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1.
de Jonge ME Huitema AD Holtkamp MJ van Dam SM Beijnen JH Rodenhuis S 《Cancer chemotherapy and pharmacology》2005,56(4):370-378
Background: Patients receiving the highly emetogenic high-dose chemotherapy regimen with cyclophosphamide, thiotepa and carboplatin (CTC) may benefit from the neurokin-1 receptor antagonist aprepitant in addition to standard anti-emetic therapy. As aprepitant has been shown to be a moderate inhibitor of the cytochrome P450 (CYP) 3A4 isoenzyme, its effect on the pharmacokinetics and metabolism of cyclophosphamide and thiotepa was evaluated. Moreover, preliminary results on the clinical efficacy of aprepitant in the CTC regimen are reported. Patients and methods: Six patients were enrolled in a protocol that employed a 4-day course of CTC high-dose chemotherapy with cyclophosphamide (1,500 mg/m2/day), thiotepa (120 mg/m2/day) and carboplatin (AUC 5 mg min/ml/day). Two patients received the tCTC protocol, which comprises two-third of the dose of CTC. In addition to standard anti-emetic therapy, the patients received aprepitant from one day before the start of their course until 3 days after chemotherapy. Blood samples were collected on days one and three of the course and analyzed for cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide, thiotepa and its main active metabolite tepa. The influence of aprepitant on the pharmacokinetics of cyclophosphamide and thiotepa was analyzed using a population pharmacokinetic analysis including a reference population of 49 patients receiving the same chemotherapy regimen without aprepitant and sampled under the same conditions. The frequency of nausea and vomiting in the six patients receiving CTC was compared with those of the last 22 consecutive patients receiving CTC chemotherapy without aprepitant. Inhibitory activity of aprepitant on cyclophosphamide and thiotepa metabolism was also tested in human liver microsomes. Results: In our patient population, the rate of autoinduction of cyclophosphamide (P=0.040) and the formation clearance of tepa (P<0.001) were reduced with 23% and 33% when aprepitant was co-administered, respectively. Exposures to the active metabolite 4-hydroxycyclophosphamide and tepa were therefore reduced (5% and 20%, respectively) in the presence of aprepitant. In human liver microsomes, the 50% inhibitory concentrations (IC50) of aprepitant for inhibition of cyclophosphamide (IC50=1.3 g/ml) and thiotepa (IC50=0.27 g/ml) metabolism were within the therapeutic range. Patients receiving aprepitant experienced less frequently CINV both during and after the CTC course compared with the reference population (nausea 3.7 days vs. 5.8 days, P=0.052; vomiting 0.5 days vs. 4.8 days, P<0.001). Conclusion: Aprepitant inhibited both cyclophosphamide and thiotepa metabolism, most probably due to inhibition of the CYP 3A4 and/or 2B6 isoenzymes. The effects of this interaction are, however, small compared to the total variability. Addition of aprepitant may provide superior protection against vomiting in patients receiving the highly emetogenic high-dose CTC chemotherapy. 相似文献
2.
de Jonge ME Huitema AD van Dam SM Beijnen JH Rodenhuis S 《Cancer chemotherapy and pharmacology》2005,55(5):507-510
Patient and method A 42-year-old male patient with relapsing germ-cell cancer was enrolled in a salvage protocol that employed two 4-day courses of CTC high-dose chemotherapy with cyclophosphamide (1,500 mg m–2 day–1), thiotepa (120 mg m–2 day–1), and carboplatin, followed by peripheral blood progenitor cell support. From five days before the start of the second CTC course the patient received phenytoin for generalized epileptic seizures. Blood samples were collected on day 1 of both CTC courses and analyzed for cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide, and for thiotepa and its main active metabolite tepa.Results Exposure (expressed as area under the plasma concentration vs time curve) to 4-hydroxycyclophosphamide and tepa in the second CTC course was increased by 51% and 115%, respectively, compared with the first CTC course, whereas exposure to cyclophosphamide and thiotepa was significantly reduced (67% and 29%, respectively). Because high exposure to 4-hydroxycyclophosphamide and tepa correlates with increased toxicity, the treatment risk of this patient was significantly increased. Therefore doses were reduced on the third day of the second course.Conclusion It was concluded that phenytoin significantly induces both cyclophosphamide and thiotepa metabolism, most probably by induction of the cytochrome p450 enzyme system. This potential clinical significant interaction should be taken into account when phenytoin is administered in combination with cyclophosphamide and thiotepa in clinical practice. 相似文献
3.
