Alocrest | 71486-22-1

• 物质功能分类: 原料药 - 抗肿瘤药 - 天然来源类抗肿瘤药
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 长春花生物碱
• 英文名称: Alocrest
• 英文别名: methyl (1R,9R,10S,11R,12R,19R)-11-acetyloxy-12-ethyl-4-[(12S)-16-ethyl-12-methoxycarbonyl-1,10-diazatetracyclo[12.3.1.03,11.04,9]octadeca-3(11),4,6,8,15-pentaen-12-yl]-10-hydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate
• CAS: 71486-22-1
• 化学式: C₄₅H₅₄N₄O₈
• 分子量: 778.9
• InChiKey: GBABOYUKABKIAF-BXZSYHTRSA-N

物化性质

• 比旋光度：
  D20 +52.4° (c = 0.3 in CHCl3)
• 密度：
  1.36±0.1 g/cm3(Predicted)
• 溶解度：
  >25.9mg/mL，溶于 DMSO
• 稳定性/保质期：

  Unopened vials of vinorelbine tartrate injection are stable at temperatures up to 25 °C for up to 72 hours. Vinorelbine tartrate injection should not be frozen.

• 旋光度：
  Specific optical rotation: +52.4 deg at 20 °C/D ( c = 0.3 in CHCl3)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  57
• 可旋转键数：
  10
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  134
• 氢给体数：
  2
• 氢受体数：
  11

ADMET

代谢

长春瑞滨在肝脏中广泛代谢。长春花碱类（例如，长春碱、长春新碱）的代谢由细胞色素P-450（CYP）同工酶中的CYP3A亚家族介导。长春瑞滨的两个代谢物，长春瑞滨N-氧化物和脱乙酰长春瑞滨，已在人体血液、血浆和尿液中检出。

Vinorelbine is extensively metabolized in the liver. The metabolism of vinca alkaloids (eg, vinblastine, vincristine) is mediated by the cytochrome P-450 (CYP) isoenzymes in the CYP3A subfamily. Two metabolites of vinorelbine, vinorelbine N-oxide and deacetylvinorelbine, have been identified in human blood, plasma, and urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

去乙酰长春瑞滨，是人类长春瑞滨的主要代谢物，已经显示出与母药相似的抗肿瘤活性。然而，长春瑞滨的治疗剂量导致血液或尿液中这两种代谢物的浓度非常小，几乎无法量化。

Deacetylvinorelbine, the primary metabolite of vinorelbine in humans, has been shown to possess antitumor activity similar to the parent drug. However, therapeutic doses of vinorelbine result in very small, if any, quantifiable concentrations of either metabolite in blood or urine.

来源:Hazardous Substances Data Bank (HSDB)

代谢

关于长春瑞滨的生物转化知之甚少。脱乙酰长春瑞滨被认为是一种次要代谢物，仅存在于尿液组分中，占注射剂量的0.25%。

... Little is known about the biotransformation of vinorelbine. Desacetylvinorelbine is considered to be a minor metabolite and is only found in urine fractions, representing 0.25% of the injected dose. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

脱乙酰化产生脱乙酰纳avelbine（DNVB）是长春瑞滨（纳avelbine，NVB）的主要代谢途径。这种细胞毒代谢物占药物整体分布的很大一部分。只有58%的给药剂量以NVB或DNVB的形式通过尿液（17%）和粪便（41%）排出。没有检测到其他代谢物。

... Deacetylation yielding deacetylnavelbine (DNVB) is the primary metabolic route for vinorelbine (navelbine, NVB). This cytotoxic metabolite accounts for a substantial part of the overall disposition of drug. Only 58% of the administered dose is excreted in the urine (17%) and feces (41%) as NVB or DNVB. No other metabolites have been detected.

