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OBJECTIVE: In pediatric patients, femoral neck fracture is a relatively rare injury with a high complication rate despite proper diagnosis and treatment. Fixation of femoral neck fractures is usually performed with screws placed along the neck axis. In this study, we aim to compare two different implants and methods in terms of biomechanics. MATERIALS AND METHODS: Twenty-eight right-left fresh femur bones of 6-month-old male Ovis aries lambs grown on the same farm were used. Bones were randomly divided into 4 groups (n=7). In group 1, the Delbet type III femoral neck fracture model was fixed with two 4.5 mm cannulated screws, one screw crossing the physis. In group 2, two 4.5 mm cannulated screws, which did not cross the physis, were used. In group 3, Delbet type III femoral neck fracture model was fixed with a 3.5 mm proximal femoral anatomical plate and five screws, one screw crossing the physis. Finally, in group 4, Delbet type III femoral neck fracture model was fixed with one 3.5 mm proximal femoral anatomical plate and five screws that did not exceed the physis. RESULTS: Biomechanical tests were performed using a Zwick/Roell AllroundLine 100 kN device. While axial failure burden (F = 6.819, p<.05, d = .46) and axial stiffness (F = 3.576, p<.05, d = .30) have been found to be significantly different between the independent treatment groups, axial failure displacement (F = .622, p>.05) and axial failure energy (F = .727, p>.05) have been found not to be significant between the independent groups. The effect sizes of the axial failure load and axial stiffness variables were 0.46 and 0.30, respectively, suggesting a moderate clinical effect. The highest axial failure load was recorded in group 3, while the smallest load was recorded in group 2. Similarly, the axial stiffness level in group 3 was statistically higher than the axial stiffness measurement recorded in group 2, p<.05. CONCLUSIONS: Consequently, we found that the biomechanical fixation success was the highest with a 3.5 mm proximal femoral anatomical plate, a 3.5 mm locking screw crossing the physis, and five 3.5 mm screws.
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Tornillos Óseos , Fracturas del Cuello Femoral , Fijación Interna de Fracturas , Animales , Fracturas del Cuello Femoral/cirugía , Fenómenos Biomecánicos , Masculino , Fijación Interna de Fracturas/instrumentación , Fijación Interna de Fracturas/métodos , Ovinos , Placas Óseas , HumanosRESUMEN
FMS kinase is a type III tyrosine kinase receptor that plays a central role in the pathophysiology and management of several diseases, including a range of cancer types, inflammatory disorders, neurodegenerative disorders, and bone disorders among others. In this review, the pathophysiological pathways of FMS kinase in different diseases and the recent developments of its monoclonal antibodies and inhibitors during the last five years are discussed. The biological and biochemical features of these inhibitors, including binding interactions, structure-activity relationships (SAR), selectivity, and potencies are discussed. The focus of this article is on the compounds that are promising leads and undergoing advanced clinical investigations, as well as on those that received FDA approval. In this article, we attempt to classify the reviewed FMS inhibitors according to their core chemical structure including pyridine, pyrrolopyridine, pyrazolopyridine, quinoline, and pyrimidine derivatives.
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Neoplasias , Humanos , Relación Estructura-Actividad , Proteínas Tirosina Quinasas Receptoras/química , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
Stereochemical and skeletal complexity are particularly important vis-à-vis the cross-talks between a small molecule and a complementary active site of a biological target. This intricate harmony is known to increase selectivity, reduce toxicity, and increase the success rate in clinical trials. Therefore, the development of novel strategies for establishing underrepresented chemical space that is rich in stereochemical and skeletal diversity is an important milestone in a drug discovery campaign. In this review, we discuss the evolution of interdisciplinary synthetic methodologies utilized in chemical biology and drug discovery that has revolutionized the discovery of first-in-class molecules over the last decade with an emphasis on complexity-to-diversity and pseudo-natural product strategies as a remarkable toolbox for deciphering next-generation therapeutics. We also report how these approaches dramatically revolutionized the discovery of novel chemical probes that target underrepresented biological space. We also highlight selected applications and discuss key opportunities offered by these tools and important synthetic strategies used for the construction of chemical spaces that are rich in skeletal and stereochemical diversity. We also provide insight on how the integration of these protocols has the promise of changing the drug discovery landscape.