Francesca Patriarca Arianna Masciulli Andrea Bacigalupo Stefania Bregante Chiara Pavoni Maria Chiara Finazzi Alberto Bosi Domenico Russo Franco Narni Giuseppe Messina Emilio Paolo Alessandrino Angelo Michele Carella Giuseppe Milone Benedetto Bruno Sonia Mammoliti Barbara Bruno Renato Fanin Francesca Bonifazi Alessandro Rambaldi 《Biology of blood and marrow transplantation》2019,25(5):932-940
We report a randomized study comparing fludarabine in combination with busulfan (FB) or thiotepa (FT), as conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis. The primary study endpoint was progression-free survival (PFS).Sixty patients were enrolled with a median age of 56 years and an intermediate-2 or high-risk score in 65%, according to the Dynamic International Prognostic Staging System (DIPSS). Donors were HLA-identical sibling (n = 25), matched unrelated (n = 25) or single allele mismatched unrelated (n = 10). With a median follow-up of 22 months (range, 1 to 68 months), outcomes at 2 years after HSCT in the FB arm versus the FT arm were as follows: PFS, 43% versus 55% (P = .28); overall survival (OS), 54% versus 70% (P = .17); relapse/progression, 36% versus 24% (P = .24); nonrelapse mortality (NRM), 21% in both arms (P = .99); and graft failure, 14% versus 10% (P = .96). A better PFS was observed in patients with intermediate-1 DIPSS score (P = .03). Both neutrophil engraftment and platelet engraftment were significantly influenced by previous splenectomy (hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.16 to 4.51; P = .02) and splenomegaly at transplantation (HR, 0.51; 95% CI, 0.27 to 0.94; P = .03). In conclusion, the clinical outcome after HSCT was comparable when using either a busulfan or thiotepa based conditioning regimen. 相似文献
4.
塞替派诱发人支气管上皮细胞恶性转化过程中的基因突变(二) 总被引:2,自引:0,他引:2
目的 观察抗癌药物塞替派诱发永生化人支气管上皮细胞恶性转化过程中相关基因的突变并分析其意义。方法 以塞替派作为致癌原诱导永生化人支气管上皮细胞(BEAS-2B),获得转化细胞(BEAS-TE)和克隆化多倍体癌前转化细胞(BEAS-STE)。采用PCR-SSCP法检测上述3种细胞p53、p16和Ki-ras 3种基因是否出现点突变,进一步测序确定其突变情况。结果 SSCP结果阳性的有BEAS-TE细胞p53第7外显子,BEAS-STE细胞p53第8外显子以及这二种细胞的p16基因第1外显子;Ki-ras基因第1外显子的结果仅为可疑阳性。测序证明,p53、Ki-ras基因存在多位点的碱基突变,而p16基因仅为单位点的碱基突变。结论 塞替哌可诱发人支气管上皮细胞p53、Ki-ras多位点的碱基突变和p16的单位点突变。分析前者为塞替派诱导细胞转化过程中发生的重要分子事件,后者是次要分子事件。 相似文献
5.
Summary The in vitro enhancement of chemotherapeutic efficacy by verapamil, a calcium antagonist, was assessed using FCB, a transplantable murine transitional cell carcinoma. Exponentially growing FCB cells were partially resistant to treatment with both thiotepa (10-4 M) and Adriamycin (10-5M), however, there was a significant reduction in cell growth when either agent was administered in combination with verapamil (10-5 M); the effect was evident over a wide range of drug concentrations (10-4–10-9 M). There was also a pronounced inhibition of DNA precursor incorporation when verapamil was used in combination with either agent. Fluorometric analysis of Adriamycin uptake indicated that verapamil caused an increase in the intracellular concentration of the agent. The data presented are consistent with the postulate that verapamil enhances chemotherapeutic efficacy by altering cellular permeability to the cytotoxic agents. Our study indicates that the use of verapamil in combination with cytotoxic agents for intravesical chemotherapy of bladder tumors may prove to be beneficial in human patients.Supported in part by a grant from the Surgery Research Fund, University of Louisville and Dr. Ballou is a postdoctoral fellow sponsored by the Graduate School, University of Louisville 相似文献
6.
