Ramatroban (Baynas, BAY u3405), a thromboxane A 2 (TxA 2 ) antagonist marketed for allergic rhinitis, has been shown to partially attenuate prostaglandin (PG)D 2 -induced bronchial hyperresponsiveness in humans, as well as reduce antigen-induced early-and late-phase inflammatory responses in mice, guinea pigs, and rats. PGD 2 is known to induce eosinophilia following intranasal administration, and to induce eosinophil activation in vitro. In addition to the TxA 2 receptor, PGD 2 is known as a ligand for the PGD 2 receptor, and the newly identified G-protein-coupled chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). To fully characterize PGD 2 -mediated inflammatory responses relevant to eosinophil activation, further analysis of the mechanism of action of ramatroban has now been performed. PGD 2 -stimulated human eosinophil migration was shown to be mediated exclusively through activation of CRTH2, and surprisingly, these effects were completely inhibited by ramatroban. This is also the first report detailing an orally bioavailable small molecule CRTH2 antagonist. Our findings suggest that clinical efficacy of ramatroban may be in part mediated through its action on this Th2-, eosinophil-, and basophil-specific chemoattractant receptor.

SUMMARYWe isolated the full length provirus of human T cell leukaemia virus type I (HTLV-I) from MT-2, a lymphoid cell line producing HTLV-I. In three non-lymphoid cell lines (COS7, human osteosarcoma HOS cells, and HeLa) this provirus expressed a transacting activity after co-transfection with a recombinant plasmid carrying a bacterial chloramphenicol acetyltransferase gene under the control of a long terminal repeat of HTLV-I provirus. The trans-acting protein p40 was detected by immunoprecipitation in transfected HOS cells. Structural proteins of HTLV-I, the gag and env products, were also formed and processed in the same manner as observed in MT-2 cells. In transfected HeLa cells, the p40 protein was mainly localized in the nucleus, while other structural proteins were detected in the cytoplasm and/or the membrane by indirect immunofluorescence. Syncytium formation was observed in HeLa cells after transfection. These results demonstrated that non-lymphoid cells could produce the major proteins of HTLV-I after DNA transfection of the cloned provirus.

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The clinical outcomes of patients with accidental gallbladder perforation were acceptable, and the use of antimicrobial prophylaxis once before the operation was sufficient.

Prostacyclin, one of the cyclooxygenase metabolites, causes various biological effects, including vasodilation and antithrombogenicity, and is also involved in several pathophysiological effects, such as inflammatory pain and bladder disorders. The prostacyclin receptor (IP receptor) agonists iloprost, cicaprost, and carbacyclin have been useful for clarifying the role of the IP receptor signaling, since the endogenous ligand, prostacyclin, is very unstable. On the other hand, only a few IP receptor antagonists have been reported to date. Here, we characterized the biological activities of 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid (compound A) in various in vitro systems. Compound A inhibited the accumulation of the second messenger cyclic AMP in the UMR-108 rat osteosarcoma cell line and primary cultured rat dorsal root ganglion (DRG) neurons in a concentration-dependent manner up to 10 M, without affecting other eicosanoid receptors. Functionally, the IP receptor plays an important role in DRG neuron sensitization, which is measured by release of the neurotransmitter substance P. Although the effects of iloprost or Lys-bradykinin, an inflammatory peptide, alone on substance P release were limited, stimulation of the neurons with both these ligands induced substantial amounts of substance P release. This synergistic effect was suppressed by compound A. Collectively, these results suggest that compound A is a highly selective IP receptor antagonist that inhibits iloprost-induced sensitization of sensory neurons. Furthermore, these findings suggest that IP receptor antagonist administration may be effective for abnormal neural activities of unmyelinated sensory afferents. Compound A should prove useful for further investigations of the IP receptor in various biological processes.Prostanoids (PGD 2 , PGE 2 , PGF 2␣ , PGI 2 , and thromboxane A 2 ) are bioactive lipid mediators generated from membrane phospholipids. They are formed from unsaturated 20-carbon fatty acids and activate second messengers via specific G protein-coupled receptors (prostaglandin D 2 receptor, CRTH2, EP 1 , EP 2 , EP 3 , EP 4 , prostaglandin F receptor, IP, and TP) (Breyer et al., 2001;Samad et al., 2002).