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Productos Biológicos , Productos Biológicos/farmacología , Productos Biológicos/química , Descubrimiento de DrogasRESUMEN
The development of robust and step-economic strategies to access structurally diverse drug-like compound collections remains a challenge. A distinct structural option that constitutes the core scaffold of many biologically significant molecules is the quinazolinone ring system. Several members of this family of privileged substructures have gained attention due to their diverse biological activities. In this context, the development of an efficient strategy for their access is needed. Herein, we report a divergent metal-free operation to access a diverse collection of C6-substituted pyrrolo[4',3',2':4,5]isoquinolino[1,2-b]quinazolin-8(6H)-one and pyrrolo[4',3',2':4,5]isoquinolino[2,1-a]quinazolin-12(6H)-one architectures. The described cascade unites Friedel-Crafts and aza-Michael addition reactions. This operationally simple protocol enables a rapid access to these scaffolds and is compatible with a wide scope of starting materials. In addition, the cascade features a promising approach for the design of unique compound libraries for drug design and discovery programs.
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The de novo assembly of stereochemically and skeletally diverse scaffolds is a powerful tool for the discovery of novel chemotypes. Hence, the development of modular, step- and atom-economic synthetic methods to access stereochemically and skeletally diverse compound collection is particularly important. Herein, we show a metal-free, stereodivergent build/couple/pair strategy that allows access to a unique collection of benzo[5,6][1,4]oxazino[4,3-a]quinazoline, quinolino[1,2-a]quinazoline and benzo[b]benzo [4,5]imidazo[1,2-d][1,4]oxazine scaffolds with complete diastereocontrol and wide distribution of molecular architectures. This metal-free process proceeds via desymmetrization of phenol derivatives. The cascade unites Mannich with aza-Michael addition reactions, providing expeditious entries to diverse classes of molecular shapes in a single operation.
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A series of adamantyl carboxamide derivatives containing sulfonate or sulfonamide moiety were designed as multitargeted inhibitors of ectonucleotide pyrophosphatases/phosphodiesterases (NPPs) and carbonic anhydrases (CAs). The target compounds were investigated for their antiproliferative activity against NCI-60 cancer cell lines panel. Three main series composed of 3- and 4-aminophenol, 4-aminoaniline, and 5-hydroxyindole scaffolds were designed based on a lead compound (A). Compounds 1e (benzenesulfonyl) and 1i (4-fluorobenzenesulfonyl) of 4-aminophenol backbone exhibited the most promising antiproliferative activity. Both compounds exhibited a broad-spectrum and potent inhibition against all the nine tested cancer subtypes. Both compounds showed nanomolar IC50 values over several cancer cell lines that belong to leukemia and colon cancer such as K-562, RPMI-8226, SR, COLO 205, HCT-116, HCT-15, HT29, KM12, and SW-620 cell lines. Compounds 1e and 1i induced apoptosis in K-562 leukemia cells in a dose-dependent manner. Compound 1i showed the highest cytotoxic activity with IC50 value of 200 nM against HT29 cell line. In addition, compounds 1e and 1i were tested against normal breast cells (HME1) and normal skin fibroblast cells (F180) and the results revealed that the compounds are safe toward normal cells compared to cancers cells. Enzymatic assays against NPP1-3 and carbonic anhydrases II, IX, and XII were performed to investigate the possible molecular target(s) of compounds 1e and 1i. Furthermore, a molecular docking study was performed to predict the binding modes of compounds 1e and 1i in the active site of the most sensitive enzymes subtypes.