来源:Hazardous Substances Data Bank (HSDB)

代谢

长春瑞滨在与大鼠肝微粒体孵化后产生了一个主要代谢物（M1）。在大鼠静脉给药后的胆汁和粪便中，通过高效液相色谱（HPLC）鉴定出了除了M1之外的几个主要代谢物。通过比较HPLC保留时间和对二维核磁共振（NMR）以及混合质谱/质谱（MS/MS）光谱的广泛分析，确定了主要代谢物的结构，分别为15,16-环氧长春瑞滨（M1）、11'-羟基长春瑞滨（M2）、19'-羟基长春瑞滨（M3a）、15,16-环氧-10'-羟基长春瑞滨（M3b）和10'-羟基长春瑞滨（M4）。

Vinorelbine produced a dominant metabolite (M1) after incubation with rat liver microsomes. Several major metabolites other than M1 were identified by HPLC in bile and feces of rat after intravenous administration. The structures of the major metabolites were identified as 15,16-epoxyvinorelbine (M1), 11'-hydroxyvinorelbine (M2), 19'-hydroxyvinorelbine (M3a), 15,16-epoxy-10'-hydroxyvinorelbine (M3b) and 10'-hydroxyvinorelbine (M4) by comparison of HPLC retention times and by extensive analyses of two-dimensional NMR and hybrid MS/MS spectra.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：大多数来源认为，在母亲抗肿瘤药物疗法期间，母乳喂养是禁忌的。由于长春瑞滨的半衰期较长，很可能在长春瑞滨疗法后恢复母乳喂养是不切实际的。化疗可能会不利地影响母乳的正常微生物组和化学成分。 ◉ 对哺乳婴儿的影响：截至修订日期，未找到相关已发布信息。 ◉ 对泌乳和母乳的影响：一位在怀孕第二季度被诊断出患有霍奇金淋巴瘤的妇女在怀孕第三季度接受了3轮化疗，并在产后4周恢复了化疗。在重新开始化疗后的16周内，在化疗前后15至30分钟收集了乳汁样本。治疗方案包括每2周一次，2小时内给予多柔比星40毫克，博来霉素16单位，长春碱9.6毫克和达卡巴嗪600毫克。将该患者的乳汁微生物群和代谢概况与8位未接受化疗的健康妇女进行比较。患者的母乳微生物群与健康妇女明显不同，其中不动杆菌属、黄色单胞菌科和窄食单胞菌属增加，而双歧杆菌属和真杆菌属减少。在接受治疗的妇女的母乳中，许多化学成分也有显著差异，尤其是DHA和肌醇含量降低。

◉ Summary of Use during Lactation:Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It is probably impractical to resume breastfeeding after vinorelbine therapy because of the drug's long half-life. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:A woman diagnosed with Hodgkin's lymphoma during the second trimester of pregnancy received 3 rounds of chemotherapy during the third trimester of pregnancy and resumed chemotherapy 4 weeks postpartum. Milk samples were collected 15 to 30 minutes before and after chemotherapy for 16 weeks after restarting. The regimen consisted of doxorubicin 40 mg, bleomycin 16 units, vinblastine 9.6 mg and dacarbazine 600 mg, all given over a 2-hour period every 2 weeks. The microbial population and metabolic profile of her milk were compared to those of 8 healthy women who were not receiving chemotherapy. The breastmilk microbial population in the patient was markedly different from that of the healthy women, with increases in Acinetobacter sp., Xanthomonadacae and Stenotrophomonas sp. and decreases in Bifidobacterium sp. and Eubacterium sp. Marked differences were also found among numerous chemical components in the breastmilk of the treated woman, most notably DHA and inositol were decreased.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

长春瑞滨和紫杉醇的联合给药可能与神经病变风险增加有关。

Concomitant administration of vinorelbine and paclitaxel may be associated with an increased risk of neuropathy.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在同时使用长春花碱和抗呕吐药阿瑞吡坦期间，建议谨慎并密切监测，因为阿瑞吡坦可能会抑制或诱导CYP3A4。

Caution and careful monitoring are advised during concomitant use of a vinca alkaloid and aprepitant, an antiemetic agent, which may inhibit or induce CYP3A4.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

因为据报道，接受长春花碱类药物的患者出现了前庭缺陷以及与第八对脑神经损伤相关的不同程度的永久性或暂时性听力损害，所以在与其他可能具有耳毒性的药物，如含有铂类的抗肿瘤药物同时使用时，应极度谨慎。

Because vestibular deficits and varying degrees of permanent or temporary hearing impairment associated with damage of the eighth cranial nerve have been reported in patients receiving vinca alkaloids, vinorelbine should be used concomitantly with other potentially ototoxic drugs, such as platinum-containing antineoplastic agents, with extreme caution.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

