Conjugation of the enantiomers of ketotifen to four isomeric quaternary ammonium glucuronides in humans in vivo and in liver microsomes.
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The antiallergic drug ketotifen is chiral due to a nonplanar seven-membered ring containing a keto group. Earlier studies have revealed glucuronidation at the tertiary amino group as a major metabolic pathway in humans. Chemical synthesis of glucuronides from racemic ketotifen now led to four isomers separable by HPLC of which two each could be ascribed to (R)-(+)- and (S)-(-)-ketotifen by synthesis from the enantiomers. According to (1)H NMR analysis of the (S)-ketotifen N-glucuronides, the conformation of the piperidylidene ring differs between the two isomers. Enzymatic hydrolysis with Escherichia coli beta-glucuronidase proceeded at a lower rate with the slower eluting (S)-ketotifen glucuronide than with the three other isomers. On incubation of the ketotifen enantiomers (0.5-200 microM) with human liver microsomes in the presence of UDP-glucuronic acid and Triton X-100, the N-glucuronides of (R)-ketotifen were produced with an apparent K(M) 15 microM and V(max) 470 pmol/min/mg protein. The two (S)-ketotifen glucuronides were formed by two-enzyme kinetics with K(M1) 1.3 microM and K(M2) 92 microM and V(max) values of 60 and 440 pmol/min/mg protein. After ingestion of 1 mg of racemic ketotifen, 10 healthy subjects excreted in urine 17 +/- 5% of the dose in the form of N-glucuronides. The (R)-ketotifen glucuronide isomers contributed one-sixth only, whereas the remainder consisted primarily of the (S)-ketotifen glucuronide isomer, which eluted last. Differential hydrolysis or membrane transport may be responsible for the discrepancy between N-glucuronide isomer ratios in vitro and in vivo. (+info)
Synthesis of 5-imino-5H-dipyrido[1,2-a; 2',3'-d]pyrimidines as potential antiallergy agents (1).
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A novel route to 5-imino-5H-dipyrido[1,2-a; 2',3'-d]pyrimidines is described. The method is based on the Ullmann condensation of 2-chloro-3-cyano-5-nitropyridine with 2-amino-pyridine 1-oxides, followed by intramolecular cyclization of the resulting 2-(3-cyano-5-nitro-2-pyridylamino)pyridine 1-oxides with phosphorous trichloride. (+info)
Antibacterial activities of cryptotanshinone and dihydrotanshinone I from a medicinal herb, Salvia miltiorrhiza Bunge.
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Cryptotanshinone and dihydrotanshinone I, constituents of a medicinal plant, Salvia miltiorrhiza Bunge, had antibacterial activity against a broad range of Gram positive bacteria. These compounds generated superoxide radicals in Bacillus subtilis lysates. A recombination-deficient mutant strain of B. subtilis was 2- to 8-fold more sensitive than a wild strain, and this hypersensitivity was reduced in the presence of dithiothreitol as an antioxidant. DNA, RNA, and protein syntheses in B. subtilis were non-selectively inhibited by these compounds. These results suggest that superoxide radicals are important in the antibacterial actions of the agents. (+info)
Tissue eosinophilia prevention represents one of the primary targets to new anti-allergic therapies. As lipoxin A4 (LXA4) and aspirin-triggered 15-epi-LXA4 (ATL) are emerging as endogenous "stop signals" produced in distinct pathologies including some eosinophil-related pulmonary disorders, we evaluated the impact of in situ LXA4/ATL metabolically stable analogues on allergen-induced eosinophilic pleurisy in sensitized rats. LXA4/ATL analogues dramatically blocked allergic pleural eosinophil influx, while concurrently increasing circulating eosinophilia, inhibiting the earlier edema and neutrophilia associated with allergic reaction. The mechanisms underlying this LXA4/ATL-driven allergic eosinophilia blockade was independent of mast cell degranulation and involved LXA4/ATL inhibition of both IL-5 and eotaxin generation, as well as platelet activating factor action. These findings reveal LXA4/ATL as a novel class of endogenous anti-allergic mediators, capable of preventing local eosinophilia. (+info)
Inhibition of neointima formation by tranilast in pig coronary arteries after balloon angioplasty and stent implantation.