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Antineoplásicos , Anhidrasas Carbónicas , Leucemia , Humanos , Antineoplásicos/química , Inhibidores de Anhidrasa Carbónica/química , Anhidrasas Carbónicas/metabolismo , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-ActividadRESUMEN
BACKGROUND AND STUDY AIMS: Polymorphisms in the DNA repair genes may influence individual capacity to repair DNA damage, which may be associated with increased genetic instability and carcinogenesis. Our aim was to evaluate the relation of genetic polymorphisms in 2 DNA repair genes, XPD Lys751Gln and XRCC1 (A399G), with colorectal cancer (CRC) susceptibility. We further investigated the potential effect of these DNA repair variants on clinicopathological parameters of CRC patients. PATIENTS AND METHODS: Both XPD and XRCC1 polymorphisms were characterised in one hundred CRC patients and one hundred healthy controls who had no history of any malignancy by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method and PCR with confronting two-pair primers (PCR-CTPP), using DNA from peripheral blood in a case control study. RESULTS: Our results revealed that the frequencies of GG genotype of XRCC1 399 polymorphism were significantly higher in the CRC patients than in the normal individuals (p⩽0.03), and did not observe any association between the XPD Lys751Gln polymorphism and CRC risk. We found association between both XRCC1 A399G polymorphisms and histological grading of disease. CONCLUSION: Our results suggested that, XRCC1 gene is an important candidate gene for susceptibility to colorectal carcinoma.
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Carcinoma/genética , Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/genética , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Adulto , Carcinoma/patología , Estudios de Casos y Controles , Neoplasias Colorrectales/patología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Arabia Saudita , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
BACKGROUND: Techniques for diagnosing choledocholithiasis pose significant morbidity and mortality risks. OBJECTIVES: We aimed to develop and validate a clinical scoring system for predicting choledocholithiasis. DESIGN: Data from a prospectively maintained database of all patients with gallstones. SETTING: Patients were admitted to the general surgery department of a military hospital. PATIENTS AND METHODS: We enrolled consecutive patients with symptomatic gallstones, biliary pancreatitis, obstructive jaundice, or cholangitis, who subsequently underwent biochemical testing and ultrasonography. A predictive model was developed from a scoring system using their imaging and laboratory data. Endoscopic retrograde cholangiopancreatography (ERCP) or intraoperative cholangiography were used for confirmatory diagnoses. The predictive efficacy of the scoring system was validated using a retrospective cohort of 272 patients. MAIN OUTCOME MEASURES: Predictive accuracy of the scoring system. RESULTS: We enrolled 155 patients in the development group. The common bile duct diameter, alkaline phosphatase of >=200 IU, elevated bilirubin levels, alanine transaminase of >=220 IU, and male age of >=50 years were significantly associated with choledocholithiasis and were included in the scoring system. Ninety-six patients (35%) had scores of >=8 (high risk), 86 patients (32%) had scores of 4-7 (intermediate risk), and 27 patients (10%) had scores of 1-3 (low risk). In the validation cohort, the positive predictive value for a score of >=8 was 91.7%, and the scoring system had an area under the curve of 0.896. CONCLUSION: Scores of >=8 were strongly correlated with choledocholithiasis in the developmental and validation groups, which indicates that our scoring system may be useful for predicting the need for therapeutic ERCP. However, prospective validation in a large multicenter cohort is needed to fully understand the benefits of the system. LIMITATIONS: The retrospective validation cohort might have introduced selection and observational biases. The study may have been underpowered because of the sample size of the developmental cohort. The delay between admission and the time of ERCP theoretically may have increased the number of negative ERCP results, but our false negative rate for ERCP was consistent with the previously reported rates.
