Phase I trial of Idarubicin (4-demethoxydaunorubicin) in adult acute leukemia

Summary Idarubicin (IDR) is a new analog of Daunorubicin (DNR) selected for clinical trials because of its outstanding activity in experimental leukemias of mice and in several experimental models when compared to DNR and Doxorubicin. This Phase I trial was designed to determine the maximal tolerated dose in adult patients with acute leukemia refractory to prior treatment, using intravenously (I.V.) daily treatments for 5 consecutive days.Eleven patients were entered in this study. The initial dose of IDR was 4 mg/m²/d × 5 I.V. The highest dose given was 8 mg/m²/d × 5 I.V. Dose limiting toxicity were gastrointestinal side effects at the 8 mg/m²/d × 5 level (mucositis-diarrhea). Antileukemic activity has been detected in acute non-lymphoblastic leukemia not pretreated with anthracyclines. For Phase II adult leukemia studies using this schedule, it is recommended that the IDR dose should be 7 mg/m²/d.     

伊达比星(4-去甲氧基柔红霉素)的结构研究Ⅰ.1H-NMR和13C-NMR的分析

伊达比星为新一代蒽环类抗肿瘤药物,目前国内已试制成功.我们对该品进行了1H-NMR、1H-1HCOSY、重水交换、13C-NMR、DEPT90°、DEPT135°、HMBC、HMQC和NOSEY的测试,最终确定其构型为α型,并对所有的1H和13C信号进行了归属.     

Phase I trial of 4-demethoxydaunorubicin (idarubicin) with single oral doses

Summary Twenty-four patients with a variety of solid tumors entered a Phase I trial with 4-demethoxydaunorubicin, a new analogue of daunorubicin. The drug was given as a single oral dose of 10–60 mg/m² repeated every 3–4 weeks.Leukopenia was the dose-limiting toxicity. Other toxic effects included mild to moderate nausea and vomiting. Sixty mg/m² was found to be the maximum tolerated dose in patients with fair tolerance to chemotherapy and normal liver function. Similar hematologic toxicity was reported in patients with very extensive prior chemotherapy or diffuse bone and/or liver metastases receiving 50 mg/m². However, the wide range of the WBC nadirs reported with the same dose in good risk cases, suggest that 40 mg/m², increased up to 50 mg/m² in the absence of significant myelotoxicity, could be more safely proposed as starting dose for Phase II trials. Pharmacokinetic studies were performed in five patients given a single dose of 40–60 mg/m². IMI-30 (NSC 256439) appears to be rapidly absorbed and rapidly eliminated from plasma by means of a rapid and extensive biotransformation to 13-OH-idarubicin. The 13-dihydroderivative was present at higher and more prolonged levels than the parent compound, with an elimination half-life of about 40 hours.Presented in part at the Third NCI-EORTC Symposium on New Drugs in Cancer Therapy, Brussels, October 13–17, 1981.     

Oral 4-demethoxydaunorubicin (idarubicin) in bronchogenic lung cancer; Phase II trial

Eighteen patients with non-small cell lung cancer were entered into a phase II protocol of oral 4-demethoxy-daunorubicin. All were evaluable for toxicity and 17 for response. The major toxicity was hematologic with eight patients developing an ECOG grade 3 or 4 toxicity. There were no responses to the treatment.     

Phase I study of 4-demethoxydaunorubicin

4-demethoxydaunorubicin (4-dm DNR), a new analog of daunorubicin, was tested at an every 3-week dose schedule in 63 evaluable patients with various forms of disseminated malignancy. Utilizing the intravenous (i.v.) route of administration, the maximum tolerated dose (MTD) was 15-18 mg/m2; with the oral route the MTD was 60 mg/m2. Myelosuppression represented the dose-limiting factor, and leukopenia was more often observed than thrombocytopenia. However, leukopenia was more frequently detected following i.v. administration while vomiting represented the most frequent toxic sign after oral administration. Loss of hair was moderate with either route of administration and comparatively less frequent and pronounced than that observed after doxorubicin (DX) and its analog 4'-epi-doxorubicin (4'-epi-DX). Aside from transient aspecific electrocardiographic changes recorded in 30% of patients, no cardiac toxicity was documented. Tumor response was documented in seven patients with malignant lymphomas, breast cancer, melanoma and carcinoma of uterine cervix. Two out of the seven responders achieved prolonged complete remission and four were resistant to doxorubicin. 4-dm DNR appears to be an analog worth further clinical trials.     

Phase-I trial of 4-demethoxydaunorubicin in acute leukaemias

Summary Eleven patients with heavily pretreated acute leukaemia were treated with 4-demethoxydaunorubicin. Dosages were escalated from 7 mg/m²/d to 15 mg/m²/d for 3 consecutive days. One patient achieved a partial remission and antitumor activity was seen in most other patients. Stomatitis was dose-limiting at 15 mg/m². Phase II trials are warranted and we propose a schedule of 12 mg/m²/d for 3 consecutive days.     

