顺铂缓释多囊脂质体的制备和体外释放性能研究

目的 制备包封率高和缓释作用好的顺铂缓释多囊脂质体,并与反相蒸发法制备的顺铂普通脂质体比较其体外释药性能。方法 用复乳法制备顺铂多囊脂质体,非火焰原子吸收分光光度法测定顺铂含量,磷脂酶试剂法测定脂质体中磷脂的浓度。测定包封率和体外释药性。结果顺铂多囊脂质体平均粒径为16.6 μm,跨距为1.0。顺铂包封率可高达80%以上。顺铂缓释多囊脂质体的体外释药符合一级释药规律, 释药t_1/2为37.7 h,比反相蒸发法制备的顺铂普通脂质体延长8.4倍。经差示热分析发现辅助膜稳定剂有明显的膜稳定作用。结论顺铂多囊脂质体包封率高,并具有良好的缓释作用。     

Clinical pharmacology of bleomycin and cisplatin

Bleomycin (Blenoxane) and cisplatin (Platinol) are two anticancer drugs, with activity for head and neck tumors, that were introduced into clinical use in the past ten years. Bleomycin is used primarily in the chemotherapy of squamous cell carcinomas, lymphomas, and testicular carcinoma, while cisplatin possesses significant activity against testicular and ovarian carcinoma, head and neck cancer, bladder cancer, and neuroblastoma. Bleomycin is rapidly excreted renally (terminal phase half-life = 2-4 h), although enzymatic inactivation also occurs in many tissues. Cisplatin is nonenzymatically converted to highly protein bound metabolites, which then undergo renal elimination, but total body clearance occurs much more slowly than with bleomycin (terminal phase half-life = 40-50 h). Both agents have acute and chronic toxicities; the acute toxicities are generally reversible but cause a great deal of patient discomfort, while the chronic toxicities are often irreversible and dose-limiting. For bleomycin, the acute toxicities are mucocutaneous are pyretic; severe nausea and vomiting represents the major acute toxicity of cisplatin therapy. Cumulative dose-related pulmonary toxicity is the most serious chronic toxicity of bleomycin. The clinical, radiographic, and pathologic presentations are nonspecific, although identification of high risk patients may be possible with serial pulmonary function tests. Cumulative nephrotoxicity occurs with cisplatin use, and its incidence and severity can be reduced by maintaining adequate hydration and diuresis during and following administration of the drug.     

Incompatibility of cisplatin and Reglan Injectable

The stability of cisplatin (cis-diamminedichloroplatinum (II)) in solutions containing Reglan Injectable, comprised of metoclopramide, sodium metabisulfite and sodium chloride, was examined. Loss of cisplatin was monitored by measuring the increasing chloride ion concentrations with a chloride ion-specific electrode. Cisplatin was stable in solution with metoclopramide alone, but degraded very rapidly in solution with metabisulfite. At concentrations similar to those which might be expected in clinical situations (cisplatin = 0.2 mg/ml, metabisulfite = 0.148 mg/ml, metoclopramide = 0.5 mg/ml) there was total loss of cisplatin within 30 min at room temperature. The results indicate that cisplatin reacts with species formed in the oxidation of bisulfite. Therefore, cisplatin should not be admixed with Reglan Injectable solution or any solution containing bisulfite or chemically related antioxidants.     