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Colangiopancreatografia Retrógrada Endoscópica/estadística & datos numéricos , Coledocolitiasis/diagnóstico por imagen , Cálculos Biliares/complicaciones , Indicadores de Salud , Medición de Riesgo/métodos , Adulto , Factores de Edad , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Área Bajo la Curva , Bilirrubina/sangre , Colangiopancreatografia Retrógrada Endoscópica/métodos , Colangitis/sangre , Colangitis/complicaciones , Colangitis/diagnóstico por imagen , Coledocolitiasis/sangre , Coledocolitiasis/etiología , Conducto Colédoco/diagnóstico por imagen , Conducto Colédoco/patología , Bases de Datos Factuales , Femenino , Cálculos Biliares/sangre , Cálculos Biliares/diagnóstico por imagen , Humanos , Ictericia Obstructiva/sangre , Ictericia Obstructiva/complicaciones , Ictericia Obstructiva/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Pancreatitis/sangre , Pancreatitis/complicaciones , Pancreatitis/diagnóstico por imagen , Valor Predictivo de las Pruebas , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Arabia Saudita/epidemiología , Factores Sexuales , UltrasonografíaRESUMEN
Gastrointestinal stromal tumors (GISTs) are rare, but remain the most common GI mesenchymal neoplasms. In the present study, six cases of GIST are reported, and one of these cases, a patient with esophageal GIST, is reported in-depth. Certain recent developments in the clinical therapy of GISTs are also discussed. The records of all surgically-resected GI stromal tumors treated at the Al-Hada Military Hospital between January 2007 and December 2012 were reviewed. There were six cases of surgically resected GISTs during this time period, three males and three females, with a mean age of 69.3±16.4 years. The stomach was involved in 66.7% of cases, the small intestine in 16.7% and the esophagus, which is an extremely rare site, in 16.7% of cases. The most common symptom at presentation was abdominal pain, followed by GI bleeding. The mean tumor size was 8.7±6.3 cm. Surgery was indicated by the presence of the aforementioned symptoms or a tumor size >5 cm. All tumors were completely resected with histologically negative margins. The diagnoses were established by immunohistochemistry. Four patients were classified as possessing a high-grade variant, and were administered with tyrosine kinase inhibitors (TKIs). Following a mean follow up of 31 months, no recurrence or mortality was detected. Complete surgical resection with tumor-free margins is the standard treatment for GISTs, and TKIs should be used as adjuvant therapy if the risk of progressive disease is high.
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The interaction between a fluid and a solid surface in relative motion represents a dynamical process that is central to the problem of laminar-to-turbulent transition (and consequent drag increase) for air, sea and land vehicles, as well as long-range pipelines. This problem may in principle be alleviated via a control stimulus designed to impede the generation and growth of instabilities inherent in the flow. Here, we show that phonon motion underneath a surface may be tuned to passively generate a spatio-temporal elastic deformation profile at the surface that counters these instabilities. We theoretically demonstrate this phenomenon and the underlying mechanism of frequency-dependent destructive interference of the unstable flow waves. The converse process of flow destabilization is illustrated as well. This approach provides a condensed-matter physics treatment to fluid-structure interaction and a new paradigm for flow control.
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BACKGROUND: Microcystic adenoma or serous cystadenoma (SCA) is an uncommon tumor type, accounting for only 1-2% of pancreatic exocrine neoplasms. Usually unifocal, SCAs present as single, large, well-demarcated, multiloculated, cystic tumors, 1-25 cm in size. CASE PRESENTATION: A 73-year-old man initially presented with epigastric abdominal pain and was diagnosed with SCA involving the whole pancreas. Eleven months later, he presented with obstructive jaundice, and total pancreatectomy was performed. The removed tissue allowed histological verification of pancreatic SCA. Histopathological examination showed both microcysts and macrocysts, lined by cuboidal epithelium, with optically clear cytoplasm and the absence of detectable mitosis or necrosis. CONCLUSIONS: Thus, although relatively rare, pancreatic SCA is one of the differential diagnoses of epigastric abdominal pain; we recommend early surgical intervention for symptomatic pancreatic SCA.
