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911.
Qiang Zhang Peng Ma Weiqun Wang Richard B Cole Guangdi Wang 《Drug metabolism and disposition》2005,33(4):508-517
Diarylpyrazoles are a group of 1,5-diphenylpyrazole analogs of which several have been found to exhibit antagonist properties toward the cannabinoid receptors. SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], the first reported antagonist, is a highly potent and selective CB1 receptor ligand that prevents or reverses CB1-mediated effects. Other analogs, such as AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] and AM281 [1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide], have also shown high binding affinities to the central cannabinoid receptor and behave as antagonists/inverse agonists. There has been no report on the metabolism of any of the diarylpyrazoles, and it is unknown whether their metabolites retain any receptor binding properties. We report a study of the in vitro metabolisms of three diarylpyrazole analogs, SR141716A, AM251, and AM281, in rat liver microsomes. The metabolic profile was obtained using high-performance liquid chromatography with UV and mass spectrometry detectors. All identified metabolites are characterized by structural modifications on the terminal group of the 3-substituent. Thus, three pairs of isomeric metabolites were identified from the microsomal incubation of SR141716A; these metabolites are products of hydroxylation, hydroxylation followed by dehydration, and a combination of the two. For AM251, only four metabolic products were detected, with two resulting from monohydroxylation of the piperidine ring and the other two being products of dehydration of the first pair of metabolites. For AM281, in which the terminal group of the 3-substituent is a morpholine ring, dehydration of the first two metabolites yielded a single third metabolite due to only one possible position for the carbon-carbon double bond on the morpholinyl ring. 相似文献
912.
913.
灯盏花素在家犬与家兔体内的药代动力学研究 总被引:5,自引:0,他引:5
目的:研究灯盏花素在家犬与家兔体内的药代动力学.方法:采用液-液萃取法制备血样供试品,HPLC法测定.结果:灯盏花素在家犬体内的过程符合双室模型,主要药动学参数为:A=56.93±23.14,B=1.61±1.11,α=0.2328±0.1321min-,β=0.0255±0.0187min-,T1/2α=2.98±1.42min,T1/2β=27.14±14.35min,K21=0.0312±0.0112min-,K10=0.1904±0.1319min-,K12=0.0367±0.0306min-1,CL=39.41±20.44ml·min-,AUC=3074±1055mg·min·L-;灯盏花素在家兔体内的过程符合双室模型,主要药动学参数为:A=2.64±1.12,B=0.28±0.12,α=0.1439±0.0681min-,β=0.0162±0.0456min-,t1/2α=4.82±1.65min,t1/2β=42.66±18.77min,K21=0.0285±0.0147min-,K10=0.0820±0.00378min-,K12=0.0496±0.0241min-,CL=337.05±156.48ml·min-1,AUC=356±114mg·min·L-1.结论:灯盏花素在家犬与家兔体内半衰期很短,其作用时间短,消除速度快. 相似文献
915.
916.
RAS mutation is associated with hyperdiploidy and parental characteristics in pediatric acute lymphoblastic leukemia. 总被引:1,自引:0,他引:1
J L Wiemels Y Zhang J Chang S Zheng C Metayer L Zhang M T Smith X Ma S Selvin P A Buffler J K Wiencke 《Leukemia》2005,19(3):415-419
We explored the relationship of RAS gene mutations with epidemiologic and cytogenetic factors in a case series of children with leukemia. Diagnostic bone marrow samples from 191 incident leukemia cases from the Northern California Childhood Leukemia Study were typed for NRAS and KRAS codon 12 and 13 mutations. A total of 38 cases (20%) harbored RAS mutations. Among the 142 B-cell acute lymphoblastic leukemia (ALL) cases, RAS mutations were more common among Hispanic children (P=0.11) or children born to mothers <30 years (P=0.007). Those with hyperdiploidy at diagnosis (>50 chromosomes) had the highest rates of RAS mutation (P=0.02). A multivariable model confirmed the significant associations between RAS mutation and both maternal age and hyperdiploidy. Interestingly, smoking of the father in the 3 months prior to pregnancy was reported less frequently among hyperdiploid leukemia patients than among those without hyperdiploidy (P=0.02). The data suggest that RAS and high hyperdiploidy may be cooperative genetic events to produce the leukemia subtype; and furthermore, that maternal age and paternal preconception smoking or other factors associated with these parameters are critical in the etiology of subtypes of childhood leukemia. 相似文献
917.