一位41岁的女性在就诊前三年接受了左侧乳房切除术治疗乳腺癌。六个月前，她出现了复发，这次是在右侧乳房和皮肤。尽管进行了第一线和第二线的化疗，肿块仍显示出疾病进展。此后，她开始了一周的长春瑞滨和曲妥珠单抗治疗，但一个月后，她出现了轻微发热和干咳。胸部CT扫描显示右肺有一个浸润阴影，呈现非特异性的间质性模式。支气管镜检查显示支气管灌洗液中淋巴细胞占优势，经支气管肺活检的组织标本中发现淋巴细胞浸润到间质并伴有纤维化。在停止上述长春瑞滨治疗后，患者的状况有所改善。因此，研究者们诊断这是一例长春瑞滨和曲妥珠单抗引起的间质性肺炎。

A 41-year-old woman had undergone a left mastectomy breast cancer three years prior to presentation. Six months /ago/ she had recurrence, this time in the right breast and skin. Despite first-and second-line chemotherapy, the mass showed progression of the disease. Thereafter, a weekly treatment of vinorelbine and trastuzumab was started, but one month later, she developed a slight fever and dry cough. A chest CT scan revealed an infiltration shadow showing non-specific interstitial pattern in the right lung. A bronchoscopic examination showed lymphocyte dominance in bronchial lavage fluid, and lymphocyte infiltration into the interstium with fibrosis in the tissue specimens was found by transbronchial lung biopsy. After discontinuing the above vinorelbine therapy, the patient's condition improved. /Investigators/ therefore diagnosed this as a case of vinorelbine-and trastuzumab-induced interstitial pneumonia.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉给药后，血浆长春瑞滨浓度最初的迅速下降代表药物向周边室分布。在给予30毫克/平方米的长春瑞滨静脉注射，持续15-20分钟后，已报道稳态分布容积为25.4-40.1升/公斤。

The initial rapid decline in plasma vinorelbine concentration following iv administration represents distribution of the drug to peripheral compartments. Following administration of vinorelbine 30 mg/sq m iv over 15-20 minutes, a steady-state volume of distribution of 25.4-40.1 L/kg has been reported.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

长春瑞滨对人类血小板的结合力较强，对淋巴细胞的结合也较高。在癌症患者中，该药物与血浆成分的结合率在79.6-91.2%之间，在混合人血浆中，观察到大约0.11的自由分数，浓度范围为234-1169 ng/mL。顺铂、氟尿嘧啶或阿霉素的存在并不影响长春瑞滨的结合。

Vinorelbine demonstrates high binding to human platelets and lymphocytes. Binding of the drug to plasma constituents in patients with cancer ranges from 79.6-91.2%, and a free fraction of approximately 0.11 was observed in pooled human plasma over a concentration range of 234-1169 ng/mL. The presence of cisplatin, fluorouracil, or doxorubicin does not affect vinorelbine binding.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉注射放射性标记的长春瑞滨后，大约46%的给药剂量在粪便中回收，18%在尿液中。在另一项研究中，大约11%的静脉给药剂量长春瑞滨以原形在尿液中排泄。

Following IV administration of radiolabeled vinorelbine, approximately 46% of the administered dose was recovered in the feces and 18% in the urine. In another study, approximately 11% of an administered IV dose of vinorelbine was excreted unchanged in the urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

食物对软胶囊制剂长春瑞滨（口服长春瑞滨）的药代动力学和安全性的影响在实体瘤或淋巴瘤的禁食和进食患者中进行了评估。一组18名患者（计划12名）被纳入了一个多中心I期药代动力学研究，该研究采用交叉设计，有1周的清洗期。患者在禁食或摄入标准的大陆早餐后接受了第一个80 mg/平方米口服长春瑞滨的剂量。一周后，在第一次给药的相反饮食条件下，给予第二个80 mg/平方米的剂量。在18名患者中，有13名符合药代动力学评估的条件。禁食患者的平均达峰时间（Tmax）较短（血液中为1.63±0.98小时，血浆中为1.67±0.96小时），而进食患者的平均达峰时间较长（血液中为2.48±1.40小时，血浆中为2.56±1.65小时），但这些差异不太可能改变口服长春瑞滨的安全性和/或有效性。进食和禁食患者的Cmax和AUC值相似，没有观察到显著差异。在这有限数量的患者中观察到的口服长春瑞滨的安全性概况似乎与通常报告的长春瑞滨的安全性相当，主要毒性为中性粒细胞减少。仅报告了一例发热中性粒细胞减少。遇到的主要非血液学毒性是胃肠道毒性，包括恶心、呕吐、腹泻和便秘。当口服长春瑞滨在标准早餐后给药时，呕吐的发生率似乎有降低的趋势。根据这项研究，口服长春瑞滨给药于禁食患者不是强制性的，因为标准早餐后给药不会导致药物在体内的暴露差异。