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Cistadenoma Seroso/complicaciones , Ictericia Obstructiva/etiología , Neoplasias Pancreáticas/complicaciones , Dolor Abdominal/etiología , Anciano , Pancreatocolangiografía por Resonancia Magnética , Cistadenoma Seroso/patología , Cistadenoma Seroso/cirugía , Humanos , Ictericia Obstructiva/diagnóstico , Ictericia Obstructiva/cirugía , Masculino , Pancreatectomía , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Valor Predictivo de las Pruebas , Factores de Riesgo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: Pancreatic paragangliomas are rare tumors, with only 16 reported cases to date. One of these cases demonstrates metastasis to lymph node, while another case was functional, however, none of these cases showed malignant and large, pancreatic paraganglioma with marked invasion. Also another unique feature was the age of our patient compared to the average reported ages in published literature (42-85 years). CASE PRESENTATION: A 19-year-old woman presented with a one-year history of intermittent abdominal pain. Physical examination showed a palpable mass in the right upper abdomen, but initial laboratory results were within normal ranges; tumor markers (CEA, AFP, and CA19-9) were negative. An abdominal and pelvic computed tomography (CT) scan showed a well-defined retroperitoneal para-aortic mass. The CT scan revealed that the surrounding lymph nodes were not enlarged, but the liver showed evidence of parenchymal infiltration. Intraoperatively, a large, firm tumor originating from the head of pancreas was found pushing on the caudate hepatic lobe and the inferior vena cava (IVC). The tumor was resected through a pancreaticoduodenectomy, involving segment VI of the liver and a small segment of the IVC. The blood pressure spiked (>220 mm Hg) when the tumor was manipulated during the operation. The final pathology report showed a 9-cm tumor with lymphovascular invasions; immunohistochemistry was positive for synaptophysin and chromogranin. All resection margins were negative and 1/15 lymph nodes was positive for metastasis. Post-operative recovery was unremarkable. One month after discharge, the patient was re-admitted with abdominal pain and found to have an abdominal collection at the resection site, which was drained under CT guidance. She received a therapeutic dose of I131-metaiodobenzylguanidine (MIBG). Follow-ups showed the absence of recurrence, and she has remained disease free. CONCLUSION: This patient was an extraordinary example of a rare tumor. Even more remarkable was that the tumor was malignant with lymph node invasion. To our knowledge, a case similar to that presented here has not been previously reported in the literature.
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Neoplasias Pancreáticas/diagnóstico , Paraganglioma/diagnóstico , Adulto , Biopsia , Femenino , Humanos , Metástasis Linfática , Recurrencia Local de Neoplasia , Páncreas/patología , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/cirugía , Paraganglioma/radioterapia , Paraganglioma/cirugía , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenRESUMEN
AIM: To find a non-invasive strategy for detecting choledocholithiasis before cholecystectomy, with an acceptable negative rate of endoscopic retrograde cholangiopancreatography. METHODS: All patients with symptomatic gallstones were included in the study. Patients with abnormal liver functions and common bile duct abnormalities on ultrasound were referred for endoscopic retrograde cholangiopancreatography. Patients with normal ultrasound were referred to magnetic resonance cholangiopancreatography. All those who had a negative magnetic resonance or endoscopic retrograde cholangiopancreatography underwent laparoscopic cholecystectomy with intraoperative cholangiography. RESULTS: Seventy-eight point five percent of patients had laparoscopic cholecystectomy directly with no further investigations. Twenty-one point five percent had abnormal liver function tests, of which 52.8% had normal ultrasound results. This strategy avoided unnecessary magnetic resonance cholangiopancreatography in 47.2% of patients with abnormal liver function tests with a negative endoscopic retrograde cholangiopancreatography rate of 10%. It also avoided un-necessary endoscopic retrograde cholangiopancreatography in 35.2% of patients with abnormal liver function. CONCLUSION: This strategy reduces the cost of the routine use of magnetic resonance cholangiopancreatography, in the diagnosis and treatment of common bile duct stones before laparoscopic cholecystectomy.
