多沙唑嗪及其光学异构体对血脂代谢的研究进展

多沙唑嗪（DOX）存在一定心脏毒性作用,已非一线降压药物,但是作为治疗良性前列腺增生症合并下尿路症状（BPH/LUTS）的一线药物仍广泛应用于临床。同时,它可以轻度降低总胆固醇（TC）和甘油三脂（TG）水平。为减轻DOX心血管的不良反应,对其进行了手性拆分,发现DOX的分子中存在一个手性中心和一对光学异构体,即右旋多沙唑嗪（（＋）DOX）和左旋多沙唑嗪（（-）DOX）。发现（-）DOX可能成为心血管不良反应较小的治疗BPH/LUTS药物。现就（±）DOX及其光学异构体对血脂代谢的作用的研究进展作一综述。     

A novel, orally active LPA1 receptor antagonist inhibits lung fibrosis in the mouse bleomycin model

Background and purpose:

The aim of this study was to assess the potential of an antagonist selective for the lysophosphatidic acid receptor, LPA₁, in treating lung fibrosis We evaluated the in vitro and in vivo pharmacological properties of the high affinity, selective, oral LPA₁-antagonist (4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid (AM966).

Experimental approach:

The potency and selectivity of AM966 for LPA₁ receptors was determined in vitro by calcium flux and cell chemotaxis assays using recombinant and native cell cultures. The in vivo efficacy of AM966 to reduce tissue injury, vascular leakage, inflammation and fibrosis was assessed at several time points in the mouse bleomycin model.

Key results:

AM966 was a potent antagonist of LPA₁ receptors, with selectivity for this receptor over the other LPA receptors. In vitro, AM966 inhibited LPA-stimulated intracellular calcium release (IC₅₀ = 17 nM) from Chinese hamster ovary cells stably expressing human LPA₁ receptors and inhibited LPA-induced chemotaxis (IC₅₀ = 181 nM) of human IMR-90 lung fibroblasts expressing LPA₁ receptors. AM966 demonstrated a good pharmacokinetic profile following oral dosing in mice. In the mouse, AM966 reduced lung injury, vascular leakage, inflammation and fibrosis at multiple time points following intratracheal bleomycin instillation. AM966 also decreased lactate dehydrogenase activity and tissue inhibitor of metalloproteinase-1, transforming growth factor β1, hyaluronan and matrix metalloproteinase-7, in bronchoalveolar lavage fluid.

Conclusions and implications:

These findings demonstrate that AM966 is a potent, selective, orally bioavailable LPA₁ receptor antagonist that may be beneficial in treating lung injury and fibrosis, as well as other diseases that are characterized by pathological inflammation, oedema and fibrosis.     

Genome-wide mapping of unselected transcripts from extraembryonic tissue of 7.5-day mouse embryos reveals enrichment in the t-complex and under-representation on the X chromosome

Mammalian embryos can only survive if they attach to the uterus (implantation) and establish proper maternal-fetal interactions. To understand this complex implantation pathway, we have initiated genomic analysis with a systematic study of the cohort of genes expressed in extraembryonic cells that are derived from the conceptus and play a major role in this process. A total of 2103 cDNAs from the extraembryonic portion of 7.5-day post-conception mouse embryos yielded 3186 expressed sequence tags, approximately 40% of which were novel to the sequence databases. Furthermore, when 155 of the cDNA clones with no homology to previously detected genes were genetically mapped, apparent clustering of these expressed genes was detected in subregions of chromosomes 2, 7, 9 and 17, with 6.5% of the observed genes localized in the t-complex region of chromosome 17, which represents only approximately 1.5% of the mouse genome. In contrast, X-linked genes were under-represented. Semi-quantitative RT-PCR analyses of the mapped genes demonstrated that one third of the genes were expressed solely in extraembryonic tissue and an additional one third of the genes were expressed predominantly in the extraembryonic tissues. The over-representation of extraembryonic-expressed genes in dosage- sensitive autosomal imprinted regions and under-representation on the dosage-compensated X chromosome may reflect a need for tight quantitative control of expression during development.      

Use of the Phoenix system for bacteriology

A dedicated microbiology data processing system with remote batched job entry to an obsolete computer, has been superseded by the inclusion of bacteriology in an on-line interactive clinical pathology system which had previously incorporated chemical pathology and haematology. The original Phoenix system has been adapted to allow for the entry of bacteriology data using mnemonic codes and to deal with the problems caused by the longer processing time of bacteriology specimens. Particular advantages of the new system include the immediate linkage of all specimens for each patient and an easy recall and display of results in the laboratories and on the wards.