918.
Randomized phase II trial of three schedules of pemetrexed and gemcitabine as front-line therapy for advanced non-small-cell lung cancer. 总被引:1,自引:0,他引:1
Cynthia X Ma Suresh Nair Sachdev Thomas Sumithra J Mandrekar Daniel A Nikcevich Kendrith M Rowland Tom R Fitch Harold E Windschitl Shauna L Hillman Steven E Schild James R Jett Coleman Obasaju Alex A Adjei 《Journal of clinical oncology》2005,23(25):5929-5937
PURPOSE: A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-na?ve patients with non-small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned to three schedules of pemetrexed 500 mg/m2 plus gemcitabine 1,250 mg/m2, separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8. RESULTS: One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms. CONCLUSION: Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated. 相似文献
919.
Sonia Maciá Escalante Carmen Guillén Ponce Ma José Molina Garrido Ma José Martínez Ortiz Inmaculada Ballester Navarro Alfredo Carrato Mena 《Clinical & translational oncology》2005,7(9):414-416
Prognosis in prostate cancer is determined, in greater part, by the presence of metastases. Bone metastases can occur in any part of the skeleton even, for example, at the base of the skull. We present a case of a 78 year old male who, in December 2001, presented with paralysis of the third cranial nerve. The NMR and CAT scans were normal and circulating levels of PSA were elevated. He was referred to the Urology Service where the treatment guidelines included complete androgen block. Subsequently, he developed retro-orbital pain, divergent strabismus and palpebral ptosis. CAT and NMR indicated a soft tissue mass at the sphenoid level. Treatment was Gamma Knife Radio-surgery. Since August 2004, in conjunction with the latest rise in PSA, the patient's general status deteriorated considerably and he was referred to the Oncology Service. there was an increase in the paralysis of the third, fourth and sixth cranial nerve (complete left ophthalmoplegia) and left-central facial paralysis. Metastases from prostate cancer can be disseminated via the lymphatic or the blood system. Currently, there are more metastases from large-size tumours. Metastases are critical in prostate cancer because of their adverse effect on the patient's survival. Measurements of circulating levels of prostate specific antigen and prostate acid phosphatase are very useful in the clinical diagnosis of the primary tumour, or its metastases. 相似文献
920.
OBJECTIVE To investigate the therapeutic potential of amphiregulin antisense RNA delivered by adenoviral vector in a human breast cancer model.METHODS Human amphiregulin cDNA was subcloned in the opposite orientation to the cytomegaloviral promoter and inserted into an E1/E3-deleted type 5 adenoviral vector to obtain an AdA4 construct which expresses amphiregulin antisense mRNA. Both in vitro and in vivo antiproliferative effects of the antisense RNA were studied by infecting transformed human breast epithelial NS2T2A1 cells and tumors.RESULTS Amphiregulin protein expression was inhibited dramatically in the NS2T2A1 cells after infection with AdA4. The in vitro cell growth was inhibited significantly at day 4 post-AdA4 infection compared with control empty virus AdC1 at a MOl of 200 and 400 pfu/cell to 69.3% and 49.8%, respectively (P<0.02, P<0.005). After 3 intra-tumoral injections of 109 pfu AdA4, tumor volumes were reduced to 40.6% of that of the control group at day 35 (P<0.005).CONCLUSION The transfer of amphiregulin RNA antisense by adenoviral vector is effective for amphiregulin targeting strategy, leading to an inhibition of in vitro cell proliferation and in vivo tumor growth in this breast cancer model. 相似文献