Biomedical subjects
Publications and source records attributed to E Amparo.
A novel series of selective HCV NS5B RNA dependent RNA polymerase inhibitors has been disclosed. These compounds contain an appropriately substituted tetrahydrobenzothiophene scaffold. This communication will detail the SAR and activities of this series.
Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.
T-gamma-lymphoproliferative disorder, a syndrome of T-cell lymphocytosis with neutropenia has been described in patients with various autoimmune disorders, especially rheumatoid arthritis. We report a case of T-gamma-lymphoproliferative disorder occurring in a 42-year-old white woman with a long history of dermatitis herpetiformis and subsequent development of Coomb's positive autoimmune hemolytic anemia and polymyositis. The peripheral blood lymphocytes showed the T-suppressor cell phenotype (CD2-, CD3-, CD8-, and CD4-). DNA analysis of the peripheral blood lymphocytes revealed a T-cell receptor beta-chain gene rearrangement and an immunoglobulin heavy-chain gene rearrangement. The patient's course was marked by numerous bouts of infection. The unique factor in this patient was the development of a plasma cell dyscrasia and amyloidosis prior to death.
A 25-year-old man with stage II Kienbock's disease of his left lunate underwent an initial period of immobilization. He was subsequently treated by ulnar lengthening, with a good outcome. Magnetic resonance imaging (MRI) was utilized to demonstrate the lack of improvement with cast immobilization and the revascularization that followed surgical treatment. This new application of MRI in cases of avascular necrosis of the lunate may be helpful in the early identification of revascularization.
Twenty patients admitted for minor or moderate closed-head injury were studied to investigate the relationship between magnetic resonance imaging (MRI) and neurobehavioral sequelae. The MRI scans demonstrated 44 more intracranial lesions than did concurrent computerized tomography (CT) scans in 17 patients (85%); most of these lesions were located in the frontal and temporal regions. Estimates of lesion volume based on MRI were frequently greater than with CT; however, MRI disclosed no additional lesions that required surgical evacuation. Neuropsychological assessment during the initial hospitalization revealed deficits in frontal lobe functioning and memory that were related to the size and localization of the lesions as defined by MRI. Follow-up MRI and neuropsychological testing at 1 month (13 cases) and 3 months (six cases) disclosed marked reduction of lesion size paralleled by improvement in cognition and memory. These findings encourage further investigation of the prognostic utility of MRI for the clinical management and rehabilitation of mild or moderate head injury.
Forty-two women with gynecologic abnormalities were studied with the use of magnetic resonance imaging. Magnetic resonance imaging correctly assessed the origin of the pelvic mass in all patients. In the evaluation of leiomyoma, magnetic resonance imaging accurately depicted the number, size, and location of the lesion. In the evaluation of endometrial carcinoma, magnetic resonance imaging depicted the location of the lesion, the presence of cervical extension, and the depth of myometrial penetration in the majority of the cases. In the analysis of adnexal cysts, magnetic resonance imaging was sensitive in localizing the lesion and was able to distinguish serous from hemorrhagic fluid. This preliminary report indicates that magnetic resonance imaging may become a valuable imaging modality in the diagnosis of gynecologic abnormalities.
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Twenty-five patients with known or suspected evidence of venous disease based on results of computed tomography, angiography, or ultrasound were imaged with magnetic resonance (MR) to determine the MR characterization of venous abnormalities. MR findings were proved by laparotomy or autopsy in 18 of 25 cases. In seven of 25 patients in whom only biopsy was performed, the MR findings were correlated with findings from other radiologic tests. On MR, the inferior vena cava (IVC), portal vein, and their major tributaries were seen in all but two cases. In those two, identification of collaterals led to the correct diagnosis of splenic vein thrombosis in one case and left renal vein thrombosis in another. MR imaging helped identify intraluminal thrombi in the IVC (12 of 12 cases), portal vein (two of two cases), renal veins (seven of seven cases), superior mesenteric vein (one case), and iliac veins (seven of seven cases). Intraluminal signal intensity secondary to slow blood flow seen in five patients was always differentiated from the thrombus. MR imaging helped identify correctly the nature of the thrombus in 11 of 16 patients. In five patients, the differentiation between tumor thrombus and blood clot thrombus was not possible. Involvement of the IVC wall by tumor was seen in four cases. MR imaging also accurately depicted slow flow in obstructed or constricted veins; encasement, compression, or displacement of veins without intraluminal occlusions; and the presence of venous collaterals. The MR imaging evaluation of venous abnormalities is accurate, easily performed, and will probably become an important application.
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In vivo measurements of the eye were obtained in 55 normal adults using computed tomography. Means and standard deviations were established for the maximum transverse and the maximum anteroposterior dimensions. Our data indicate that the widely used methods of Sweet and Pfeiffer-Comberg (for intraorbital foreign body localization) underestimate the actual in vivo dimensions of the eye.