顺铂白芨胶微球在犬体内的药动学

目的研究顺铂白芨胶微球肝动脉灌注后体内药动学过程,判别其体内靶向性和缓释性能,为其临床治疗提供科学依据.方法犬麻醉后经股动脉穿刺引入5F单弯血管造影导管,透视下插至肝动脉分别灌注顺铂白芨胶微球和顺铂注射液,不同时间点采血,通过原子吸收光谱法检测血药浓度,通过DAS2.0药动学计算软件计算顺铂不同剂型在犬体内的药动学参数.结果白芨胶微球中的顺铂和顺铂注射液在犬体内的药动学模型为二室模型,其中顺铂注射液药动学参数t1/2α(2.3±0.9)h,t1/2β(75.1±2.0)h,AUC(0-t)(49.2±1.8)mg·h·L-1,AUC(0-∞)(64.3±3.8)mg·h·L-1,MRT(0-t)(58.0±1.9)h,MRT(0-∞)(120.7±10.2)h,C(max)(1.72±0.17)mg·L-1,t(max)(0.057±0.098)h;顺铂白芨胶微球的顺铂药动学参数t1/2α(11.5±4.3)h,t1/2β(143.2±42.4)h,AUC(0-t)(31.2±1.5)mg·h·L-1,AUC(0-∞)(47.4±6.O)mg·h·L-1,MRT(0-t)(62.1±1.7)h,MRT(0-∞)(152.4±48.2)h,C(max)(0.77±0.05)mg·L-1,t(max)(1.30±0.27)h.结论顺铂白芨胶微球在体内栓塞治疗的同时,通过其被动靶向作用在肝组织缓慢释放药物,降低其在外周血液和组织的药物浓度,长时间提高其在病灶部位的有效浓度,达到提高临床治疗效果,减少其不良反应的目的.     

Evolution of high-dose cisplatin

Summary High-dose cisplatin therapy, defined as 200 mg/m²/course, is currently undergoing extensive clinical trials in a variety of solid tumors. The reduction of the incidence and severity of cisplatin-induced nephrotoxicity has led to clinical trials of higher doses of cisplatin. By maintaining nephrotoxicity to acceptable levels, dose response relationships have shown increased efficacy of cisplatin therapy. However, new dose-limiting toxicities, primarily severe neurotoxicity and myelosuppression, have prevented further dosing increases. The following review will trace the evolution and the current status of high-dose cisplatin therapy. In addition, a summary of the dose-limiting non-renal toxicities and their relationship to pharmacokinetics and dosing schedules will be discussed.     

Pharmacokinetics and toxicodynamics of cisplatin and its metabolites in rats: relationship between renal handling and nephrotoxicity of cisplatin

The renal handling of cisplatin and its metabolites and the relationship between the pharmacokinetics of these platinum species in the kidney and nephrotoxicity in rats were studied by carrying out pharmacokinetic-pharmacodynamic analysis. Rats received cisplatin intravenously as a bolus (2-10 mgkg(-1)) or by constant infusion (55 and 140 microg min(-1) kg(-1)). After intravenous administration of each platinum species, the platinum concentrations of unchanged cisplatin and its mobile and fixed metabolites were determined separately. Nephrotoxicity was estimated by measuring the blood urea nitrogen (BUN) levels and the sigmoid Emax model was used to determine the relationship between pharmacokinetic parameters and BUN levels 5 days after cisplatin administration. Cisplatin and its mobile metabolites in plasma distributed more rapidly and extensively into the kidney (mean apparent kidney-to-plasma concentration ratios were 2.69 and 7.12 mL (g tissue)(-1), respectively) than into the liver (less than 1 mL (g tissue)(-1)). Concomitant administration of mobile metabolites did not significantly alter the disposition of cisplatin. Nephrotoxicity, estimated by measuring BUN levels, appeared to be related to the plasma concentration of intact cisplatin, not total platinum, because mobile metabolites formed from cisplatin showed little nephrotoxicity. The sigmoid Emax model showed the maximum BUN level reached after cisplatin administration was related to the area under the renal cisplatin concentration-time curve (AUCk).     

Embryotoxicity of cisplatin in rats and mice

Cisplatin [cis-dichlorodiammineplatinum (II)], a broad spectrum antitumor agent, was tested for possible teratogenic and embryolethal effects on Wistar rats and Swiss Webster mice. Rats were given a single ip injection of 0.3, 1.0, 2.5, or 3.0 mg/kg cisplatin on Day 6, 8, 11, or 14 of gestation, whereas mice were given a single ip injection of 0.3, 3.0, 6.0, 8,0, or 13.0 mg/kg on Day 8 only. The embryonic LD50's in the rat were 2.88, 1.28, and 1.0 mg/kg for day 6, 8, and 11, respectively. There was no significant increase in embryolethality at any of the doses given on Day 14. The embryonic LD50 for mice was 5.24 mg/kg. An increase in the incidence of growth retardation or gross malformations was not discernable in the surviving fetuses with the number of dams used in this study. Cisplatin is highly embryolethal in rats and mice at dosages well below the adult therapeutic dosage in humans. This embryolethality is gestational stage-specific with the highest mortality corresponding to the period of rapid DNA replication in early organogenesis.     

