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21.
Lowe G Droz AS Vilaivan T Weaver GW Tweedale L Pratt JM Rock P Yardley V Croft SL 《Journal of medicinal chemistry》1999,42(6):999-1006
A range of (2,2':6',2'-terpyridine)platinum(II) complexes are shown to possess antiprotozoal activity in vitro against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei,the causative organisms of tropical diseases leishmaniasis and trypanosomiasis. The best compounds caused 100% and 78% inhibition of growth of the intracellular amastigote forms of L. donovani and T. cruzi, respectively, at a concentration of 1 microM and 100% inhibition of growth of the bloodstream trypomastigote forms of T. brucei at a concentration of 0.03 microM. The results obtained with complexes in which the fourth ligand to platinum(II) is capable of being substituted with a substitution inert hydroxyethanethiolate complex are compared. The ammine complexes show high antiprotozoal activity suggesting that the trans influence of the 2,2':6',2'-terpyridine ligand has a profound effect on the ease of displacement of the fourth ligand in (2,2':6',2' -terpyridine)platinum(II) complexes, although nonbonded interaction between the ammine ligand and the 6 and 6' ' hydrogens probably also weakens the ligation to Pt(II). 相似文献
22.
Z L Zhou S X Cai E R Whittemore C S Konkoy S A Espitia M Tran D M Rock L L Coughenour J E Hawkinson P A Boxer C F Bigge L D Wise E Weber R M Woodward J F Keana 《Journal of medicinal chemistry》1999,42(15):2993-3000
A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)-4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC(50) = 0.63 microM). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for alpha(1)-adrenergic receptors and inhibition of neuronal K(+) channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a approximately 25-fold increase in NR1A/2B potency (IC(50) = 0.025 microM). p-Methyl substitution on the benzyl ring (10b) produced a approximately 3-fold increase in MES activity (ED(50) = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for alpha(1) receptors and reduction in inhibition of K(+) channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperid ine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation. 相似文献
23.
Dichloromethane extracts of the root bark and stem bark of Kigelia pinnata collected from Zimbabwe exhibited antitrypanosomal activity against Trypanosoma brucei brucei in vitro. Activity-guided fractionation led to the isolation of four naphthoquinones from both the root and stem bark of the plant. The compounds were identified as 2-(1-hydroxyethyl)-naphtho[2,3-b]furan-4,9-quinone (1), isopinnatal (2), kigelinol (3), and isokigelinol (4). Subsequently, the compounds were assessed for antitrypanosomal activity against T. brucei brucei and T. brucei rhodesiense bloodstream form trypomastigotes in vitro. Compound 1 with a furanonaphthoquinone structure was found to possess pronounced activity against both parasites with IC50 values of 0.12 and 0.045 microM, respectively, although it was less active than the standard drug pentamidine. Compounds 2, 3, and 4 also exhibited activity against the parasites, although to a lesser extent. The activities of the compounds were further assessed by comparison with the cytotoxic activities obtained against KB cell lines. 相似文献
24.
Cerebrospinal fluid (CSF) leaks can be responsible for significant patient morbidity and mortality. While the majority of leaks induced after head trauma will seal without intervention, spontaneous or surgically-induced leaks often require operative repair. Many modifications on standard surgical technique are available for repair of CSF fistulae, but none assures adequate closure. We have studied the efficacy of a novel fibrin-based composite tissue adhesive (CTA) for closure of experimentally-induced CSF leaks in rats. Fistulae were created in two groups of animals. Two weeks after creation of the leaks, the animals were sacrificed and analyzed for persistence of leak. A 58% leakage rate was noted in the control group (n = 12), and no leaks were noted in the experimental group closed after application of CTA to the surgical defect followed by skin closure (n = 11). Comparing the control group to the experimental group, results were statistically significant (p = 0.015). These data suggest that CTA may be effective as an adjunct for the closure of CSF fistulae. 相似文献
25.
B S Hurst B L Tjaden A Kimball W D Schlaff M D Damewood J A Rock 《The Journal of reproductive medicine》1992,37(3):237-241
Patients undergoing human menopausal gonadotropin (hMG) superovulation were reviewed retrospectively to determine whether fecundity was greater for intrauterine insemination (IUI) than timed intercourse. Forty patients with unexplained infertility, American Fertility Society I or II endometriosis, luteal phase defect and/or cervical factor were treated with hMG alone or hMG plus IUI. Twenty-eight underwent 52 cycles of hMG/IUI, and 19 underwent 31 cycles of hMG. The probability of pregnancy after four cycles was significantly better in the hMG/IUI group (.90) than the hMG group (.37, P = .049). There was a 54.5% multiple pregnancy rate, and one patient was admitted to the hospital for hyperstimulation. When traditional therapy fails, hMG/IUI significantly increases the pregnancy rates as compared to hMG with timed intercourse in a "good prognosis" group of patients. 相似文献
26.
27.
Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. 总被引:8,自引:0,他引:8
M S Czuczman A Koryzna A Mohr C Stewart K Donohue L Blumenson Z P Bernstein P McCarthy A Alam F Hernandez-Ilizaliturri M Skipper K Brown A Chanan-Khan D Klippenstein P Loud M K Rock M Benyunes A Grillo-Lopez S H Bernstein 《Journal of clinical oncology》2005,23(4):694-704
PURPOSE: To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naive or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS: This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. RESULTS: An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naive and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. CONCLUSION: Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma. 相似文献
28.
Complete uterine prolapse was noted shortly after birth in a female infant with a meningomyelocele at the level of the iliac crest with a palpable dimpled defect caudal to the primary lesion. The vagina and uterus were restored to their normal position with a rubber nipple placed into the vagina. The prolapse resolved on the sixth day of life after a repair of the meningomyelocele. Thus, conservative therapy with temporary support provides a satisfactory solution for newborn procidentia. 相似文献
29.
Beta‐2 transferrin is detectable for 14 days whether refrigerated or stored at room temperature 下载免费PDF全文
Thomas M. Zervos MD Mohamed Macki MD Bernard Cook PhD Lonnie R. Schultz PhD Jack P. Rock MD John R. Craig MD 《International forum of allergy & rhinology》2018,8(9):1052-1055