The effects of food on the pharmacokinetics and safety profile of a soft-gel capsule formulation of vinorelbine (Navelbine Oral) were evaluated in fed and fasted patients with solid tumours or lymphomas. A group of 18 patients (12 planned) were entered into a multicenter phase I pharmacokinetic study following a crossover design with a 1-week wash-out period. Patients received the first dose of 80 mg/sq m oral vinorelbine either after fasting or after ingestion of a standard continental breakfast. The second dose of 80 mg/sq m was administered 1 week later in the alternate feeding condition to the first dose. Of the 18 patients, 13 were eligible for pharmacokinetic evaluation. The mean time to maximum concentration (T(max)) was shorter in fasted patients (1.63+/-0.98 hr in blood, 1.67+/-0.96 hr in plasma) than in fed patients (2.48+/-1.40 hr in blood, 2.56+/-1.65 hr in plasma) but these differences are not likely to modify the safety and/or efficacy of oral vinorelbine. Values for C(max) and AUC were similar in fed and fasted patients and no significant differences were observed. The safety profile of oral vinorelbine observed in this limited number of patients appears to be comparable to that usually reported for vinorelbine, the main toxicity being neutropenia. Only one episode of febrile neutropenia was reported. The main nonhematological toxicities encountered were gastrointestinal, consisting of nausea, vomiting, diarrhea and constipation. A tendency for a lower incidence of vomiting was suggested when oral vinorelbine was administered after a standard breakfast. Based on this study, the administration of oral vinorelbine to fasted patients is not mandatory since administration after a standard breakfast does not lead to differences in body exposure to the drug. ...

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

功效与作用

长春瑞宾（Navelbine）是Pierre Fabre公司在20世纪90年代中期开发的一种新型长春花碱类药物。它是一种半合成衍生物，由长春花属植物中的化合物衍生而来，主要通过抑制细胞有丝分裂，在有丝分裂中期对细胞活动进行阻断。长春瑞宾与微管蛋白单体结合，阻碍微管形成。如果没有足够的微管，新复制的染色体会无法被拉开，导致细胞分裂受阻并诱导细胞凋亡。该药物具有高度脂溶性，能够完全解聚微管。

可治疗的恶性肿瘤

长春瑞宾适用于以下几种癌症：

• 乳腺癌
• 睾丸癌
• 卵巢上皮细胞癌
• 非小细胞肺癌

用法用量

给药方法一般为25～30mg/m²，静脉滴注，每周1次，连续4～6次为一个疗程。最新研究显示，每2～3周给予一次50mg/m²的剂量也能被多数患者耐受。

不良反应

常见不良反应包括：

• 骨髓抑制：导致血小板、红细胞及白细胞减少和贫血，大部分在7天内恢复。
• 神经毒性：表现为腱反射减低、便秘或腹泻，罕见麻痹性肠梗阻。此外还有手足麻木、气短、恶心、呕吐和脱发。

注意事项

1. 由于此药可能导致出生缺陷，妊娠或准备妊娠的妇女不应使用该药物。正在使用的患者不宜哺乳。
2. 正在接受该药物治疗的患者不应进行预防接种，因为这会因白细胞减少导致免疫力下降而增加感染风险。同时应避免与刚口服过“脊灰”疫苗的人接触。
3. 药物对静脉有刺激性，注射完毕后应再给予100～250ml生理盐水冲洗静脉，以防止外渗。
4. 用药时避免药物沾染眼球，以免造成角膜溃疡。
5. 使用前需用生理盐水或5%葡萄糖注射液稀释，并在密封玻璃瓶中于室温下保存24小时。

化学性质

• [α]D₂₀+52.4° (C=0.3，氯仿)
• UV最大吸收：乙醇中为215、268、282、293、310nm（ε 3700、11000、9500、7600、4400）
• 二酒石酸长春瑞滨 (Vinordbine Ditartrate): C₄₅H₅₄N₄O_{8·2C4H6O6>，黄白色无定形粉末。溶于水或乙醇。}