顺铂所致的周围神经毒性及其防治措施

顺铂是一种对各种实体瘤疗效显著的抗肿瘤药物,但以顺铂为基础的化疗方案往往伴随一些毒副作用.自从用水化方案大大降低了肾毒性后,其周围神经毒性就成为剂量限制性毒性.顺铂所致周围神经毒性的机制可能与背根神经节中神经元的DNA损伤有关.目前用来防治其神经毒性的药物有维生素E、org2766、还原型谷胱甘肽、尼莫地平、神经生长因子、氨磷汀等.     

Nephrotoxicity of cisplatin,carboplatin and transplatin

The present study was designed to compare the nephrotoxicity induced by the three platinum compounds cisplatin (CDDP), carboplatin (CBDCA) and transplatin (TDDP) in vitro and to obtain information to elucidate the mechanism of platinum compound-induced nephrotoxicity. Rat or rabbit renal cortical slices were incubated for different periods of time in platinum compound-containing media (0.42 or 1.67 mM) and thereafter monitored for platinum content, tetraethylammonium(TEA) and paraaminohippurate(PAH) accumulation and gluconeogenesis. Malondialdehyde(MDA) content of slices was determined as a parameter of lipid peroxidation. Activity of glucose-6-phosphatase of rat renal microsomes was investigated after platinum-compound exposure. In all series of experiments the effect of the antioxidant N,Ndiphenyl-p-phenylenediamine (DPPD) was tested. CBDCA showed no effects on all parameters of renal cell function at all concentrations and all time points investigated, except for the activity of glucose-6-phosphatase, which was slightly affected by CBDCA. CBDCA-induced MDA production was lower, compared to CDDP, which showed marked toxic effects on TEA and PAH accumulation, gluconeogenesis and glucose-6-phosphatase activity. The onset of CDDP-induced alterations was dependent on drug concentration. MDA production was reduced by DPPD. Protection against the platinum compound-induced decrease in TEA and PAH accumulation was observed after the use of DPPD. DPPD had no protective effect on CDDP-induced inhibition of gluconeogenesis and glucose-6-phosphatase, which might indicate an effect on gluconeogenesis by direct inhibition of glucose-6-phosphatase. DPPD did not alter uptake of platinum compounds in rat renal cortical slices. TDDP showed different in vitro properties compared to in vivo conditions. In conclusion, association of CDDP-induced nephrotoxicity with lipid peroxidation was shown. CBDCA induced less generation of lipid peroxidation products and only very small nephrotoxic effects. Antioxidants may restrict CDDP-induced alterations in renal cell function.     

顺铂软膏制备及质量控制

目的 :研制顺铂软膏 ,建立测定顺铂含量的方法。方法 :采用顺铂衍生物经萃取后紫外分光光度法进行含量测定。软膏中顺铂用二乙基硫代氨基甲酸钠 (DDTC)衍生化 ,其产物溶于氯仿在 34 7.5nm波长处可进行测定。结果 :顺铂溶液 4～ 16 μg·ml-1范围内浓度与吸收度有良好线性关系 ,其回归方程为C =14.7377A - 0 .2 486 (r =0 .9992 ) ,平均回收率 (n =10 )为 80 .88% ,RSD =1.0 5 %。结论 :顺铂软膏性质稳定 ,应用紫外分光光度法测定软膏中顺铂含量快捷准确 ,简便易行     

