Phase I trial of ilmofosine as a 24 hour infusion weekly

Ilmofosine, an ether lipid derivative of lysophosphatidylcholine has antineoplastic activityin vitro andin vivo. Maximum efficacy in preclinical models is associated with prolonged exposure to the drug. In a Phase I trial of a weekly 2 hour infusion schedule of ilmofosine, a syndrome of lethargy, diminished performance status, and mild hepatotoxicity was dose-limiting at 550 mg/m². To avoid the higher drug concentrations associated with a brief infusion, a Phase I study of a weekly 24 hour infusional schedule was undertaken in an attempt to maximize dose-intensity. Doses were escalated from 550 to 800 mg/m². Toxicities included nausea, anorexia, fatigue, and minor elevations of liver function tests. The dose limiting toxicity at 800 mg/ m² was a syndrome of severe abdominal pain. No neutropenia or thrombocytopenia was observed except in one patient who was found to have a myelodysplastic syndrome, thought not to be related to drug therapy. The more prolonged infusion schedule of ilmofosine did not result in a substantial increase in the tolerable dose.     

Supersensitivity to the negative chronotopic action of carbachol and methacholine in the rat

Pretreatment of rats for 6 days with the ganglion blocking agent, chlorisondamine, produces a 2-3 fold increase in the sensitivity of the heart to the negative chronotropic action of carbachol and methacholine.     

Understanding coeliac disease: symptoms and long-term risks

Coeliac disease is a chronic, potentially life-threatening condition affecting as many as one in 300 men and women in the (UK). The Coeliac Society currently has more than 36,000 members. Essentially, coeliac disease is a complication of the gastrointestinal tract. Coeliac patients must avoid gluten in food products in order to avoid debilitating symptoms which include diarrhoea and iron deficiency. This article looks at the patients who are likely to be 'at-risk' of having coeliac disease and how they should be treated via adherence to a permanent gluten-free diet. The article focuses on osteoporosis, a common long-term condition associated with coeliac disease, and the risks coeliac patients face. The aim of this article is to provide background information on coeliac disease and its treatment, related conditions, and supporting patient and professional organizations.     

Characterization of ZK 245186, a novel,selective glucocorticoid receptor agonist for the topical treatment of inflammatory skin diseases

Background and purpose:

Glucocorticoids are highly effective in the therapy of inflammatory diseases. Their value, however, is limited by side effects. The discovery of the molecular mechanisms of the glucocorticoid receptor and the recognition that activation and repression of gene expression could be addressed separately opened the possibility of achieving improved safety profiles by the identification of ligands that predominantly induce repression. Here we report on ZK 245186, a novel, non-steroidal, low-molecular-weight, glucocorticoid receptor-selective agonist for the topical treatment of inflammatory dermatoses.

Experimental approach:

Pharmacological properties of ZK 245186 and reference compounds were studied in terms of their potential anti-inflammatory and side effects in functional bioassays in vitro and in rodent models in vivo.

Key results:

Anti-inflammatory activity of ZK 245186 was demonstrated in in vitro assays for inhibition of cytokine secretion and T cell proliferation. In vivo, using irritant contact dermatitis and T cell-mediated contact allergy models in mice and rats, ZK 245186 showed anti-inflammatory efficacy after topical application similar to the classical glucocorticoids, mometasone furoate and methylprednisolone aceponate. ZK 245186, however, exhibits a better safety profile with regard to growth inhibition and induction of skin atrophy after long-term topical application, thymocyte apoptosis, hyperglycaemia and hepatic tyrosine aminotransferase activity.

Conclusions and implications:

ZK 245186 is a potent anti-inflammatory compound with a lower potential for side effects, compared with classical glucocorticoids. It represents a promising drug candidate and is currently in clinical trials.This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009     

多肽研究——Ⅸ.乙型肝炎病毒表面抗原(HBsAg)Pre-S区域肽段的合成和抗原特异性测定

采用溶液法和固相法,合成了HBsAg Pre-S蛋白区域七个六肽片段。将其与载体蛋白结合。用多克隆抗HBsAg和单克隆抗“α”测定了肽—蛋白结合物的抗原特异性,结果表明P_1和P_5有较高的抗原特异性。     

The Association of the COMT V158M Polymorphism with Endometrial/Ovarian Cancer in HNPCC Families Adhering to the Amsterdam Criteria

Catechol-O-methyltransferase (COMT) is vital for the conjugation of catechol estrogens that are produced during oestrogen metabolism. The efficiency of this process varies due to a polymorphism in COMT, which changes valine to methionine (V158M). The Met genotypes slow the metabolism of catechol oestrogens, which are agents that are capable of causing DNA damage through the formation of DNA adducts and reactive oxygen species (ROS) production. The slower metabolism of catechol oestrogens results in there being a higher circulating concentration of these oeastrogens and consequently greater probability of DNA damage. To determine whether metabolic inefficiencies of oeastrogen metabolism are associated with the development of malignancy in hereditary non-polyposis colorectal cancer (HNPCC), we studied the V158M polymorphism in COMT in a large cohort of 498 HNPCC patients from Australia and Poland that were either mutation positive (n = 331) or negative (n = 167) for mismatch repair (MMR) gene mutations (hMLH1 or hMSH2). HNPCC is a familial predisposition to colorectal cancer (CRC) and extracolonic cancers that include endometrial cancer.Using Real Time PCR, the COMT V158M polymorphism was examined and its association with disease expression, age of diagnosis of cancer, mutation status and mutation type was assessed in the HNPCC MMR mutation positive and negative groups. This study showed that the V158M polymorphism had no association with disease risk in the HNPCC MMR mutation positive population. However, the polymorphism was significantly associated with endometrial/ovarian cancer risk in HNPCC MMR mutation negative patients (p = 0.002). The heterozygous (Val/Met) genotype was associated with an increased risk of developing endometrial/ovarian cancer whereas the homozygous mutant (Met/Met) showed a decreased risk. The results suggest heterosis, where there is an apparent greater effect of the heterozygous state in this dichotomous trait. In conclusion, this study shows that the COMT V158M polymorphism alters the risk of developing endometrial/ovarian cancer in patients that adhere to the Amsterdam HNPCC criteria but do not have a DNA mismatch repair gene mutation.     

多肽研究——Ⅸ.乙型肝炎病毒表面抗原(HBsAg)Pre-S区域肽段的合成和抗原特异性测定

采用溶液法和固相法,合成了HBsAg Pre-S蛋白区域七个六肽片段。将其与载体蛋白结合。用多克隆抗HBsAg和单克隆抗“α”测定了肽—蛋白结合物的抗原特异性,结果表明P₁和P₅有较高的抗原特异性。