伊立替康脂质体制备工艺及处方优化研究

目的:通过优化手段筛选脂质体最佳处方工艺,制备伊立替康脂质体,并对其进行质量评价。方法:采用薄膜分散法,改良薄膜分散法,逆向蒸发法,主动载药等方法制备伊立替康脂质体,通过包封率测定优选出最佳制备方法。采用正交试验设计,以包封率为考察指标,优化伊立替康脂质体的处方和工艺。结果:用最优处方制得的脂质体外观好,包封率达到90%以上,透射电镜观察外观圆整,均匀,粒径小于20nm。结论:改良薄膜分散法用于制备水溶性药物伊立替康脂质体是一种较好的制备方法。     

甘草酸对伊立替康在大鼠体内的肠道毒性影响及其作用机制研究

目的：研究甘草酸（glycyrrhizin,GL）能否防治伊立替康（irinotecan,CPT-11）所致的大鼠迟发性腹泻,并探讨其可能的作用机制。方法：大鼠随机分成4组：正常对照组、GL组、CPT-11腹泻模型组、GL＋CPT-11腹泻治疗组。腹泻模型采用连续4天尾静脉（iv）给予CPT-11（80mg·kg-1·d-1）。观察大鼠在静脉给予GL（25mg·kg-1·d-1）治疗下,腹泻得分、体重等指标变化;同时检测血浆和结肠炎症因子前列腺素E2（PGE2）水平变化。结果：相比CPT-11腹泻模型组,GL＋CPT-11腹泻治疗组大鼠提早1天腹泻改善、体重回升,血浆和结肠中PGE2水平也明显低于腹泻模型组。结论：GL对CpT-11诱导的严重迟发性腹泻模型的大鼠有-定的防治作用。其作用机制可能与GL抗炎作用有关。     

The effect of granisetron on in vitro metabolism of doxorubicin,irinotecan and etoposide

ABSTRACT

Objective: Doxorubicin, irinotecan and etoposide are all associated with the debilitating side-effects of nausea and vomiting, thereby necessitating concomitant antiemetic therapy. However, this may increase the potential for drug–drug interactions by inhibition or induction of the cytochrome P450 enzymes. A study was undertaken to investigate the effects of the 5-HT₃-receptor antagonist granisetron on the metabolism of doxorubicin, irinotecan and etoposide in vitro in human liver microsomal preparations.

Research design and methods: Doxorubicin, 20?µM, irinotecan, 10?µM, and etoposide, 50?µM, were incubated in the presence of granisetron, 0?nM, 20?nM, 200?nM and 2000?nM, in human liver microsomal preparations (250?µg). The levels of unchanged doxorubicin, irinotecan and etoposide in the incubation mixture were determined by high-performance liquid chromatography. Positive controls were ketoconazole, 20?µM, a potent inhibitor of CYP3A metabolism, for irinotecan and etoposide and quercitrin, 2?mM, a potent inhibitor of aldo-keto reductase, for doxorubicin.

Results: In the absence of granisetron, unchanged doxorubicin, irinotecan and etoposide levels decreased by 34.2 ± 5.5%, 21.3 ± 2.9% and 13.4 ± 1.6% of control, respectively. Ketoconazole prevented the breakdown of both irinotecan and etoposide, while quercitrin inhibited the breakdown of doxorubicin. Granisetron had no effect on the rate of reduction of doxorubicin, irinotecan or etoposide.

Conclusions: The results from this study suggest that granisetron neither inhibits nor induces the enzymes involved in the metabolism of doxorubicin, irinotecan or etoposide. Thus, granisetron can be used safely to treat nausea and vomiting induced by these agents with minimal risk of drug–drug interactions.     

