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Li QZ Cho HS Jeun SH Kim KJ Choi SJ Sung KW 《Biological & pharmaceutical bulletin》2011,34(7):1109-1115
Proanthocyanidin is a phenolic compound present in plants, that has antioxidant, antinociceptive, anti-emetic, and neuroprotective properties. We investigated the actions of proanthocyanidin from grape seeds on 5-hydroxytryptamine (5-HT)(3) receptors in NCB-20 neuroblastoma cells using a whole-cell voltage clamp technique. Co-treatment of proanthocyanidin (0.3-100 μg/ml) and 3 μM 5-HT (near EC(50)) produced a slight inhibition of 5-HT-induced inward peak current (I(5-HT)) in NCB-20 cells, but pretreatment with proanthocyanidin for 30 s before application of 5-HT induced a much larger inhibition of I(5-HT) in an irreversible, concentration- and time-dependent manner (IC(50)=6.5±0.4 μg/ml, Hill coefficient=2.5±0.1). Proanthocyanidin also produced a concentration-dependent inhibition of currents induced by 30 μM 5-HT, near-maximal concentration (IC(50)=22.1±0.4 μg/ml, Hill coefficient=2.4±0.1). High concentrations (≧30 μg/ml) of proanthocyanidin caused a concentration-dependent inhibition of the activation and desensitization of currents induced by 30 μM 5-HT. Further studies showed that pretreatment of 20 μg/ml proanthocyanidin caused not only a rightward shift of the dose-response curve for 5-HT (EC(50) shift from 2.7±0.4 to 6.2±0.5 μM), but also a decreased E(max) (inhibition by 37.5±1.3%). The proanthocyanidin-induced inhibition of 5-HT(3) receptors did not show a significant difference within the testing holding potential ranges (-50-+30 mV). These results suggest that proanthocyanidin inhibits 5-HT(3) receptor function in NCB-20 cells in a noncompetitive mode, and that this inhibitory effect of proanthocyanidin probably contributes to the pharmacological actions of proanthocyanidin. 相似文献
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Jeong Hyehyun Hong Yong Sang Kim Jeong Eun Lim Hyeong-Seok Ahn Joong Bae Shin Sang Joon Park Young Suk Kim Seung Tae Han Sae-Won Kim Tae-You Kim Tae Won 《Investigational new drugs》2021,39(5):1335-1347
Investigational New Drugs - Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an... 相似文献
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Sangmin Choe Gayeong Kim Hyeong-Seok Lim Sang-Heon Cho Jong-Lyul Ghim Jin Ah Jung Un-Jib Kim Gyujeong Noh Kyun-Seop Bae Dongho Lee 《The Korean journal of physiology & pharmacology》2012,16(4):273-280
Busulfan is an antineoplastic agent with a narrow therapeutic window. A post-hoc population pharmacokinetic analysis of a prospective randomized trial for comparison of four-times daily versus once-daily intravenous busulfan was carried out to search for predictive factors of intravenous busulfan (iBu) pharmacokinetics (PK). In this study the population PK of iBu was characterized to provide suitable dosing recommendations. Patients were randomized to receive iBu, either as 0.8 mg/kg every 6 h or 3.2 mg/kg daily over 4 days prior to hematopoietic stem cell transplantation. In total, 295 busulfan concentrations were analyzed with NONMEM. Actual body weight and sex were significant covariates affecting the PK of iBu. Sixty patients were included in the study (all Korean; 23 women, 37 men; mean [SD] age, 36.5 [10.9] years; weight, 66.5 [11.3] kg). Population estimates for a typical patient weighing 65 kg were: clearance (CL) 7.6 l/h and volume of distribution (Vd) 32.2 l for men and 29.1 L for women. Inter-individual random variabilities of CL and Vd were 16% and 9%. Based on a CL estimate from the final PK model, a simple dosage scheme to achieve the target AUC0-inf (defined as median AUC0-inf with a once-daily dosage) of 26.18 mg/l·hr, was proposed: 24.79·ABW0.5 mg q24h, where ABW represents the actual body weight in kilograms. The dosing scheme reduced the unexplained interindividual variabilities of CL and Vd of iBu with ABW being a significant covariate affecting clearance of iBU. We propose a new simple dosing scheme for iBu based only on ABW. 相似文献
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BACKGROUND: The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (-24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival. RESULTS: Among 8 polymorphisms, 3435TT and 2677TT were associated with AUC(SN-38G) and CL(SN-38G). When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUC(SN-38G) (P = .006), whereas 2677GG/3435CC carriers showed significantly higher AUC(SN-38) (P = .039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1(st) cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 -24TT and 3972TT genotypes were associated with higher response rates (P = .031 and .046, respectively) and longer progression-free survival (P = .035 and .038, respectively), which was sustained in haplotype analysis. CONCLUSIONS: Specific polymorphisms of ABCB1 and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan-based chemotherapy in patients with advanced NSCLC. 相似文献
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Hee Youn Choi Yo Han Kim Mi Jo Kim Shi Hyang Lee Keunsu Bang Song Han Hyeong-Seok Lim Kyun-Seop Bae 《Drugs in R&D》2014,14(3):165-176
Purpose
Gemigliptin is approved for the treatment of type II diabetes mellitus. Sulfonylureas are commonly used in combination with other antidiabetic drugs to improve glycemic control. The objective of this study was to evaluate the pharmacokinetics, safety, and tolerability of gemigliptin and glimepiride combination therapy compared with those of monotherapies.Methods
A randomized, open-label, crossover study was performed on healthy Korean male volunteers. Each subject received the following treatments (A and B) with a 7-day washout period: treatment A consisted of gemigliptin 50 mg once daily administered orally for 6 days, followed by concomitant oral dosing of glimepiride 4 mg and gemigliptin 50 mg on day 7; treatment B consisted of a single dose of glimepiride 4 mg. Blood samples were collected up to 24-h postdose on day 6 (gemigliptin) and day 7 (gemigliptin and glimepiride) following treatment A, and on day 1 (glimepiride) following treatment B. Concentrations of gemigliptin, glimepiride, and metabolites were determined using validated liquid chromatography–tandem mass spectrometry (LC–MS/MS). Safety assessments were performed throughout the study.Results
Twenty-three subjects completed the study. The geometric mean ratios (GMRs) of Cmax,ss and AUCτ,ss for gemigliptin were 1.0097 [90 % confidence interval (CI) 0.924–1.103] and 0.9997 (90 % CI 0.976–1.024), respectively. For glimepiride, the GMRs of Cmax and AUClast were 1.031 (90 % CI 0.908–1.172) and 0.995 (90 % CI 0.902–1.097), respectively. Both combination and monotherapy were well tolerated, and no serious adverse events were reported.Conclusion
Gemigliptin and glimepiride did not alter the pharmacokinetic properties of each other when they were co-administered in healthy volunteers, and were generally tolerated. 相似文献30.
Seok-Joon Jin Kyun-Seop Bae Sang-Heon Cho Jin-Ah Jung Unjib Kim Sangmin Choe Jong-Lyul Ghim Yook-Hwan Noh Hyun-Jung Park Hee-sun Kim Hyeong-Seok Lim 《Pharmaceutical research》2014,31(7):1801-1812