复方苦参注射液联合顺铂与顺铂单药治疗恶性腹水的临床观察比较

目的:采用复方苦参注射液(岩舒)静脉滴注联合顺铂(DDP)腹腔内给药或单药顺铂腹腔内给药两种方法治疗恶性肿瘤并恶性腹水患者,以评价其临床疗效和不良反应。方法:将46例患者随机分为两组,A组予顺铂腹腔内注射联合复方苦参注射液静脉滴注;B组予单药顺铂腹腔内注射;两组均每周治疗1次,共4次,以评价临床疗效和不良反应。结果:顺铂联合复方苦参注射液组(A组)较单药顺铂组(B组)有效率有所提高(60.9%vs 30.4%),差异有统计学意义(P<0.05);不良反应方面,顺铂联合复方苦参注射液组(A组)出现的Ⅲ～Ⅳ度胃肠道反应及肝功能损害较单药顺铂组(B组)少,两组的差异有统计学意义(P<0.05)。结论:复方苦参注射液联合顺铂治疗恶性腹水在提高临床疗效的同时,可减轻顺铂腹腔内化疗出现的不良反应。     

Biochemical mechanisms of cisplatin cytotoxicity

Since the discovery by Rosenberg and collaborators of the antitumor activity of cisplatin 35 years ago, three platinum antitumor drugs (cisplatin, carboplatin and oxaliplatin) have enjoyed a huge clinical and commercial hit. Ever since the initial discovery of the anticancer activity of cisplatin, major efforts have been devoted to elucidate the biochemical mechanisms of antitumor activity of cisplatin in order to be able to rationally design novel platinum based drugs with superior pharmacological profiles. In this report we attempt to provide a current picture of the known facts pertaining to the mechanism of action of the drug, including those involved in drug uptake, DNA damage signals transduction, and cell death through apoptosis or necrosis. A deep knowledge of the biochemical mechanisms, which are triggered in the tumor cell in response to cisplatin injury not only may lead to the design of more efficient platinum antitumor drugs but also may provide new therapeutic strategies based on the biochemical modulation of cisplatin activity.     

多西他赛和吉西他滨分别联合顺铂治疗晚期非小细胞肺癌效果比较

目的 比较多西他赛与吉西他滨联合顺铂方案治疗晚期非小细胞肺癌(NSCLC)的临床疗效及不良反应.方法 120例晚期非小细胞肺癌患者完全随机分为2组.多西他赛组60例给予多西他赛37.5 mg/m2,第1、8天;顺铂25 mg/m2,第1～3天.吉西他滨组60例给予吉西他滨1000 mg/m2,第1、8天;顾铂用量同前.化疗每3周重复,每周期评价不良反应,评价疗效并随访生存期.结果 20例患者均可评价疗效和不良反应,2组有效率分别为多西他赛组45.0%(27/60)和吉西他滨组43.3%(26/60),1年生存率分别为45%和43.3%,两组之间有效率和1年生存率均无统计学意义(P＞0.05).不良反应主要为骨髓抑制和肝功能损害[多西他赛组白细胞产减少率为85.0%(51/60),吉西他滨组为78.0%(47/60),2组差异无统计学意义(P＞0.05);2组肝功能损害率分别为33.3%(20/60)、26.7%(16/60),差异有统计学意义(P＜0.05)].结论 多西他赛与吉西他滨联合顺铂方案治疗晚期NSCLC均具有较好的疗效,且两者的疗效相似,不良反应可以耐受,可以作为临床一线治疗.

Abstract：

Objective To compare the efficacy and safety of docetaxel plus cisplatin and gemcitabine plus cisplatin in advanced non-small cell lung cancer (NSCLC). Methods A total of 120 patients with advanced NSCLC were divided into two groups. The patients received docetaxel in docetaxel group. In gemcitabine group the patients received gemcitabine and cisplatin. The treatment schedule was repeated every 3 weeks. The toxicity,quality response and survival rate of life were evaluated after every cycle. Results The response rates of the docetaxel group and the gemcitabine group were 45% and 43.3%,respectively. One-year survival rates in the two groups were 45% and 43.3%,respectively. The response rate,one-year survival time showed no significance (P ＞0.05). The main side effects were myelosupp ression,nausea and vomiting. Conclusion Regimens of DC and GC are both safe and effective in the treatment of advanced stage NSCLC. They can be used as the first regimen of chemotherapy in patients with advanced stage NSCLC.     