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OBJECTIVES: We evaluated the effect of orally administered tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, on histologic and histomorphometric changes after angioplasty or stent implantation in pig coronary arteries. BACKGROUND: Tranilast, which has antikeloid and antiallergic properties and therefore may modulate the fibrotic and inflammatory tissue responses to angioplasty and stenting, has been shown to inhibit angiographic restenosis in small clinical trials. However, its effect on histomorphometric changes in coronary arteries after angioplasty and stenting is unknown. METHODS: Following initial pharmacokinetic studies in two pigs to determine desirable plasma levels of orally administered tranilast, 36 crossbred juvenile pigs were randomized to placebo or tranilast before undergoing balloon angioplasty in both the left anterior descending and left circumflex plus stent implantation in the right coronary artery. Oral tranilast was administered at 3 g/day starting 3 days before coronary injury and continued for 28 days until euthanasia. Injured vessels were harvested and sections analyzed by computer-assisted microscopic planimetry. RESULTS: In balloon-injured vessels, tranilast was associated with a 37% reduction in neointimal area normalized to fracture length (0.47 +/- 0.01 vs. 0.74 +/- 0.03 mm; p < 0.001) and a 23% reduction in adventitial area normalized to vessel size (0.43 +/- 0.02 vs. 0.56 +/- 0.03; p = 0.003). In stented arteries, neointimal area normalized to injury score was 32% lower in the tranilast-treated group compared to control (1.94 +/- 0.17 vs. 2.86 +/- 0.29; p = 0.01). CONCLUSIONS: In pig coronary arteries, tranilast was associated with a reduction in neointima formation and adventitial reaction after balloon injury. In stented vessels, tranilast was associated with a reduction in neointima formation normalized to injury score. (+info)
Role of cysteinyl leukotrienes in CD4(+) T cell-driven late allergic airway responses.
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Cysteinyl leukotrienes (cys LTs) play an important role in late responses to allergen challenge of actively sensitized rats. The aim of this study was to determine whether T cell-dependent late airway responses (LARs) also are mediated by cys LTs. To do this we tested the effects of the selective and potent LTD(4) antagonist pranlukast on airway responses to ovalbumin (OVA) challenge of naive recipients of CD4(+) T cells isolated from the cervical lymph nodes of OVA-sensitized donor rats. CD4(+) T cells (5 million) were purified by immunomagnetic separation and administered i.p. 2 days before OVA challenge. The pulmonary resistance was measured for 8 h after challenge and bronchoalveolar lavage (BAL) was performed for analysis of leukocytes and major basic protein-positive cells. The LAR, determined as the area under the curve of pulmonary resistance against time from 3 to 8 h after challenge, was 8.9 +/- 1.79 cm H(2)O/ml/s x min after OVA compared with 2.8 +/- 0.50 cm H(2)O/ml/s x min (P <.01) after OVA and pranlukast treatment. The total cell count in BAL was not significantly greater in the OVA challenged group (3.55 +/- 0.41 x 10(6) cells) compared with the OVA- and pranlukast-treated group (2.65 +/- 0.45 x 10(6) cells). However, lymphocytes and eosinophils were reduced in numbers by pranlukast. Interleukin-5 mRNA-positive cells were diminished by 50% in pranlukast-treated animals. In conclusion, pranlukast inhibits LAR, BAL eosinophilia, and Interleukin-5 expression in rats with adoptively transferred LAR, indicating an important role for cys LTs in these T cell-driven responses. (+info)
Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment.
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Activated CD4 Th1 lymphocytes can enter the brain in the absence of an inflammatory focus. However, the molecular mediators that regulate this early migration of lymphocytes into the brain have remained unclear. We hypothesized that the entry of these 'pioneer' lymphocytes into the brain is regulated by a set of molecular events that are distinct from those used once inflammation has been established. Using cells fluorescently labelled with the lipophilic dye DiI, myelin basic protein (MBP)-specific CD4 lymphocytes that expressed low or high levels of very late antigen-4 (VLA-4) and non-antigen-specific activated splenocytes homed to mouse brain in similar quantities 2 h after adoptive transfer. However, antigen specificity and VLA-4 expression were required for more robust recruitment by 24 h. Immunocytochemistry revealed endothelial and microenvironmental upregulation of vascular cell adhesion molecule (VCAM), intercellular cell adhesion molecule 1 (ICAM-1), MHC class II and interferon-gamma 48 h after transfer of MBP-specific cells. In contrast, expression of meningeal and choroid plexus-associated P selectin was upregulated 2 h after adoptive transfer, but not at 48 h. Monoclonal antibody to P selectin, but not to VLA-4, inhibited early migration of high VLA-4-expressing MBP-specific lymphocytes. These results suggest that early migration occurs independent of the lymphocyte integrin VLA-4 and endothelial VCAM, but does require increased surface expression of endothelial P selectin. (+info)
Anti-type I allergic mechanisms of mao-bushi-saishin-to in mice.
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We investigated the anti-allergic effect of mao-bushi-saishin-to (MBS) on the type I allergy model in mice. When MBS was administered orally at a dose of 0.5 or 1.0 g/kg, edema of the footpad, the amount of plasma IgE and the ratio of eosinophilic leukocytes in peritoneal exudate cells were all dose-relatedly suppressed. Moreover to investigate the anti-type I allergic mechanisms of MBS, enzyme-linked immunosorbent assay was performed to determine the interleukin (IL)-4, IL-5 and interferon (IFN)-gamma production from splenocytes that were stimulated by pokeweed mitogen for 48 h. In addition, we assayed IgE production from splenic B cells stimulated with the lipopolysaccharide and IL-4 for 7 days. MBS inhibited the IL-4 and IFN-gamma production, but IL-5 and IgE production were not affected. Thus possibly, the inhibition of IL-4 production may partially be involved in the expression of the anti-type I allergic effects of MBS. (+info)