冯勋强 《菏泽医学专科学校学报》2001,13(4):1-2
目的 观察噻替哌和卡介苗化学免疫预防膀胱癌术后复发的疗效。方法 对65例浅表性膀胱癌患术后应用噻替哌40mg和卡介苗60mg,每周1次进行交替膀胱灌注,共灌注12次,以后每间隔3个月灌注1次,持续2年。结果 随访2-9年,平均4.6年,肿瘤复发率为8.1%。结论 噻替哌和卡介苗交替膀胱灌注具有协同治疗,经只应用其中一种可明显减少膀胱癌术后复发率。 相似文献
7.
2周期大剂量化疗联合自体外周血干细胞移植治疗转移性乳腺癌的临床疗效观察 总被引:4,自引:0,他引:4
目的观察2周期大剂量化疗方案联合自体外周血干细胞移植(D—HDC)治疗转移性乳腺癌的疗效及其安全性。方法将28例转移性乳腺癌患者分为2个组。D—HDC组预处理方案:多西紫杉醇(DXL)110~130mg/m^2 噻替哌(THPA)300~400mg/m^2十卡铂(CBP)650~750mg/m^2,预处理后第2天回输外周血干细胞,间隔3~5周重复,共治疗2个周期;S—HDC组预处理方案:DXL110-130mg/m^2 THPA350-450mg/m^2 CBP750-950mg/m^2,预处理后第2天回输外周血干细胞,治疗1个周期。分别评价2组肿瘤客观缓解率和治疗相关的不良反应。结果D-HDC组和S-HDC组的客观缓解率分别为66.7%(10/15),54.5%(6/11);2组白细胞毒性相近,但D-HDC组血小板毒性较低,Ⅲ~Ⅳ度发热,恶心呕吐,腹泻和黏膜炎的发生例数较少。结论D-HDC治疗转移性乳腺癌客观缓解率较高,血小板毒性较轻,Ⅲ~Ⅳ度非血液学毒性发生例数较少,患者耐受性良好。 相似文献
8.
目的观察羊膜移植联合塞替哌应用治疗翼状胬肉的疗效。方法对135例153只眼行胬肉切除,将羊膜移植到胬肉处的巩膜上,术后联合应用1:2000塞替哌治疗。结果术后反应轻,移植片平整,7只眼复发,复发率为3.9%。结论羊膜移植联合塞替哌应用治疗翼状胬肉,是一种简便安全、有效的方法,值得临床推广。 相似文献
10.
Purpose We report a patient with metastatic breast cancer who received three cycles of high-dose chemotherapy with cyclophosphamide
[1,000 mg/(m2 day)], thiotepa (80 mg/(m2 day) and carboplatin (dose calculated based on modified Calvert formula with 3.25 mg min/ml as daily target AUC) over 4 days,
followed by peripheral blood progenitor cell support. During the first two cycles the patient concomitantly used carbamazepine
for the treatment of epilepsy. Due to severe nausea and vomiting the patient was unable to ingest carbamazepine; therefore,
this was discontinued after the second cycle.
Methods Blood samples were drawn on 2 days (day 1 and 2, 3 or 4) of each cycle and plasma levels of cyclophosphamide, its active metabolite
4-hydroxycyclophosphamide, thiotepa, its main, active metabolite tepa and carboplatin were determined.
Results Exposure to 4-hydroxycyclophosphamide and tepa on day 1 was increased in the presence of carbamazepine (58 and 75%, respectively),
while exposure to cyclophosphamide and thiotepa was reduced (40 and 43%, respectively).
Conclusion Since increased exposure to the active metabolites is associated with an increased risk of toxicity, it is important to be
aware of this drug–drug interaction. 相似文献