UGT1A1基因多态性在FOLFIRI方案二线治疗转移性结直肠癌中的临床意义

目的 探讨尿苷二磷酸葡萄糖醛酸转移酶（UGT）1A1基因多态性在FOLFIRI方案二线治疗转移性结直肠癌（mCRC）中的安全性和作为疗效预测指标的价值。方法在FOLFIRI方案化疗前分离mCRC患者外周血中单核细胞,采用荧光定量PCR-HRM法测定UGT1A1基因型。根据NCI CTC 3.0和RECIST 10标准分别评价化疗的不良反应和疗效,并分析UGT1A1基因多态性与不良反应和近期有效率（RR）的关系。用Kaplan-Meier法进行生存分析,Log-rank 检验分析UGT1A1基因型对无进展生存期（PFS）的影响。结果38例患者中,UGT1A1*28位点的野生型（TA6／6）有31例（81.6％）,杂合突变型（TA6／7）2例（5.3％）,纯合突变型（TA7／7）5例（13.2％）;UGT1A1*6位点的野生型（G／G）有28例（73.7％）,杂合突变型（G／A）8例（21.1％）,纯合突变型（A／A）2例（5.3％）。在3～4级延迟性腹泻和中性粒细胞减少的发生率方面,UGT1A1*28的野生型（TA6／6）显著低于TA6／7和TA7／7基因型（P＜0.05）,UGT1A1*6的野生型（G／G）也显著低于G／A和A／A基因型（P＜0.05）。RR和PFS在UGT1A1各种基因型之间差异无统计学意义（P＞0.05）。结论 在FOLFIRI方案二线治疗mCRC中,UGT1A1*28位点和UGT1A1*6位点突变可以作为严重的延迟性腹泻和中性粒细胞减少的预测指标,但UGT1A1基因多态性与疗效无关。     

A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer

Background:

PEP02, also known as MM-398, is a novel nanoliposomal irinotecan that has improved pharmacokinetics and tumour bio-distribution of the free drug. This phase 2 study evaluated PEP02 monotherapy as second-line treatment for pancreatic cancer.

Methods:

Patients who had metastatic pancreatic adenocarcinoma, Karnofsky performance status ⩾70, and had progressed following gemcitabine-based therapy were eligible. Intravenous injection of PEP02 120 mg m⁻² was given every 3 weeks. Simon 2-stage design was used. The primary objective was 3-month survival rate (OS_3-month).

Results:

A total of 40 patients were enrolled. The most common severe adverse events included neutropenia, abdominal pain, asthenia, and diarrhoea. Three patients (7.5%) achieved an objective response, with an additional 17 (42.5%) demonstrating stable disease for a minimum of two cycles. Ten (31.3%) of 32 patients with an elevated baseline CA19-9 had a >50% biomarker decline. The study met its primary end point with an OS_3-month of 75%, with median progression-free survival and overall survival of 2.4 and 5.2 months, respectively.

Conclusion:

PEP02 demonstrates moderate antitumour activity with a manageable side effect profile for metastatic, gemcitabine-refractory pancreatic cancer patients. Given the limited treatment options available to this patient population, a phase 3 trial of PEP02 (MM-398), referred to as NAPOLI-1, is currently underway.     

含伊立替康方案二线治疗35例晚期食管癌的临床观察

目的观察含伊立替康的联合化疗方案在晚期食管癌二线治疗中的临床疗效及毒性反应。方法 35例既往经紫杉醇联合铂类一线化疗无效或进展的晚期食管癌患者,二线化疗使用伊立替康＋顺铂方案20例（伊立替康180mg/m^2静滴第1天,顺铂50mg/m^2静滴第2天）;使用伊立替康＋氟尿嘧啶＋亚叶酸钙（FOLFIRI）方案15例（伊立替康180mg/m^2静滴第1天,氟尿嘧啶2 400mg/m^2持续静滴46h,亚叶酸钙400mg/m^2静滴第1天）,均为双周化疗方案。结果完全缓解（CR）0例,部分缓解（PR）8例,稳定（SD）12例,进展（PD）15例,有效率为22.8%,疾病控制率为57.1%,中位无进展生存期（PFS）2.7个月,中位总生存期（OS）7.3个月。主要毒副反应为血液学毒性及恶心呕吐、腹泻,全组无毒性相关死亡。结论含伊立替康的联合化疗方案作为晚期食管癌的二线治疗方案安全有效,毒副反应可耐受,值得在临床上进一步观察及研究。     

FOLFIRI regimen in metastatic pancreatic adenocarcinoma resistant to gemcitabine and platinum-salts

