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261.
CH Verhoeven SF Krebbers GN Wagenaars CJ Booy GM Groothuis P Olinga RM Vos 《Canadian Metallurgical Quarterly》1998,26(11):1102-1112
The metabolism of Org 30659 [(17alpha)-17-hydroxy-11-methylene-19-norpregna-4, 15-dien-20-yn-3-one], a new potent progestagen currently under clinical development by NV Organon for use in oral contraceptive and hormone replacement therapy, was studied in vivo after oral administration to rats and monkeys and in vitro using rat, rabbit, monkey, and human liver microsomes and rat and human hepatocytes. After oral administration of [7-3H]Org 30659 to rats and monkeys, Org 30659 was extensively metabolized in both species. Fecal excretion appeared to be the main route of elimination. In rats, opening of the A-ring, resulting in a 2-OH,4-carboxylic acid, 5alpha-H metabolite of Org 30659, was the major metabolic route in vivo. Other metabolic routes involved the introduction of an OH group at C15beta, followed by a shift of the Delta15-double bond to a 16/17-double bond with subsequent removal of the OH group at C17 and reduction of the 3-keto,Delta4 moiety followed by sulfate conjugation of the 3-OH substituent. These metabolic routes observed in vivo were also major routes in incubations with rat hepatocytes. In rat liver microsomes, Org 30659 was metabolized by reduction of the 3-keto,Delta4 moiety. Rat hepatocyte incubations with Org 30659 were more representative of the in vivo metabolism of Org 30659, compared with rat microsomal incubations. Both in vitro and in vivo, the majority of the metabolites were 3alpha-OH,4,5alpha-dihydro derivatives. In monkeys, Org 30659 was mainly metabolized at the C3- and C17-positions in vivo. The 3-keto moiety was reduced to both 3beta-OH and 3alpha-OH substituents. In addition to phase I metabolites, glucuronic acid conjugates were observed in vivo. In monkey liver microsomes, the 6beta-OH metabolite of Org 30659 was the major metabolite present. Similar to the monkey liver microsomes, rabbit and human liver microsomes converted Org 30659 to the 6beta-OH metabolite. This metabolite was also the major metabolite in incubations with human hepatocytes. 相似文献
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In a very short period of time, the Internet has risen from being viewed as a peculiarity of the defence and academic community of the late sixties to become a significant component of many of our working and home lives. The possible impact of this technology has the futurists talking of the collapse of national borders, the bypass of tax systems and traditional commerce and the emancipation of the individual from the clutches of government, corporations and the boundaries of culture, gender and physical constraints. Most users' experience of the Internet is through browser software and applications such as e-mail, World Wide Web, Newsgroups and media plug-ins. Beneath this glossy, graphical, multimedia world exists the architectural and protocol components which have enabled the Internet evolution to reach into so many parts of everday life in such a short time. The aim of this paper is to outline some of these components, their characteristics and limitations, and their ongoing development to address those limitations and add new capabilities. Even though an overview of Internet protocols is included in this paper, basic knowledge of Internet technology is assumed. 相似文献
266.
CM Meireles J Czelusniak I Sampaio H Schneider SF Ferrari AF Coimbra-Filho A Pissinatti JA Muniz HS Ferreira MP Schneider 《Canadian Metallurgical Quarterly》1998,36(7-8):229-244
Five hundred forty-three blood samples from 15 populations of the four genera of callitrichin primates were studied electrophoretically. Polymorphism and genetic distances were estimated for 20 loci, 13 of which were polymorphic. The lion tamarin (Leontopithecus) studied here exhibited the least variability for these loci, while the monospecific Cebuella showed the most. The genetic distances observed between Callithrix and Cebuella genera support previous evidence indicating a close taxonomic relationship between them. Genetic distance values obtained in this study also support the synonimyzation of the kuhli form with Callithrix jacchus penicillata. 相似文献
267.
