RESUMO
PURPOSE: Mandibular repositioning devices (MRDs) are an effective treatment option for obstructive sleep apnea syndrome (OSAS), particularly in patients who refuse or cannot tolerate continuous positive airway pressure (CPAP). However, sex differences in the response to therapy and predictors of response are not clearly defined. This analysis of data from the long-term prospective ORCADES trial compared MRD efficacy in men and women with OSAS. METHODS: The ORCADES study included patients with newly diagnosed mild-to-moderate or severe OSAS who refused or were non-compliant with CPAP. MRD therapy was titrated over 3-6 months. The primary endpoint was treatment success (≥ 50% decrease in apnea-hypopnea index (AHI)). Complete response was defined using a range of AHI cut-off values (< 5/h, < 10/h, < 15/h). RESULTS: Overall treatment success rates were 89% in women and 76% in men (p = 0.019); corresponding rates in those with severe OSAS (AHI > 30/h) were 100% and 68% (p = 0.0015). In women vs. men, overall complete response rates at AHI cut-off values of < 5/h, <10/h, and < 15/h were 49 vs. 34% (p = 0.0052), 78 vs. 62% (p = 0.016), and 92 vs. 76% (p = 0.0032). On multivariate analysis, significant predictors of MRD treatment success were overbite and baseline apnea index in men, and neck circumference and no previous CPAP therapy in women. There were sex differences in the occurrence of side effects. Temporomandibular joint pain was the most common reason for stopping MRD therapy. CONCLUSIONS: MRD therapy was effective in women with OSA of any severity, with significantly higher response rates compared with men especially in severe OSAS. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01326143).
Assuntos
Avanço Mandibular/métodos , Qualidade de Vida , Apneia Obstrutiva do Sono/terapia , Adulto , Pressão Positiva Contínua nas Vias Aéreas , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Polissonografia , Fatores Sexuais , Resultado do TratamentoRESUMO
Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.
Assuntos
Inibidores Enzimáticos/farmacologia , Lactamas/farmacologia , 1-Alquil-2-acetilglicerofosfocolina Esterase , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Lactamas/administração & dosagem , Lactamas/síntese química , Lactamas/química , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Radiculomegaly affecting incisors, canines or premolars is a rare radiological finding (Maden et al., 2010) but is pathognomomic of a rare x-linked dominant syndrome called oculo-facio-cardio-dental syndrome (OFCDS). As this syndrome includes cardiac malformations and can lead to blindness due to congenital glaucoma, oral and maxillofacial surgeons should be aware of the somatic anomalies potentially associated with radiculomegaly. We report a typical case of OFCDS and provide the first description of the microscopic dental anomalies associated with this syndrome.
Assuntos
Catarata/congênito , Dente Canino/anormalidades , Dentina/anormalidades , Defeitos dos Septos Cardíacos/patologia , Microftalmia/patologia , Raiz Dentária/anormalidades , Adulto , Anodontia/diagnóstico por imagem , Dente Pré-Molar/anormalidades , Catarata/patologia , Tomografia Computadorizada de Feixe Cônico/métodos , Dente Canino/diagnóstico por imagem , Esmalte Dentário/anormalidades , Feminino , Humanos , Incisivo/anormalidades , Ápice Dentário/anormalidades , Raiz Dentária/diagnóstico por imagemRESUMO
Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure and facilitates the localisation of transcriptional complexes to specific genes, thereby regulating epigenetically controlled processes including gene transcription and mRNA elongation. Inhibitors of the bromodomain and extra-terminal (BET) proteins BRD2-4 and T, which prevent bromodomain binding to acetyl-modified histone tails, have shown therapeutic promise in several diseases. We report here the discovery of 1,5-naphthyridine derivatives as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures of naphthyridine isomers have been solved and quantum mechanical calculations have been used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mouse model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology.