AIM: To evaluate the efficacy and safety of the FOLFIRI regimen in patients with metastatic pancreatic adenocarcinoma (PAC) after the failure of gemcitabine and platinum salts.METHODS: All consecutive patients with histologically confirmed, metastatic PAC and World Health Organization performance status (PS) ≤ 2 received FOLFIRI-1 [irinotecan 180 mg/m² on day 1 and leucovorin 400 mg/m² followed by 5-fluorouracil (5-FU) 400 mg/m² bolus, then 5-FU 2400 mg/m² as a 46-h infusion, biweekly] or FOLFIRI-3 (irinotecan 100 mg/m² on day 1 and leucovorin 400 mg/m², then 5-FU 2400 mg/m² as a 46-h infusion and irinotecan 100 mg/m² repeated on day 3, biweekly) after failure of gemcitabine and platinum-based chemotherapies as a systematic policy in two institutions between January 2005 and May 2010. Tumor response, time to progression (TTP), overall survival rate (OS) and grade 3-4 toxicities were retrospectively studied. Subgroup analyses were performed to search for prognostic factors.RESULTS: Sixty-three patients (52.4% male, median age 59 years) were analyzed. Among them, 42.9% were PS 0, 38.1% were PS 1 and 19.0% were PS 2. Fifty one patients (81.0%) had liver metastases. Before the FOLFIRI regimen, patients had received 1 line (n = 19), 2 lines (n = 39) or 3 lines (n = 5) of chemotherapy. Median TTP obtained with the line before FOLFIRI was 3.9 mo (95% CI: 3.4-5.3 mo). A total of 480 cycles was completed (median: 6 cycles, range: 1-51 cycles). The main reason for discontinuing FOLFIRI was tumor progression (90.3%). Tumor control was achieved in 25 patients (39.7%) (partial response: n = 5, stable disease: n = 20) with FOLFIRI. Median TTP was 3.0 mo (95% CI: 2.1-3.9 mo) and median OS was 6.6 mo (95% CI: 5.3-8.1 mo). Dose adaptation was required in 36 patients (57.1%). Fifteen patients (23.8%) had grade 3-4 toxicities, mainly hematological (n = 11) or digestive (n = 4). Febrile neutropenia occurred in 3 patients. There was no toxic death. PS 2 was significantly associated with poor TTP [hazard ratio (HR): 16.036, P < 0.0001] and OS (HR: 4.003, P = 0.004).CONCLUSION: The FOLFIRI regimen had an acceptable toxicity and an interesting efficacy in our study, limited to patients in good condition (PS 0-1).     

伊立替康联合奈达铂治疗中晚期宫颈癌的临床效果

目的:观察伊立替康联合奈达铂治疗中晚期宫颈癌的临床效果。方法:将96例中晚期宫颈癌患者随机分为对照组和研究组(n=48)。所有病人行宫颈癌根治术。在手术治疗的基础上,研究组进行伊立替康联合奈达铂治疗(伊立替康用量为160mg·(m2)-1,奈达铂60mg·(m2)-1一次性静滴给药)。比较两组的疗效和副作用。结果:对照组和研究组总有效率为74.99%和89.59%,两组有显著性差别。研究组毒副作用较轻,包括血液学毒性、胃肠道反应等。结论:伊立替康联合奈达铂治疗中晚期宫颈癌具有较好的疗效。     

Irinotecan-encapsulated double-reverse thermosensitive nanocarrier system for rectal administration

Intravenously administered for the treatment of rectum cancer, irinotecan produces severe side effects due to very high plasma concentrations. A novel irinotecan-encapsulated double reverse thermosensitive nanocarrier system (DRTN) for rectal administration was developed as an alternative. The DRTN was fabricated by dispersing the thermosensitive irinotecan-encapsulated solid lipid nanoparticles (SLN) in the thermosensitive poloxamer solution. Its gel properties, pharmacokinetics, morphology, anticancer activity and immunohistopathology were assessed after its rectal administration to rats and tumor-bearing mice. In the DRTN, the solid form of the SLN and the liquid form of the poloxamer solution persisted at 25?°C; the former melted to liquid, and the latter altered to gel at 36.5?°C. The DRTN was easily administered to the anus, gelling rapidly and strongly after rectal administration. Compared to the conventional hydrogel and intravenously administered solution, it retarded dissolution and initial plasma concentration. The DRTN gave sustained release and nearly constant plasma concentrations of irinotecan at 1–3?h in rats, resulting in improved anticancer activity. It induced no damage to the rat rectum and no body weight loss in tumor-bearing mice. Thus, this irinotecan-encapsulated DRTN associated with a reduced burst effect, lack of toxicity and excellent antitumor efficacy would be strongly recommended as a rectal pharmaceutical product alternative to commercial intravenous injection in the treatment of rectum and colon cancer.