SF Slovin HI Scher CR Divgi V Reuter G Sgouros M Moore K Weingard R Pettengall M Imbriaco A El-Shirbiny R Finn J Bronstein C Brett D Milenic A Dnistrian L Shapiro J Schlom SM Larson 《Canadian Metallurgical Quarterly》1998,4(3):643-651
To assess the tumor targeting, safety, and efficacy of monoclonal antibody 131I-labeled CC49 in patients with androgen-independent prostate cancer, 16 patients received 75 mCi/m2 of the radiolabeled antibody after 7 days of IFN-gamma pretreatment. Sequential tumor biopsies in three patients showed a median 5-fold (range, 2-6-fold) increase in the proportion of cells staining positively for the TAG-72 antigen, whereas one showed a decrease in staining. Fourteen patients received 131I-labeled CC49, whereas 2 showed a disease-related decrease in performance status, precluding antibody treatment. The antibody localized to sites of metastatic androgen-independent prostate cancer in 86% (12 of 14; 95% confidence interval, 57-95%) of cases. Both osseous and extraosseous sites were visualized, and in six (42%) patients, more areas were visible when the radioimmunoconjugate was used than were apparent when conventional scanning techniques were used. The localization of the conjugate in the marrow cavity was usually a site not visualized by the radionuclide bone scan, in which the isotope localizes primarily to the tumor-bone interface. The dose-limiting toxicity was thrombocytopenia because five (36%) patients showed grade IV and seven (50%) showed grade III effects. In addition, six (42%) patients, four of whom were hospitalized, showed a flare in baseline pain, and four showed a decrease in pain. No patient showed a >50% decline in prostate-specific antigen, although radionuclide bone scans remained stable in four cases for a median of 4 months. The results are consistent with dosimetry estimates showing that the delivered dose to tumor was subtherapeutic and suggest that approaches that exclusively target the bone tumor interface or the marrow stroma may be unable to completely eradicate disease in the marrow cavity. For CC49, improving outcomes would require repetitive dosing, which was precluded by the rapid development of a human antimouse antibody response. 相似文献
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A Gangjee Y Zhu SF Queener P Francom AD Broom 《Canadian Metallurgical Quarterly》1996,39(9):1836-1845
The synthesis and biological activity of 42 6-substituted-2,4-diaminopyrido[3,2-d]pyrimidines (2,4-diamino-8-deazafolate analogues) are reported. The compounds were synthesized in improved yields compared to previous classical analogues using modifications of procedures reported previously by us. Specifically, the S-phenyl-; mono-, di-, and trimethoxyphenyl-; and mono-, di-, and trichlorophenyl-substituted analogues with H or CH3 at the N10 position and methyl and trifluoromethyl phenyl ketone analogues with H, CH3, and CH2C identical to CH at the N10 position were synthesized. The S10 and N10 alpha- and beta-naphthyl analogues along with the N10 CH3 analogues were also synthesized. These compounds were evaluated as inhibitors of dihydrofolate reductases (DHFR) from Pneumocystis carinii (pc) and Toxoplasma gondii (tg); selectivity ratios were determined against rat liver (rl) DHFR as the mammalian reference enzyme. Against pcDHFR the IC50 values ranged from 0.038 x 10-6 M for 2,4-diamino-6-[(N-methyl-2'-naphthylamino)methyl]pyrido[3,2-d]pyrimidine (28) to 5.5 x 10(-6) M for 2,4-diamino-6[(2',4'-dimethoxyanilino)methyl]pyrido[3,2-d]pyrim idi ne (15). N10 methylation in all instances increased potency. None of the analogues were selective for pcDHFR. Against tgDHFR the most potent analogue was 2,4-diamino-6-[(N-methylanilino)methyl]pyrido[3,2-d]pyrimidine (5) (IC50 0.0084 x 10(-6) M) and the least potent was 2,4-diamino-6[(2'-naphthylamino)methyl]-pyrido[3,2-d]pyrimidine (37) (IC50 0.16 x 10-6 M). N10 methylation afforded an increase in potency up to 10-fold. In contrast to pcDHFR, several of the 8-deaza analogues were significantly selective for tgDHFR, most notably 2,4-diamino-6-[(2'-chloro-N-methylanilino)-methyl]pyrido[3,2-d] pyrimidine (13), 2,4-diamino-6-[(3',4',5'-trimethoxyanilino)methyl]pyrido[3,2-d]pyr pyrimidine (29), and 2,4-diamino-6-[(2',4',6'-trichloroanilino)methyl]pyrido[3,2-d] pyrimidine (32) which combined high potency at 10-8 M along with selectivities of 8.0, 5.0, and 12.4, respectively. The potency of these three analogues are comparable to the clinically used agent trimetrexate while their selectivities for tgDHFR are 17-43-fold better than trimetrexate. 相似文献
270.