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Colangiopancreatografia Retrógrada Endoscópica , Pancreatocolangiografía por Resonancia Magnética , Coledocolitiasis/diagnóstico , Técnicas de Apoyo para la Decisión , Cálculos Biliares/diagnóstico , Pruebas de Función Hepática , Adulto , Anciano , Algoritmos , Distribución de Chi-Cuadrado , Colecistectomía Laparoscópica , Coledocolitiasis/diagnóstico por imagen , Coledocolitiasis/cirugía , Femenino , Cálculos Biliares/diagnóstico por imagen , Cálculos Biliares/cirugía , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Selección de Paciente , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Ultrasonografía , Procedimientos Innecesarios , Adulto JovenRESUMEN
We describe the treatment of a 46-year-old Saudi man with advanced stage liver metastatic neuroendocrine rectal cancer. The patient presented with a large liver lesion and rectal bleeding. He was cachectic, with a firm tender mass 20 mm above the anal verge. Computed tomography (CT) showed a mass 9.5 × 13 cm in size in the right hemi-liver, abutting the middle hepatic vein. The patient refused treatment, and consulted another hospital. After 3 months, he presented with the same symptoms in addition to delirium. Colonoscopy showed an ulcerating anorectal mass, from which a biopsy was taken. Repeat CT showed an increase in the size of the liver lesion to 17 cm and no change in the pelvis. The final histopathology report identified anaplastic small cell carcinoma. The patient underwent extended right liver resection followed by abdominoperineal resection, then 13 cycles of chemotherapy and monthly somatostatin injections. At the most recent follow-up, the patient had been disease-free for 48 months. Surgical resection (R0) of the primary and secondary tumor, followed by platinum-based chemotherapy can result in good survival in cases of small cell carcinoma with large liver metastasis, irrespective of whether the primary or secondary tumor is resected first.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Carcinoma/patología , Carcinoma Neuroendocrino/patología , Carcinoma de Células Pequeñas/patología , Cisplatino/administración & dosificación , Etopósido/administración & dosificación , Humanos , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias del Recto/patología , Literatura de Revisión como Asunto , Somatostatina/administración & dosificación , Tomografía Computarizada por Rayos XRESUMEN
UNLABELLED: Morbid obesity is associated with cholesterol gallstone formation, a risk compounded by rapid weight loss. Laparoscopic gastric banding allows for a measured rate of weight loss, but the subsequent risk for developing gallstones is unknown. METHOD: Twenty-six normal-weight volunteers (body mass index [BMI] less than 30) were compared with 14 morbidly obese patients (BMI greater than 40). Gallbladder volumes were measured ultrasonographically, after fasting and following stimulation with intravenous cholecystokinin-octapeptide (CCK-8) RESULTS: Preoperatively, fasting gallbladder volume and residual volume after CCK stimulation were both two times greater in the obese group (P<0.02 versus controls). Per cent gallbladder emptying was not different. Gallbladder refilling was four times higher in the obese patients (P<0.01). By six weeks postoperatively, the obese patients lost 1.4+/-0.1% body weight per week. Gallbladder emptying decreased 18.4% (80.3+/-3.9% to 65.5+/-6.9%; P<0.05); residual volume rose one-third (not significant), and refilling fell 60.5% (0.43+/-0.09 to 0.26+/-0.04 mL/min; P=0.07). Three patients with weight losses of greater than 1.7% per week developed gallstones; gallbladder emptying fell outside the 95 percentile. By six months, weight loss slowed to 0.5+/-0.1% per week; gallbladder motility improved modestly. No further stones developed. CONCLUSION: Rapid weight loss following laparoscopic gastric banding impairs gallbladder emptying and when pronounced, gallstones form by six weeks postoperatively. The accompanying reduction in gallbladder emptying, increased gallbladder residual volume and decreased refilling promote gallbladder stasis and hence stone formation.
