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Ziprasidone (Geodone), a novel atypical antipsychotic agent, is recently approved for the treatment of schizophrenia. It undergoes extensive metabolism in preclinical species and humans after oral administration, and only a very small amount of administered dose is excreted as unchanged drug. In vitro studies using human liver microsomes have shown that the oxidative metabolism of ziprasidone is mediated primarily by CYP3A4. However, coadministration of ziprasidone with ketoconazole, a CYP3A4 inhibitor, showed only a modest increase in its exposure. Therefore, in vitro metabolism of ziprasidone was investigated in hepatic cytosolic fractions to further understand its clearance mechanisms in preclinical species and humans. The major metabolite from incubation of ziprasidone in cytosolic fractions of rat, dog, and human was characterized by liquid chromatography-tandem mass spectrometry and found to be the product of reductive cleavage. Derivatization and hydrogen/deuterium exchange were used to deduce that the addition of two hydrogen atoms had occurred at the benzisothiazole moiety. Further studies to determine the enzyme involved in the formation of this metabolite are currently in progress. The identification of this novel metabolite in cytosol has clarified the clearance mechanism of ziprasidone in humans and preclinical species. 相似文献
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This study was designed to address the question; does expression of paternal histocompatibility antigens by fetal cells make them susceptible to immune attack in vivo during normal pregnancy? The experimental design was based on the rationale that, if alloantigens are presented by trophoblasts or other fetal cells in a manner which allows accessibility, in vitro-generated immune effector cells of combined helper/cytotoxic phenotype should produce fetal rejection of abortion. Similarly generated effector cells are capable of accelerating skin graft rejection and, when combined with IL-2 in vivo, are capable of causing regression of antigenic, but operationally non-immunogenic, tumors. The alloimmune effector cells generated in vitro during the current study were highly cytotoxic against normal adult target cells, whereas placental cells were completely resistant to cytolysis and fetal cells were only slightly susceptible. Adoptive transfer of effector cells to mice at different stages of gestation had no apparent effect on pregnancy outcome. In vivo administration of IL-2 and/or indomethacin, which expand effector cell numbers in vivo and block PGE2-mediated immune suppression, respectively, failed to potentiate the cellular effect. The data provide additional evidence that paternal histocompatibility antigens are not expressed in a format which allows susceptibility to immune attack during pregnancy. The data are discussed with respect to the role of the trophoblast in protecting developing embryos. 相似文献
5.
J L Guéant L Kamel D A Moneret-Vautrin S Widmer M C Laxenaire J P Nicolas 《Annales fran?aises d'anesthèsie et de rèanimation》1986,5(6):570-573
A radio-immunoassay (RIA) was used to screen for specific IgE to myorelaxants. Alcuronium was coupled to epoxy-activated Sepharose. Sixteen patients with anaphylaxis to alcuronium (n = 2), gallamine (n = 2) or suxamethonium (n = 12) were studied. The diagnosis was established by intradermal tests (ID), passive cutaneous anaphylaxis tests and human basophil degranulation tests. The amount of non specific label retained by Sepharose-ethanolamine (with sera of patients) and Sepharose-alcuronium (with sera of 11 control subjects) was estimated. The RIA was positive 10/16 (8/14 patients having reacted to a muscle relaxant other than alcuronium). The RIA seemed to be useful in the diagnosis of anaphylaxis to muscle relaxants. Drug-reactive antibodies were specific of the quaternary ammonium radical, which was the common allergenic determinant of all molecules of muscle relaxants. This test accounted for in vitro cross-reactivity, but had no predictive value for the clinical risk of crossed-anaphylaxis. This risk was best assessed by ID; it was positive in three cases. Although it was not possible to compare ID and RIA, the interpretation of which was different, both tests should be recommended for the detection of sensitivity to muscle relaxants. 相似文献
6.
Gamal Kamel Muhammed Ali O. A. Danilova 《Bulletin of experimental biology and medicine》1980,89(3):364-367
The volume of the nuclei and nucleoli of certain hypothalamic centers (SON, PVN, SCN, AN, VMN) was determined in control rats and in rats after deafferentation of the mediobasal hypothalamus. Sex differences were found in the parvocellular formations of the control animals: The volumes of nuclei and nucleoli of neurons of AN and VMN, and also of the nucleolus of SCN neurons were larger in females than in males. After deafferentation of the mediobasal hypothalamus the volume of the cell nuclei was increased, especially in hypothalamic formations located outside the isolated zone. This increase was more clearly defined in rats constantly in a state of estrus after the operation. Statistically significant differences between volumes of both nuclei and nucleoli of the cells in subgroups of rats with permanent estrus and with permanent diestrus were found only in the case of SCN. No such differences were found for AN, despite the considerable difference in the constant of luteinizing hormone in the pituitary of the same rats. It is suggested that gonadotropin releasing factors are not produced by the cells of AN and that control over the succession of phases of the sex cycle may be exerted by SCN.Laboratory of Neuroendocrinology, I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Leningrad. (Presented by Academician of the Academy of Medical Sciences of the USSR V. N. Chernigovskii.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 89, No. 3, pp. 352–354, March, 1980. 相似文献
7.
