Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma

PURPOSE: Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways. EXPERIMENTAL DESIGN: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. RESULTS: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib-induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr(1054/1059), increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. CONCLUSION: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.     

Efficacy of contact lens multipurpose solutions against serratia marcescens.

PURPOSE: To compare the susceptibilities of clinical isolates of Serratia marcescens and the standard ISO ATCC 13880 strain to five contact lens multipurpose disinfection solutions (MPDSs). METHODS: Five commercially available MPDSs, containing either a polymeric biguanide or polyquaternium, were tested using ISO/CD 14729 stand-alone test for contact lens care products against four ocular isolates of S. marcescens and the strain ATCC 13880. An average log reduction in bacterial numbers at the manufacturer's minimum recommended disinfection time was determined and compared with the criteria for stand-alone disinfection products for each MPDS against each bacterial strain. RESULTS: All the MPDSs tested met the stand-alone criteria of 3-log reduction of viable bacteria against the ATCC strain of S. marcescens. However, there was more variability in their ability to meet disinfection criteria when tested against the clinical isolates. Two of the clinical isolates were significantly more resistant to disinfection than was the recommended ISO strain (p < or = 0.034). Two of the polyquaternium-1-based disinfection solutions (solutions D and E, p < or = 0.005) were less effective overall than the other MPDSs against S. marcescens. CONCLUSIONS: The importance of strain selection for the testing of MPDSs is indicated, and the use of a single laboratory strain may be insufficient to provide assurance that the disinfection solution will be effective against clinical isolates. Furthermore, clinical isolates of S. marcescens may show increased resistance to disinfection with polyquaternium.     

Leuprolide acetate elevates prolactin during ovarian stimulation with gonadotropins

Objective The purpose of this study was to determine whether gonadotropin-releasing hormone agonist further increases the prolactin rise accompanying ovarian stimulation.Design Serum prolactin concentrations were compared between cycles with and cycles without the use of leuprolide acetate (LA) matched for estradiol levels. Relationships of prolactin levels to cycle outcomes were examined.Setting The study took place at a private fertility center.Patients Patients were women receiving stimulation for oocyte retrieval using human menopausal gonadotropins.Interventions No interventions were used.Main Outcome Measures Serum prolactin level, fertilization rate, embryo quality, and pregnancy were the main outcome measures.Results Higher serum prolactin was associated with both higher estradiol levels and use of LA but did not have any effects on fertilization rate, embryo quality, or occurrence of pregnancy.Conclusion LA stimulates prolactin release during ovarian stimulation but without apparent consequence.     

A DNA vaccine encoding a conserved Eimeria protein induces protective immunity against live Eimeria acervulina challenge

Coccidiosis is caused by several distinct intestinal protozoa of Eimeria sp., and is responsible for intestinal lesions and severe body weight loss in chickens. To develop a DNA vaccination strategy for coccidiosis, an expression vector pMP13 encoding a conserved antigen of Eimeria was constructed by subcloning 3-1E cDNA into pBK-CMV and used to elicit protective immunity against E. acervulina. One-day-old chickens were immunized intramuscularly (IM) or subcutaneously (SC) with various doses of pMP13 expression vector ranging from 5 to 100 ug two weeks apart and were challenged with 5x10(3) E. acervulina. Chickens immunized with 5, 10, 50 or 100 ug of pMP13 plasmid, but not control plasmid, pBK-CMV, showed significantly reduced oocysts following challenge infection with E. acervulina. Two injections were in general more effective than one injection with higher dose of DNA eliciting better protection. At 10 days post challenge infection, maximum levels of circulating antibodies were detected regardless of the routes of injection, although IM injection provided higher levels of serum antibodies compared to SC injection. Serum antibody levels demonstrated a dose-dependent response showing higher antibody production at higher DNA dose. DNA immunization with pMP13 also induced significant changes in T-cell subpopulations in the spleen and duodenum intraepithelial lymphocytes. At 4 days post DNA immunization, pMP13-immunized chickens showed lower CD8, and higher CD4(+) and gammadelta T(+) cells in the duodenum compared to the pBK-CMV-immunized chickens. Following challenge infection with E. acervulina, pMP13-immunized chickens showed lower CD8(+) and alphabeta T(+) cells, and higher CD4(+) cells than pBK-CMV-immunized chickens in the duodenum. These findings demonstrate that DNA immunization with pMP13 induce local and systemic host immune responses against Eimeria.     

Oral and cutaneous lesions in Crohn's disease. A case report

Cutaneous and buccal manifestations of Crohn's disease are common. They are diagnostically helpful either by their specificity or from a biopsy which whilst access is easy offers less satisfactory results with buccal lesions. Stomatological clinical aspects are varied, most commonly of aphthoid or vesicular stomatitis type (as in the case reported here).     

Evidence for dissolution rate-limited absorption of COL-3, a matrix metalloproteinase inhibitor,leading to the irregular absorption profile in rats after oral administration

Purpose. This study was undertaken to elucidate the underlying mechanism of the irregular absorption profiles of COL-3, a matrix metalloproteinase inhibitor, with a double- or plateau-peak concentration after a single oral dose administration of COL-3 suspension to rats. Methods. The gastrointestinal absorption profiles of COL-3 in rats were assessed by comparing serum drug concentration curves after the following various modes of drug administration: oral and intraduodenal doses, oral doses of COL-3 in fine and coarse suspensions, intraduodenal dosing to the bile-duct intact and cannulated (BDC) rats, and oral doses with and without food. In addition, the biliary excretion of COL-3 in the BDC rats was examined. Results. Neither variable gastric emptying nor enterohepatic recycling was the source of the irregular gastrointestinal absorption of COL-3 in rats. Reduction in particle size, presence of food and endogenous bile emerged as the determinants of the oral absorption of COL-3 by enhancing the dissolution of the solid drug in the gastrointestinal fluids. Flip-flop of the absorption and elimination rate constants was noted only for COL-3 after intraduodenal administration of the coarse suspension to the BDC rats with the bile flow diverged out of the body. Conclusions. Variability in dissolution rate-limited absorption was the main cause of the irregular absorption of COL-3 after oral administration of its solid dosage form.     

Natural history of hyperlactataemia in human immunodeficiency virus-1-infected patients during highly active antiretroviral therapy

A study on the course of hyperlactataemia during highly active antiretroviral therapy (HAART) and the association between hyperlactataemia and antiretroviral drugs was conducted at the outpatient department, Rigshopitalet, Copenhagen. Lactate levels were monitored in 848 patients during a study period of 1 y. Longitudinal analysis was performed on all human immunodeficiency virus-1-infected patients who had plasma lactate > 2.1 mM. Hyperlactataemia was found in 178 patients (21%), of whom 7 patients needed treatment modification, owing to symptomatic hyperlactataemia in 3 and neuropathy in 4 patients, while 171 remained on unchanged therapy. Lactate levels increased in 20 patients during the study period, but the increases were modest with a mean of 0.6 mM (range 0.1-1.7 mM). The association between antiretroviral drugs and hyperlactataemia was studied using logistic regression in 263 patients with data on their treatment regimen available in electronic form. Only stavudine and ritonavir were significantly associated with hyperlactataemia, with odds ratios of 5.1 and 2.6, respectively. In conclusion, symptomatic hyperlactataemia is uncommon, while asymptomatic hyperlactataemia is a frequent and apparently benign condition unlikely to progress to lactic acidosis. A significant association between stavudine and hyperlactataemia was confirmed. The unexpected association between ritonavir and hyperlactataemia will need confirmation in future studies.