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991.
The phosphate ester, BMS-292655, was developed as a water-soluble prodrug of the antifungal agent, ravuconazole (BMS-207147). BMS-292655 was comparatively stable in rat, beagle dog, cynomolgus monkey and human plasma, but was hydrolysed upon incubation with liver S9 preparations from all species. The major product in rat, monkey and human S9 was BMS-207147, while in dog S9, the intermediate ester, BMS-300043, predominated. BMS-300043 itself was more stable in dog S9 than in S9 preparations from the other species. Intravenous administration of BMS-292655 to rats, beagle dogs and cynomolgus monkeys indicated species differences in the extent of formation of BMS-207147 (monkeys>rats>dogs). The lower overall generation of BMS-207147 in dogs was consistent with the presence of circulating plasma levels of BMS-300043. BMS-300043 was present in monkey plasma but not detectable in rat plasma. The conversion of BMS-292655 to BMS-207147 in the presence of human S9 indicated the potential for BMS-292655 to function as a BMS-207147 prodrug in humans. The similarity in the hydrolysis of BMS-292655 when incubated with human and monkey S9 in vitro, coupled with the effective release of BMS-207147 from BMS-292655 upon i.v. administration to monkeys, is consistent with this conclusion. 相似文献
992.
Delayed emotional recovery after taxane-based chemotherapy 总被引:1,自引:0,他引:1
BACKGROUND: There are few patient-reported data regarding quality of life after taxane-based adjuvant chemotherapy and none regarding mental health outcomes. METHODS: This was a naturalistic, longitudinal study that used a case-control design. Data were derived from a randomized clinical trial in patients who had stage II/III breast cancer (N = 227). Paclitaxel (Taxol) was approved for use midway during the accrual period (1994-1999). Patients who received taxanes as part of their adjuvant chemotherapy (the taxane group; n = 55) were matched with patients receiving regimens without taxanes (the no-taxane group; n = 83) on trial arm, lymph node status, surgery type, menopausal status, and partner status. Mixed-effects models tested for group differences in nurse evaluations of patients' symptoms and Karnofsky performance status and in patient-reported quality of life (the 36-item Medical Outcomes Study Short Form) and emotional distress (Profile of Mood States; Center for Epidemiological Studies Depression scale). RESULTS: As expected, patients in the taxane group experienced significantly higher rates of selected toxicities, including arthralgia/myalgia (45% vs 26%) and ataxia (20% vs 5%). Patients in the taxane group also had significantly worse emotional distress and mental quality of life throughout adjuvant treatment. Rates of probable clinical depression also were high. In contrast, these outcomes were improving for patients in the no-taxane group (all P < .023). Emotional recovery for patients in the taxane group required 2 years on average versus 6 to 12 months for patients in the no-taxane group. During Years 3 through 5, the groups had similar outcomes. CONCLUSIONS: These data suggested that taxane-based chemotherapies confer risk for significant psychological symptoms. Depression, in particular, should be monitored. 相似文献
993.
Ramalingam S Perry MC La Rocca RV Rinaldi D Gable PS Tester WJ Belani CP 《Cancer》2008,113(3):542-546
BACKGROUND: The purpose of this study was to compare the outcomes between elderly (aged > or = 70 years) patients treated with paclitaxel on a weekly basis and with carboplatin (every 4 weeks) versus the standard 3-weekly regimen of carboplatin and paclitaxel for first-line therapy of advanced nonsmall cell lung cancer. METHODS: Of the 444 patients enrolled, 136 (31%) were aged > or = 70 years. Seventy-two patients were randomized to the weekly schedule (paclitaxel, 100 mg/m(2) weekly for 3 of 4 weeks; carboplatin, area under the curve [AUC] = 6 mg/mL.min on Day 1 every 4 weeks), and 64 patients were randomized to the standard schedule (paclitaxel, 225 mg/m(2); carboplatin, AUC = 6 mg/mL.min on Day 1 every 21 days). Patients with stable disease or objective response after 4 cycles of therapy were eligible for maintenance therapy with weekly paclitaxel (70 mg/m(2), 3 of 4 weeks). RESULTS: The response rate for elderly patients was 26% on the weekly regimen and 19% on the standard schedule. The median survival duration for the weekly and the standard schedules was 37 weeks and 31 weeks, respectively. The 1-year survival rates were similar at 31% and 33%. Grade 3 to 4 anemia was more common on the weekly schedule (16% vs 6%), whereas grade 3 neuropathy was less common (5.5% vs 9.5%). Nausea and emesis were also less frequent on the weekly schedule. CONCLUSIONS: Efficacy was similar between the weekly regimen and the standard regimen of carboplatin and paclitaxel for elderly patients with advanced NSCLC and may be advantageous based on its favorable tolerability profile. 相似文献
994.
995.
Okuda K Hirose T Ishida H Kusumoto S Sugiyama T Ando K Shirai T Ohnishi T Horichi N Ohmori T Adachi M 《Cancer chemotherapy and pharmacology》2008,61(5):829-835
Purpose This trial was conducted to determine the maximum tolerated dose (MTD), principal toxicity, and recommended dose for phase
II study of the combination of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer (NSCLC).
Methods Patients with previously untreated NSCLC, either stage IIIB with pleural effusion or stage IV, were eligible if they had a
performance status of 0–2, were 75 years or younger, and had adequate organ function. The respective doses of nedaplatin (day
1) and weekly paclitaxel (days 1, 8, and 15) studied were 80/60, 80/70, 80/80, 80/90, and 100/90 (mg m−2), repeated every 4 weeks.
Results From May 2004 through June 2005, 21 patients (18 men and 3 women; median age, 63 years; age range, 53–75 years) were enrolled.
