 (27.9%) were fTRAM flaps, 6,206 (38.8%) were DIEP flaps, and 245 (1.5%) were SIEA flaps. The mean total charges for pTRAM, fTRAM, DIEP, and SIEA flaps were $17,765.5, $22,637.6, $25,814.6, and $26,605.2, respectively (p < 0.0001). The mean LOS for pTRAM, fTRAM, DIEP, and SIEA flaps were 96.5, 106.5, 106.7, and 108.9 hours, respectively (p = 0.002). The rates for return to the OR for the revision of a vascular anastomosis for pTRAM, fTRAM, DIEP, and SIEA were 0.0%, 1.72%, 2.66%, and 5.64%, respectively (p < 0.0001). CONCLUSIONS: There is variation in the total charges, LOS, and early complications between pTRAM, fTRAM, DIEP, and SIEA flap-based breast reconstruction. fTRAM, DIEP, and SIEA flaps incur higher hospital total charges, have longer lengths of stay, and experience more immediate complications compared with pTRAM. Well-designed prospective trials are required to better understand the findings from this study with the inclusion of other critical outcomes such as patient satisfaction, aesthetic results, and long-term outcomes such as abdominal wall morbidity.


Assuntos
Neoplasias da Mama/cirurgia , Retalhos de Tecido Biológico/irrigação sanguínea , Mamoplastia , Mastectomia , Retalho Perfurante/irrigação sanguínea , Complicações Pós-Operatórias/cirurgia , Reto do Abdome/transplante , Neoplasias da Mama/economia , Estudos Transversais , Estética , Feminino , Preços Hospitalares , Humanos , Tempo de Internação/economia , Tempo de Internação/estatística & dados numéricos , Mamoplastia/economia , Mamoplastia/métodos , Mastectomia/economia , Mastectomia/métodos , Pessoa de Meia-Idade , Satisfação do Paciente , Complicações Pós-Operatórias/economia , Complicações Pós-Operatórias/fisiopatologia , Estudos Retrospectivos , Resultado do Tratamento
18.
Cytokine ; 110: 420-427, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29784508

RESUMO

Interstitial cystitis (IC), also known as painful bladder syndrome (PBS), is a debilitating chronic condition that afflicts over 3 million women above the age of 18 in the U.S., and most patients fail to respond to current treatment options. Mast cells have previously been implicated as both a diagnostic and prognostic marker in IC/PBS. Patients with IC/PBS have been shown to have elevated levels of IL-33, a cytokine released in response to tissue insult, in their urine. We hypothesize that mast cell-mediated inflammation induced from IL-33 may play an important role in initiating pain and inflammation in IC/PBS. A human cathelicidin, LL-37, which is found at elevated levels in IC/PBS patients, was used to induce an IC/PBS-like state of inflammation and bladder pain in mast cell deficient C-kit (-/-) and wild type C57Bl/6 (WT) mice. Inflammation was quantified using myeloperoxidase (MPO) expression in bladder tissues measured via ELISA. Response rate to suprapubic stimulation from von Frey filaments was used to assess the relative pain and discomfort. Both types of mice increased IL-33 expression in response to LL-37 exposure. However, mast cell deficient mice demonstrated significantly lower levels of inflammation (p < 0.001) and reduced pain response (p < 0.001) compared to WT mice. These findings implicate an IL-33-mast cell dependent axis with a potential etiology of pain and inflammation in IC/PBS. Future therapeutics aimed at targeting the IL-33 - mast cell axis could potentially serve as useful targets for treating IC/PBS.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Cistite Intersticial/metabolismo , Inflamação/metabolismo , Interleucina-33/metabolismo , Mastócitos/metabolismo , Dor/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Bexiga Urinária/metabolismo
19.
ACS Med Chem Lett ; 9(12): 1170-1174, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30613321

RESUMO

BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11ß-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.

20.
Am J Clin Exp Urol ; 5(2): 10-17, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29034266

RESUMO

Our goal was to evaluate the pain response in an LL-37 induced murine model for interstitial cystitis/painful bladder syndrome (IC/PBS). In particular, we sought to characterize the dose dependence, time-course, and relationship of LL-37 induced bladder inflammation and pain. The IC/PBS model was induced in C57Bl/6 mice by instilling 50 µL of LL-37, an immunomodulatory human cathelicidin (anti-microbial peptide), in the bladder for 1 hr. Pain responses were measured using von Frey filaments (0.04 gm to 4.0 gm) before and after LL-37 instillation. Inflammation was evaluated using tissue myeloperoxidase (MPO) assay, gross inspection, and microscopic histologic examination. The dose response experiment demonstrated a graded pain response, with higher concentrations of LL-37 challenge yielding higher pain responses across all stimuli tested. Statistical significance was seen when comparing 1.0 gm von Frey filament results at 320 µM (68 ± 8% response) vs. 0 µM (38 ± 6% response). Interestingly, pain responses did not attenuate across time but increased significantly after 5 (p=0.0012) and 7 days (p=0.0096). Comparison with MPO data suggested that pain responses could be independent of inflammation. We demonstrated within our LL-37 induced IC/PBS model pain occurs in a dose-dependent fashion, pain responses persist beyond the initial point of insult, and our dose response and time course experiments demonstrated that pain was independent of inflammation.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...