用途

• 半合成长春花生物碱，具有广谱抗肿瘤活性且毒性较低。
• 干扰细胞有丝分裂期微管的聚集而产生细胞毒作用。
• 主要用于非小细胞肺癌、乳腺癌、卵巢癌、软组织及内脏转移癌和淋巴癌。

药理药效

主要通过与微管蛋白结合，干扰细胞在有丝分裂过程中微管的形成。

生产方法

长春瑞宾由脱水长春碱（Anhydmvinblastine）经过1步或2步反应得到。

文献信息

• [EN] METHODS OF TREATING CANCER<br/>[FR] PROCÉDÉS DE TRAITEMENT DU CANCER
  申请人：ENDOCYTE INC

  公开号：WO2012065085A1

  公开（公告）日：2012-05-18

  Described are methods and compositions for treating epithelial tumors with a folate-vinca conjugate in combination with at least one other chemotherapeutic agent in which the tumors include ovarian, endometrial or non-small cell lung cancer tumors, including platinum-resistant ovarian tumors and platinum-sensitive ovarian tumors.

  本发明涉及使用叶酸-长春瑞滨偶联物与至少一种其他化疗药物联合治疗上皮肿瘤的方法和组合物，其中肿瘤包括卵巢、子宫内膜或非小细胞肺癌肿瘤，包括铂类耐药性卵巢肿瘤和铂类敏感性卵巢肿瘤。
• Anthracyclin induced immunogenic dead or dying cells composition
  申请人：Institut Gustave Roussy

  公开号：EP1712238A1

  公开（公告）日：2006-10-18

  The present invention is aimed at a composition comprising immunogenic dead or dying cancer cells or infected cells and fragments or fractions thereof obtained by treatment with anthracyclins, to a process of manufacturing said composition and to its use for treating cancer, for preparing a vaccine or for treating infectious diseases. It also relates to a medicament comprising at least one anthracyclin to be injected into or at the vicinity of the tumor.

  本发明的目的是一种由免疫原性死亡或濒死癌细胞或感染细胞及其经蒽环类药物处理后获得的片段或组分组成的组合物、制造上述组合物的工艺及其用于治疗癌症、制备疫苗或治疗传染病的用途。它还涉及一种包含至少一种蒽环类化合物的药物，可注射到肿瘤内或肿瘤附近。
• Devices and methods for determining and/or isolating cells such as circulating cancer or fetal cells
  申请人：Analiza, Inc.

  公开号：US10928405B2

  公开（公告）日：2021-02-23

  Some embodiments of the present invention generally relate to devices and methods for determining and/or isolating cells. For example, one aspect is generally directed to methods and devices for detecting, identifying, counting, and/or potentially sorting cells of interest in blood or other biological sample. In some embodiments, blood samples (or other biological fluids) may be treated with signaling entities, such as pH-sensitive entities, that change color or otherwise produce a signal in suitable internal environments. For example, certain cells, such as cancer or fetal cells, may have differences in intracellular pH compared to other cells, which can be detected using pH-sensitive entities. In certain embodiments, the cells may be sorted based on such signaling entities; for example, illumination of cells in a suitable machine for sorting cells (e.g., using fluorescent light) may allow determination of the cells, which may also be recovered or isolated for further manipulation in some cases.

  本发明的一些实施方案一般涉及用于确定和/或分离细胞的装置和方法。例如，一个方面一般涉及用于检测、识别、计数和/或可能分选血液或其他生物样本中相关细胞的方法和装置。在某些实施方案中，血液样本（或其他生物液体）可以用信号实体（如 pH 敏感实体）处理，这些实体会变色或在合适的内部环境中产生信号。例如，某些细胞（如癌细胞或胎儿细胞）与其他细胞相比，细胞内 pH 值可能存在差异，可使用 pH 值敏感实体进行检测。在某些实施方案中，可根据此类信号实体对细胞进行分选；例如，在用于分选细胞的合适机器中对细胞进行照射（如使用荧光灯），可对细胞进行测定，在某些情况下，还可对细胞进行回收或分离，以便进一步操作。
• EP2576778B1
  申请人：——

  公开号：EP2576778B1

  公开（公告）日：2017-08-09
• METHODS OF TREATING CANCER
  申请人：Endocyte, Inc.

  公开号：EP2638395A1

  公开（公告）日：2013-09-18