The MTD was determined to be 100 mg m−2 of nedaplatin and 90 mg m−2 of weekly paclitaxel. Dose-limiting toxicities at the MTD were neutropenic fever and hepatic dysfunction. We recommend doses
of 80 mg m−2 of nedaplatin and 90 mg m−2 of weekly paclitaxel for phase II study. Grade 3–4 hematologic toxicities included neutropenia in 29% of patients, thrombocytopenia
in 0%, and anemia in 5%. Although the most frequent non-hematologic toxicity was hepatic dysfunction, all cases were only
mildly to moderately severe. Although two patients had grade 3 or 4 pulmonary toxicity due to Pneumocystis carinii pneumonia, these patients recovered after receiving trimetoprim-sulfamethoxazole, steroid therapy, and supplemental oxygen.
There were no treatment-related deaths. The overall response rate was 19.0% (95% confidence interval, 5.4–41.9%), and all
responses were in patients receiving the recommended doses. The median dose-intensities for nedaplatin and paclitaxel were
91.6 and 87.1%, respectively, of the planned doses.
Conclusion This combination chemotherapy is active and well tolerated and warrants phase II study. 相似文献
996.
Tangjitgamol S Manusirivithaya S Choomchuay N Leelahakorn S Thawaramara T Pataradool K Suekwatana P 《The journal of obstetrics and gynaecology research》2007,33(2):218-224
The prognosis of large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is generally poor despite multimodality of treatments. We report a case of advanced stage cervical LCNEC that showed definite response to paclitaxel/carboplatin, resulting in years of survival. The patient was referred to our institution after undergoing a simple hysterectomy with bilateral salpingo-oophorectomy in her local hospital because of a ruptured metastatic ovarian mass. She declined pelvic radiation treatment, so adjuvant chemotherapy (six cycles of paclitaxel/carboplatin) was given for the residual pelvic nodal diseases. Clinical complete remission was obtained, with a disease-free period of 19 months. Systemic recurrent diseases also showed partial response to the same drug regimen for months with only minimal toxicity. However, she subsequently had progressive diseases in the liver and brain and finally died at 44 months after primary diagnosis and 19 months after recurrent diseases. 相似文献
997.
Ross J. Baldessarini Aubrey E. Boyd Nora S. Kula Robert J. Borgman 《Psychoneuroendocrinology》1979,4(2):173-175
(1) An O,O′-diester of apomorphine mimicked the prolactin-lowering action of apomorphine in the estrogen-primed male rat. (2) Its effects were somewhat slower in onset, but much longer-lasting than those of apomorphine. (3) These effects closely parallel previously observed long-lasting behavioral effects in rodents following the administration of apomorphine esters. (4) We believe these effects are mediated by central dopaminergic actions of apomorphine slowly liberated from these ester “prodrugs” by esterase hydrolysis. 相似文献
998.
Maryanoff BE McComsey DF Costanzo MJ Yabut SC Lu T Player MR Giardino EC Damiano BP 《Chemical biology & drug design》2006,68(1):29-36
Compound 2 (RWJ-445167; 3DP-10017), a dual inhibitor of thrombin and factor Xa, was advanced into human clinical studies. However, its oral bioavailability in humans proved to be below acceptable limits. To address this issue, we explored a prodrug approach involving numerous guanidine derivatives. Prodrug candidates of classes A (carbamate derivatives), B (imidate derivatives), and C (alkyl and acyl derivatives), compounds 3-6, were synthesized and evaluated for anticoagulant activity at 2 h after oral administration to rats. In comparison to the parent drug (2), little worthwhile improvement was observed for the prodrug candidates. 相似文献
999.
Takano M Kikuchi Y Yaegashi N Kuzuya K Ueki M Tsuda H Suzuki M Kigawa J Takeuchi S Tsuda H Moriya T Sugiyama T 《British journal of cancer》2006,94(10):1369-1374
A retrospective analysis was performed to evaluate the clinical characteristics and prognostic factors in the patients with clear cell carcinoma (CCC) of the ovary. After central pathological review and scanning of the medical records of nine Japanese institutions between 1992 and 2003, a total of 254 patients with CCC of the ovary were enrolled in the present study. Mean age was 52.4 years (range 23-73 years). Tumours were 13% (33/254) stage Ia, 36% (92/254) stage Ic, 13% (33/254) stage II, 30% (80/254) stage III, and 6% (16/254) stage IV. Five-year progression-free survival and overall survival was 84 and 88% in stage I, 57 and 70% in stage II, 25 and 33% in stage III and 0 and 0% in stage IV, respectively. Retroperitoneal lymph node metastasis was observed in 9% in pT1a tumours, 7% in pT1c tumours, 13% in pT2 tumours, and 58% in pT3 tumours, respectively. There was no survival benefit according to chemotherapeutic differences in the patients who received complete surgical staging procedures and conventional chemotherapy. Peritoneal cytological status was an independent prognostic factor in stage Ic patients (P=0.03) and only residual tumour diameter was an independent prognostic factor in stage III, IV patients (P=0.02). Our results suggest that cytoreductive surgery resulting in no residual tumour only could improve the prognosis of advanced CCC patients. 相似文献
1000.
Mochiki E Ohno T Kamiyama Y Aihara R Haga N Ojima H Nakamura J Ohsawa H Nakabayashi T Takeuchi K Asao T Kuwano H;North Kanto Gastric Cancer Study Group 《British journal of cancer》2006,95(12):1642-1647
Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m-2 day-1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m-2 day-1. The dose was increased in a stepwise manner to 70 mg m-2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m-2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m-2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1-17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer. 相似文献