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1.
Otolaryngol Head Neck Surg ; 167(6): 964-970, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35316101

RESUMEN

OBJECTIVE: Endoscopic endonasal transsphenoidal surgery is safe and effective for sellar and parasellar tumor removal. Partial middle turbinate (MT) resection is sometimes performed to optimize the surgical field and facilitate postoperative care. Disturbances in olfaction are concerning because of the lack of randomized studies in this field. STUDY DESIGN: Prospective randomized trial. SETTING: Single academic medical center. METHODS: We resected the lower halves of bilateral MTs in the resected group and laterally fractured bilateral MTs in the preserved group. Olfactory outcomes and sinonasal conditions were assessed by using the validated Taiwan Smell Identification Test and Lund-Kennedy Endoscopy Score, respectively. Forty-nine patients were enrolled in the final analysis, of whom 23 underwent partial MT resection. RESULTS: The average Taiwan Smell Identification Test result was 36.9 one month after surgery, with a significant change of -4.4 ± 3.1 (mean ± SD; P < .01) from baseline. The impact was not significant at 3 months (-2.1 ± 2.6, P = .13) or 6 months (0.3 ± 2.0, P = .79). Between the MT resection and preservation groups, there were no significant differences at postoperative 1 month (P = .60), 3 months (P = .86), and 6 months (P > .99). Lund-Kennedy Endoscopy Score was still higher at 3 months (P = .006) after surgery but returned to the preoperative level at 6 months (P = .63). CONCLUSIONS: Endoscopic endonasal transsphenoidal surgery may affect olfaction at 1 month after surgery, and olfactory function is expected to return after 3 months. Partial MT resection did not result in additional olfactory loss. It is safe to perform partial MT resection during surgery without compromising the olfactory outcomes.


Asunto(s)
Neoplasias Hipofisarias , Olfato , Humanos , Cornetes Nasales/cirugía , Estudios Prospectivos , Neoplasias Hipofisarias/cirugía , Complicaciones Posoperatorias/etiología , Endoscopía/efectos adversos , Resultado del Tratamiento
3.
J Med Chem ; 57(6): 2683-91, 2014 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-24520947

RESUMEN

Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.


Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridazinas/síntesis química , Piridazinas/farmacología , Bazo/enzimología , Amidas/síntesis química , Amidas/farmacología , Animales , Biología Computacional , Simulación por Computador , Diseño de Fármacos , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Conformación Molecular , Mutagénesis/efectos de los fármacos , Pruebas de Mutagenicidad , Inhibidores de Proteínas Quinasas/farmacocinética , Piridazinas/farmacocinética , Ratas , Bazo/efectos de los fármacos , Relación Estructura-Actividad , Difracción de Rayos X
4.
J Med Chem ; 56(1): 345-56, 2013 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-23214979

RESUMEN

The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.


Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Ciclopropanos/síntesis química , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Pirazinas/síntesis química , Pirroles/síntesis química , Administración Oral , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Células CACO-2 , Cristalografía por Rayos X , Ciclopropanos/farmacocinética , Ciclopropanos/farmacología , Técnicas de Silenciamiento del Gen , Ensayos Analíticos de Alto Rendimiento , Humanos , Interleucina-2/fisiología , Janus Quinasa 1/genética , Janus Quinasa 1/metabolismo , Janus Quinasa 3/genética , Janus Quinasa 3/metabolismo , Ratones , Modelos Moleculares , Pirazinas/farmacocinética , Pirazinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , ARN Interferente Pequeño/genética , Ratas , Receptores de Interleucina-6/fisiología , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo
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