Toxicological studies with a novel synthetic anthracycline, the bis-hydrazone bridged analog of 4-demethoxydaunorubicin (SC-33428)

The toxicological effects of SC-33428, a bis-hydrazone bridged analog of 4-demethoxydaunorubicin were evaluated in rats. The bone marrow depressant effects were more pronounced than those caused by equal doses of doxorubicin, but the cardiotoxic and the nephrotoxic effects were clearly less marked. The concentrations of SC-33428 in serum, heart and kidneys after single and repeated i.p. injections were considerably lower than those reached with doxorubicin. Since the drug is at least as active as doxorubicin in various tumor models, it is likely that it will distinguish itself in the clinic by a broader margin of safety.     

Oral Idarubicin

Drugs & Aging - Idarubicin is an anthracycline agent available as both oral and intravenous formulations. The oral formulation has demonstrated efficacy in the treatment of advanced breast...     

Pharmacokinetics of idarubicin (4-demethoxydaunorubicin; IMI-30; NSC 256439) following intravenous and oral administration in patients with advanced cancer.

The plasma pharmacokinetics of idarubicin (4-demethoxydaunorubicin) were studied in 20 patients with advanced malignant disease after intravenous (21 occasions) and oral (14 occasions) administration. Idarubicin plasma concentrations were measured by high performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters calculated for the intravenous plasma drug concentration, time data revealed a terminal half-life of 12.9 +/- 6.0 h (mean +/- s.d.), clearance 98.7 +/- 47.3 1 h-1 m-2 and volume of distribution 1533 +/- 536 1 m-2. A bi-exponential equation corresponding to a two compartment open model best fitted the data. Half-life and clearance were not significantly different following oral administration. Bioavailability of oral idarubicin was 0.29 +/- 0.20 (mean +/- s.d.). There was a wide range of bioavailability between and within subjects. Plasma concentrations of idarubicinol (the only metabolite detected) rapidly exceeded those of the parent drug, and exposure to this metabolite was greater than to the parent drug. The mean half-life of idarubicinol was not significantly different after i.v. (63.1 +/- 28.2 h) and oral (45.8 +/- 16.0 h) administration. Much larger amounts of this metabolite were formed following the oral route of administration. This may have implications for the clinical use of this drug as idarubicinol may have appreciable cytotoxic activity.     

The new anthracycline 4-demethoxydaunorubicin by oral route in advanced pretreated breast cancer and melanoma. A pilot study

4-Demethoxydaunorubicin (4-DMDR) was administered orally at the dose of 15 mg/m2 daily for 3 consecutive days at three-weekly intervals to 28 patients with advanced pretreated breast cancer and 9 patients with disseminated pretreated melanoma. A partial remission was observed in 6 out of 20 evaluable breast cancer patients (30%) for a median duration of 6 months and in one out of 7 evaluable patients with melanoma (14%) for a duration of 3 months. Side-effects included leucopenia in 78% of patients (less than 1000 wbc/cmm in 8%), nausea in 32% and mild vomiting in 16%. The preliminary results of this ongoing study on 4-DMDR administered orally show that the regimen is well tolerated in the majority of patients and that it has antitumour activity in advanced breast cancer.     

GC测定盐酸伊达比星原料药中的残留溶剂

目的 建立盐酸伊达比星原料药中残留溶剂的检查方法。方法 采用毛细管色谱柱顶空进样气相色谱程序升温法测定。色谱柱为DB-624石英毛细管柱(30.0 m×0.530 mm,3.00 mm);进样口温度：200 ℃;氢火焰离子化检测器(FID)温度：250 ℃;柱温：程序升温,初始温度50 ℃,保持6 min,再以10 ℃·min^-1的升温速率升至165 ℃,维持2.5 min;载气：氮气;流速：4.0 mL·min^-1。顶空进样,平衡温度：105 ℃,平衡时间：20 min,进样体积：1.0 mL。以二甲基甲酰胺(DMF)为溶解介质。结果 各被测溶剂均能良好分离,各溶剂峰面积与浓度均呈良好的线性关系,方法的精密度良好,各溶剂的回收率较为理想。结论 该法适用于盐酸伊达比星原料药的残留溶剂测定。     

实例(4)

某作者采用青霉素与双黄连对小儿呼吸道感染进行治疗效果观察 ,作者用一年的时间 ,收集到小儿呼吸道感染患者 1 54例 ,将全部病例分为两组。治疗组 80例 ,男 49例 ,女 31例。急性扁桃体炎 36例 ,急性咽炎 2 5例 ,支气管炎 1 3例 ,肺炎 6例。对照组 74例 ,男 40例 ,女 34例。急性扁桃体炎 34例 ,急性咽炎 2 4例 ,支气管炎 1 1例 ,肺炎 5例。治疗组采用青霉素与双黄连治疗 ;对照组只用青霉素治疗。两组病例中上呼吸道感染疗程 3～ 5天 ,下呼吸道感染疗程 5～ 7天。治疗结果 ,对照组显效 32例 ,有效 30例 ,总有效率83.6% ;治疗组显效 45例 …