2-甲酰(乙酰)取代喹啉缩氨基硫脲的合成

缩氨基硫脲类化合物有抗肿瘤、抗病毒和抗菌等多种药理活性。Barret等首次报道了乙二醛二缩氨基硫脲(Ⅰ)的抗疟活性。Klayman等研究了缩     

Xenogeneic transplantation of porcine hepatocytes into the CCl4 cirrhotic rat model

Liver support using extracorporeal devices and hepatocyte transplantation has received renewed interest for the management of acute and chronic liver failure. The aim of this study was to determine whether xenogeneic porcine hepatocytes could integrate into the liver parenchyma of cirrhotic Lewis rats when administered by an intrasplenic route. Cirrhosis was induced by carbon tetrachloride (CCl4) inhalation and confirmed histologically. Freshly isolated porcine hepatocytes were infused directly into the splenic pulp at laparotomy over a 5-15-min interval. Using (111)In-labeled hepatocytes, the degree of localization of porcine hepatocytes to the spleen and liver was found to be greater than 60% in both control and cirrhotic rats. Integration of porcine hepatocytes into the rat liver parenchyma was determined by immunohistochemical staining for porcine albumin in rat liver sections. Further confirmation was provided by in situ hybridization using a porcine-specific probe that binds to a distinct repetitive element (PRE) in porcine DNA. Evidence of integrated porcine hepatocytes was seen for over 50 days in animals under cyclosporine immunosuppression. These data demonstrate the integration of xenogeneic porcine hepatocytes into the liver of the cirrhotic rat and their ability to produce porcine albumin for up to 50 days.     

Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium

Confluent cultures of endothelial cells from human umbilical cord were used to study the effect of activated human protein C (APC) on the production of plasminogen activators, plasminogen activator-inhibitor, and factor VIII-related antigen. Addition of APC to the cells in a serum-free medium did not affect the production of tissue-type plasminogen activator (t-PA) or factor VIII-related antigen; under all measured conditions, no urokinase activity was found. However, less plasminogen activator-inhibitor activity accumulated in the conditioned medium in the presence of APC. This decrease was dose dependent and could be prevented by specific anti-protein C antibodies. No decrease was observed with the zymogen protein C or with diisopropylfluorophosphate-inactivated APC. APC also decreased the t-PA inhibitor activity in endothelial cell-conditioned medium in the absence of cells, which suggests that the effect of APC is at least partly due to a direct effect of APC on the plasminogen activator- inhibitor. High concentrations of thrombin-but not of factor Xa or IXa-- had a similar effect on the t-PA inhibitor activity. The effect of APC on the plasminogen activator-inhibitor provides a new mechanism by which APC may enhance fibrinolysis. The data suggest that activation of the coagulation system may lead to a secondary increase of the fibrinolytic activity by changing the balance between plasminogen activator(s) and its (their) fast-acting inhibitor.     

Multicenter trial of octreotide in patients with refractory acquired immunodeficiency syndrome-associated diarrhea

Diarrhea is a significant problem in patients with acquired immunodeficiency syndrome (AIDS). The aim of this study was to determine octreotide effectiveness in refractory AIDS-associated diarrhea. In a 3-week protocol, 129 patients with a stool weight of >500 g/day despite standard antidiarrheal therapy were randomized to receive octreotide or placebo (3:2 ratio). Octreotide dose was increased 100 μg weekly to a maximum of 300 μg three times a day based on weekly 72-hour stool collections. Subsequently, patients received open-label octreotide at doses of up to 500 μg three times a day. A 30% decrease in stool weight defined response. After 3 weeks, 48% of octreotide- and 39% of placebo-treated patients had responded (P = 0.43). At 300 μg three times a day, 50% of octreotide- and 30.1% of placebo-treated patients responded (P = 0.12). At a baseline stool weight of 1000–2000 g/day, 57% of octreotide- and 25% of placebo-treated patients responded (P = 0.06). Response rates based on CD4 counts, diarrhea duration, body weight, human immunodeficiency virus risk factor, and presence or absence of pathogens showed no benefit of octreotide. Adverse events were more frequent in the octreotide-treated group. In the doses studied, octreotide was not more effective than placebo in patients with refractory AIDS-associated diarrhea. This lack of effectiveness may be attributable to inadequate sample size, doses, and duration of study treatment.     

Isolation and characterization of peptides from the protein core of bovine gallbladder mucin

Gallbladder mucin may promote cholesterol gallstone formation by accelerating cholesterol monohydrate crystal nucleation in supersaturated bile. In this study, peptides were isolated from the mucin protein core by protease digestion and molecular-sieve high-performance liquid chromatography. Tryptic peptides were purified by anion exchange or reverse-phase high-performance liquid chromatography, and amino acid compositions were determined. Tryptic peptides were (a) nonglycosylated, (b) selectively enriched in serine, glutamic acid plus glutamine, and glycine, and (c) depleted in threonine and proline compared with native gallbladder mucin. Bilirubin derivatized with Woodward's reagent K covalently bound to purified mucin. Tryptic digestion of the mucin-bilirubin complex yielded low-molecular-weight nonglycosylated peptides with covalently bound bilirubin. These data indicate that the mucin protein core contains at least two distinct domains. One domain is rich in threonine and proline and contains the majority of covalently bound carbohydrate. A second domain, possibly internally located, is nonglycosylated, enriched in serine, glutamic acid plus glutamine, and glycine, and binds hydrophobic ligands such as bilirubin and 1-anilino-8-naphthalene sulfonate. Hydrophobic domains on the mucin protein core may contribute to the pathogenesis of cholesterol cholelithiasis.     

Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy

Anemia and decreased health-related quality of life (HRQL) are common in patients receiving combination therapy of interferon alfa (IFN) and ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. In a randomized, prospective study evaluating the effectiveness of epoetin alfa in maintaining RBV dose, alleviating anemia, and improving HRQL in anemic (Hb < or = 12 g/dL) HCV-infected patients receiving combination therapy, patients receiving epoetin alfa had significant improvements in HRQL compared with placebo. In this study, 185 patients were randomized to 40,000 units of epoetin alfa subcutaneously weekly or placebo for an 8-week double-blind phase (DBP), followed by an 8-week open-label phase during which all patients received epoetin alfa. To further assess the impact of epoetin alfa on HRQL, post hoc analyses were conducted in the same patient population to compare the HRQL of these patients at randomization with norms of other populations, and to determine the critical relationship between hemoglobin (Hb) levels and HRQL. Mean HRQL scores of anemic HCV-infected patients receiving combination therapy at randomization were significantly lower than those of both the general population and patients who had other chronic conditions. Patients receiving epoetin alfa who had the greatest Hb increases from randomization to the end of the DBP also had the largest improvements in HRQL. Hb improvement was an independent predictor of HRQL improvement in these patients. In conclusion, epoetin alfa provided clinically significant HRQL improvement in HCV-infected patients receiving IFN/RBV therapy.     

Longitudinal correlations between MRE,MRI-PDFF,and liver histology in patients with non-alcoholic steatohepatitis: Analysis of data from a phase II trial of selonsertib

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