T-钙黏蛋白联合顺铂对黑色素瘤顺铂 耐药株的作用研究

摘要：目的 探讨T-钙黏蛋白联合顺铂对黑色素瘤顺铂耐药株的作用。方法 采用大剂量冲击和逐步增加剂 量相结合的方法诱导建立小鼠黑色素瘤B16F10顺铂耐药细胞株（CDDP-R B16F10）。MTT法检测CDDP-R B16F10 的增殖能力。将T-钙黏蛋白转染肿瘤细胞。分别采用反转录聚合酶链式反应（RT-PCR）和免疫组化SP法检测转染 后T-钙黏蛋白mRNA和蛋白的表达。实验将CDDP-R B16F10细胞分为空白对照组、pEGFP-N1组、pEGFP-N1-T cadherin组、顺铂组、pEGFP-N1联合顺铂组、pEGFP-N1-T-cadherin 联合顺铂组。采用Wound-healing 划痕实验和 transwell侵袭实验检测T-钙黏蛋白联合顺铂对CDDP-R B16F10细胞迁移和侵袭力的影响。结果 成功建立黑色素 瘤顺铂耐药细胞株。MTT法结果显示,CDDP-R B16F10细胞增殖能力与B16F10细胞相比差异无统计学意义（P＞ 0.05）。RT-PCR和免疫组化SP法检测表明,转染后细胞可稳定转录和表达T-钙黏蛋白。pEGFP-N1-T-cadherin联 合顺铂组细胞迁移率和穿膜细胞数低于pEGFP-N1-T-cadherin组（P＜0.05）,而pEGFP-N1-T-cadherin组低于空白 对照组、pEGFP-N1 组、顺铂组和 pEGFP-N1 联合顺铂组（P＜0.05）。析因分析显示,T-钙黏蛋白与顺铂联合对 CDDP-R B16F10细胞迁移率及侵袭力的抑制有交互作用（P＜0.05）。结论 T-钙黏蛋白可恢复顺铂对黑色素瘤顺 铂耐药细胞株迁移及侵袭力的抑制作用。     

环磷酰胺与顺铂联合化疗时间节律性研究

目的探索环磷酰胺与顺铂联合化疗时间节律性特征,从而确定最佳给药模式。方法对42例卵巢癌和恶性淋巴瘤患者随机分为6组,分别按昼夜6个节律点静脉给药,比较不同时间外周血象、肾功能、肝功能的变化,评价药物时间化疗的不良反应。结果上午9:00化疗组白细胞抑制率和淋巴细胞损伤最大,血肌酐、血尿素氮、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)显著下降;而17:00化疗组血象在正常范围,肾功能、肝功能损伤发生频率低。结论环磷酰胺与顺铂联合化疗存在时间节律性,17:00化疗为最佳给药模式。     

Stability of cisplatin and etoposide in intravenous admixtures

The stability of various concentrations of etoposide and cisplatin in intravenous admixtures under various storage conditions was studied. Admixtures containing etoposide (200 and 400 micrograms/mL) with cisplatin (200 micrograms/mL) were prepared in 0.9% sodium chloride injection and in 5% dextrose and 0.45% sodium chloride injection. The admixtures were stored in either polyvinyl chloride bags or glass bottles. Mannitol and potassium chloride were added to selected admixtures. Half of the admixtures were protected from light, while the other half were exposed to fluorescent light. All admixtures were stored at room temperature. Samples were visually inspected and assayed for etoposide and cisplatin content by high-performance liquid chromatography within 15 minutes after admixture preparation and after 8, 24, and 48 hours of storage. Etoposide and cisplatin concentrations decreased less than 10% from the initial concentration after eight hours of storage. At 24 hours, the admixtures containing etoposide 400 micrograms/mL and cisplatin 200 micrograms/mL (with additives) in 0.9% sodium chloride injection precipitated. The decrease in etoposide concentrations during the first 24 hours in the rest of the admixtures was less than 10% of the initial concentration. The change in etoposide concentration was related to the type of i.v. solution and the presence of additives. After 24 hours, the change in cisplatin concentrations was less than 10% of the initial concentration, except in the admixtures that precipitated. For cisplatin, the presence of light was related to an increased loss of cisplatin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparative pharmacokinetic study of cycloplatam and cisplatin

Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 29, No. 4, pp. 24–26, April, 1995.