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Anti-Inflamatórios não Esteroides/farmacologia , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Proteínas Cromossômicas não Histona , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Histonas/química , Histonas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Naftiridinas/química , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína/efeitos dos fármacos , Relação Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismoRESUMO
UNLABELLED: Growing evidence show that human dental pulp stem cells (DPSCs) could provide a source of adult stem cells for the treatment of neurodegenerative pathologies. In this study, DPSCs were expanded and cultured with a protocol generally used for the culture of neural stem/progenitor cells. METHODOLOGY: DPSC cultures were established from third molars. The pulp tissue was enzymatically digested and cultured in serum-supplemented basal medium for 12 h. Adherent (ADH) and non-adherent (non-ADH) cell populations were separated according to their differential adhesion to plastic and then cultured in serum-free defined N2 medium with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Both ADH and non-ADH populations were analyzed by FACS and/or PCR. RESULTS: FACS analysis of ADH-DPSCs revealed the expression of the mesenchymal cell marker CD90, the neuronal marker CD56, the transferrin receptor CD71, and the chemokine receptor CXCR3, whereas hematopoietic stem cells markers CD45, CD133, and CD34 were not expressed. ADH-DPSCs expressed transcripts coding for the Nestin gene, whereas expression levels of genes coding for the neuronal markers ß-III tubulin and NF-M, and the oligodendrocyte marker PLP-1 were donor dependent. ADH-DPSCs did not express the transcripts for GFAP, an astrocyte marker. Cells of the non-ADH population that grew as spheroids expressed Nestin, ß-III tubulin, NF-M and PLP-1 transcripts. DPSCs that migrated out of the spheroids exhibited an odontoblast-like morphology and expressed a higher level of DSPP and osteocalcin transcripts than ADH-DPSCs. CONCLUSION: Collectively, these data indicate that human DPSCs can be expanded and cultured in serum-free supplemented medium with EGF and bFGF. ADH-DPSCs and non-ADH populations contained neuronal and/or oligodendrocyte progenitors at different stages of commitment and, interestingly, cells from spheroid structures seem to be more engaged into the odontoblastic lineage than the ADH-DPSCs.
RESUMO
AMP-activated protein kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme that is activated in shortage of energy and suppressed in its surfeit. AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia and hyperlipidemia, and inhibits proinflammatory changes. Thus, AMPK is a well-received therapeutic target for type 2 diabetes and other metabolic disorders. Here, we will report the discovery of pyrrolopyridone derivatives as AMPK direct activators. We will illustrate the synthesis and structure-activity relationships of the series as well as some pharmacokinetic results. Some compounds exhibited encouraging oral exposure and were evaluated in a mouse diabetic model. Compound 17 showed oral activity at 30 mg/kg on blood glucose.
RESUMO
The discovery, synthesis and biological evaluation of a novel series of 7-isoxazoloquinolines is described. Several analogs are shown to increase ApoA1 expression within the nanomolar range in the human hepatic cell line HepG2.
Assuntos
Apolipoproteína A-I/metabolismo , Descoberta de Drogas , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Quinolinas/química , Regulação para Cima/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Células Hep G2 , Histona Acetiltransferases , Chaperonas de Histonas , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso , Proteínas Nucleares/metabolismo , Quinolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: This study evaluated the effectiveness of a protocol to prevent bleeding after dental extraction in patients with hemophilia, von Willebrand's disease (VWD), or platelet disorders. STUDY DESIGN: Replacement therapy was used in cases involving general anesthesia, and nerve trunk infiltration was used in patients with severe bleeding disorders (severe-to-moderate hemophilia or type 2-3 VWD). Desmopressin was used in good responders with mild hemophilia A, type 1 VWD, and platelet disorders. Local hemostatic measures and antifibrinolytic treatment were used systematically. RESULTS: Ninety-three patients underwent 103 dental extractions; 2 of these patients had secondary bleeding requiring surgical hemostasis. CONCLUSION: The indication for replacement therapy depended on the type of anesthesia that was used. Coagulation factor concentrates or desmopressin were necessary to avoid upper airway hematoma with general anesthesia or nerve trunk infiltration. With local anesthesia, substitutive treatment was indicated in patients with severe-to-moderate hemophilia and type 2-3 VWD. Inexpensive desmopressin was effective in those who responded well. Local hemostatic measures and antifibrinolytic treatment were performed systematically.