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Colelitiasis/etiología , Colelitiasis/fisiopatología , Vesícula Biliar/fisiopatología , Vesícula Biliar/cirugía , Motilidad Gastrointestinal/fisiología , Gastroplastia/efectos adversos , Laparoscopía/efectos adversos , Obesidad Mórbida/complicaciones , Obesidad Mórbida/cirugía , Complicaciones Posoperatorias , Adulto , Índice de Masa Corporal , Colelitiasis/cirugía , Femenino , Estudios de Seguimiento , Vesícula Biliar/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/fisiopatología , Evaluación de Resultado en la Atención de Salud , Ultrasonografía , Pérdida de Peso/fisiologíaRESUMEN
Endothelin levels are elevated in shock, sepsis, and cholestatic jaundice, and an effect on biliary motility may be postulated. The aim of this study was to determine whether (1) endothelin-1 and endothelin-3 induce gallbladder contraction in vivo, (2) the response is caused by changes in blood pressure, and (3) the response is nerve mediated. Gallbladder pressure and blood pressure were measured in 38 anesthetized possums. Endothelin-1 or endothelin-3 (5 to 200 pmol/kg) was administered by close intra-arterial injection. Tetrodotoxin (9 microg/kg) or the mixed endothelin antagonist tezosentan was infused at a rate of 10 or 100 nmol/kg/min (close intra-arterial injection). Maximum changes in gallbladder pressure (% of carbachol-induced contraction) and blood pressure (mm Hg) were determined. Statistical analysis was carried out by means of repeated-measures analysis of variance and Kruskal-Wallis test. Both endothelin-1 and endothelin-3 induced dose-dependent increases in gallbladder pressure and blood pressure (P < 0.05), which were unaffected by pretreatment with tetrodotoxin. The endothelin-1-induced gallbladder pressure but not blood pressure was reduced by the higher dose of tezosentan (P < 0.03). The lower dose of tezosentan also produced a decrease in the endothelin-3-induced gallbladder pressure (P < 0.02) but not in blood pressure, whereas the higher dose reduced the blood pressure with no further reduction in gallbladder pressure (P < 0.05). Endothelins increase gallbladder motility in vivo, acting directly on the smooth muscle and independent of changes in blood pressure.
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Presión Sanguínea/fisiología , Endotelinas/farmacología , Vesícula Biliar/efectos de los fármacos , Contracción Muscular/fisiología , Esfínter de la Ampolla Hepatopancreática/fisiología , Anestésicos Locales/administración & dosificación , Animales , Australia , Relación Dosis-Respuesta a Droga , Vesícula Biliar/fisiología , Inyecciones Intraarteriales , Modelos Animales , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Fibras Nerviosas/fisiología , Zarigüeyas , Piridinas/administración & dosificación , Receptores de Endotelina/metabolismo , Esfínter de la Ampolla Hepatopancreática/efectos de los fármacos , Esfínter de la Ampolla Hepatopancreática/inervación , Tetrazoles/administración & dosificación , Tetrodotoxina/administración & dosificación , Vasodilatadores/administración & dosificaciónRESUMEN
BACKGROUND: Endothelins are produced by gallbladder epithelial cells, suggesting a role in the regulation of gallbladder function. AIMS: To characterize the effect of endothelin-3 (ET-3) on human and Australian possum gallbladder contractility and identify the receptor(s) involved. METHODS: Human and possum gallbladder muscle strips were exposed to cumulative concentrations of ET-3 (10 pmol/L-100 nmol/L). Strips were pretreated with either tetrodotoxin (TTX) (1 micro mol/L), the selective ET receptor antagonists BQ-123 (ET(A)), BQ-788 (ET(B)), alone or together, or the mixed ET antagonist tezosentan (all 1 micro mol/L). Maximal changes in tone were measured and expressed as percentage of carbachol (100 micro mol/L)-induced tone. ANOVA was used for statistical analysis. RESULTS: Endothelin-3 induced a concentration-dependent increase in tone in both human and pos-sum strips (P < 0.05) and at 100 nmol/L represented 44.2 +/- 4.5% and 40.3 +/- 4.6% of carbachol-induced tone, respectively. The effect on human strips was TTX insensitive, whereas the possum concentration-response curve was shifted to the right. Individually, BQ-123 and BQ-788 shifted the human concentration-response curve to the right, but a greater inhibition by BQ-788 was achieved in the possum (P < 0.05). However, BQ-123 plus BQ-788 further reduced the ET-3 effect (P < 0.001) to a level comparable to that observed in the presence of tezosentan in both human and possum strips. CONCLUSION: Endothelin-3 produces potent gallbladder contraction in vitro, acting mainly via ET(B) receptors and also interacting with ET(A)receptors. The receptors are located on the smooth muscle, but in possum gallbladder, neural receptors may also be involved. These findings suggest that ET-3 may regulate motility of possum and human gallbladder.