Y Soini D Kamel M Apaja-Sarkkinen I Virtanen V P Lehto 《Journal of clinical pathology》1993,46(3):218-221
AIMS: To determine the distribution of tenascin in normal and pathological bone marrow. METHODS: 48 different bone marrow lesions were studied immunohistochemically using a monoclonal antibody to tenascin. RESULTS: Tenascin immunoreactivity was found in lesions with increased fibrosis and high numbers of reticular fibres. The strongest immunoreactivity was found in myelofibrosis. Bone marrow from acute and chronic myeloid and lymphatic leukaemias showed weak or moderate immunoreactivity. In hyperplasias inconsistent reticular tenascin immunoreactivity was found; in normal bone marrow, only a few scattered positive fibres were occasionally seen. CONCLUSIONS: Tenascin was generally observed in conditions in which megakaryocytic hyperplasia was a feature. This is in line with the notion that tenascin synthesis in bone marrow fibroblasts is stimulated by TGF-beta which is synthesised by the megakaryocytic lineage. Tenascin also contains EGF-like repeats. It might therefore function as a growth promoter and in this way could also stimulate synthesis of other matrix components. On the other hand, tenascin could function as an adhesive molecule to some cells of the bone marrow. The presence of tenascin in many pathological states of the bone marrow suggests that it may have a role in their pathogenesis and that it also could be a potential marker of disease. 相似文献
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Chromosomal aberrations and micronucleus frequency in nurses occupationally exposed to cytotoxic drugs 总被引:4,自引:1,他引:4
Anwar Wagida A.; Salama Somaia I.; Serafy Mostafa M.EI; Hemida Samia A.; Hafez Ahmed S. 《Mutagenesis》1994,9(4):315-317
In this study, we evaluated the effect of low level occupationalexposure of nurses in a medical oncology unit in Cairo, Egypt,to anticancer drugs. Twenty nurses who constantly handled thesedrugs and 20 controls, matched according to age and sex, wereexamined. Metaphase chromosomes were studied. Percentages ofmetaphases with chromosomal aberrations were significantly higher(P < 0.001) in the exposed group (6.1 ± 2.7) versusthe controls (2.6 ± 1.6). The detected chromosomal aberrationswere in the form of chromatid gaps, chromatid breaks and acentricfragments. Micronucleated peripheral blood lymphocytes werealso analyzed in cytochalasin B treated binucleated lymphocytes.There was significant increase in cells with micronuclei (P< 0.001) in nurses (10.05 ± 4.71) in comparison tothe matched control (5.42 ± 2.22) (P < 0.001). Nursesexposed to the cytotoxic drugs for 相似文献
10.
Rejiba S Limam F Belhadj C Belhadj O Ben-Mahrez K 《Microbial drug resistance (Larchmont, N.Y.)》2002,8(1):9-13
Pseudomonas aeruginosa 802 was isolated at Rabta hospital in Tunis and was resistant to extended-spectrum cephalosporins and aztreonam. It produced a pI 7.6 extended-spectrum beta-lactamase (ESBL). The ESBL, named LBT 802, was purified to homogeneity by filtration on Sephadex G-75 followed by CM-Sepharose chromatography and high-performance liquid chromatography (HPLC) on a TSK-gel SP-5PW column. The LBT 802 enzyme had a molecular mass of 30 kDa. It showed a broad-substrate profile by hydrolyzing benzylpenicillin, ampicillin, cephalothin, cephaloridine, cefotaxime, ceftriaxone, and cefpirome but not ceftazidime, cefoxitin, imipenem, or aztreonam. The highest hydrolytic efficiency (Vmax/Km) was obtained for ampicillin, cephalothin, cephaloridine, and benzylpenicillin. Among extended-spectrum cephalosporins the best substrate was ceftriaxone followed by cefotaxime and cefpirome. LBT 802 activity was inhibited by clavulanic acid, sulbactam, imipenem, cefoxitin, and aztreonam. It showed its lowest Ki values for clavulanic acid, imipenem and sulbactam. 相似文献