Functional study of four neurotoxins as inhibitors of post-traumatic nerve regeneration

OBJECTIVES/HYPOTHESIS: Chemical inhibition of nerve regeneration was studied as a potential adjunct in the treatment of injuries to the facial or recurrent laryngeal nerve. We propose that by treating selected muscles with an inhibitor of nerve regeneration shortly after injury, synkinesis may be controlled. STUDY DESIGN: Nerve regeneration after crush injury was studied in the rat posterior tibial and sciatic nerves, well-established models for the study of peripheral nerve injuries. METHODS: Four days after controlled crush injury to the posterior tibial nerve, the gastrocnemius muscle was injected with saline (control, n = 8), phenol (n = 6), doxorubicin (n = 6), or vincristine (n = 11). Injection without crush injury was performed using vincristine (n = 4) or botulinum toxin (n = 4). Four rats underwent crush injury to the sciatic nerve followed 4 days later by botulinum toxin injection to the gastrocnemius muscle. The percent of functional recovery (%FR) of the nerve was assessed using walking track analysis. RESULTS: Vincristine significantly retarded nerve regeneration. Five weeks after injury, %FR returned to normal in controls, as well as in the phenol, doxorubicin, and botulinum toxin groups, while in the vincristine group %FR was less than 60% of baseline (P <.0001). Vincristine injections without crush injury showed no significant reduction in print length factor. Functional recovery in the botulinum/crush group was more rapid than the botulinum without crush group. CONCLUSIONS: Application of vincristine to the gastrocnemius muscle significantly inhibits regeneration of the posterior tibial nerve after crush injury. Botulinum toxin does not prolong functional recovery after nerve injury; rather, crush injury protects against the prolonged chemodenervation seen with botulinum toxin. Doxorubicin and phenol injection did not prolong functional recovery at the doses tested.     

Spinal MRI of vincristine neuropathy mimicking Guillain-Barré syndrome

A 4.3-year-old girl with acute leukaemia, who was being treated with chemotherapy (including vincristine), developed paraplegia. Spinal MRI showed diffusely enhancing nerve roots on contrast-enhanced images. Spinal fluid analysis showed a normal protein level. Vincristine neuropathy mimicking Guillain-Barré syndrome is thought to be the cause of the MRI abnormalities.     

瑞香狠毒提取物尼地吗啉与长春新碱和阿霉素体外抗癌活性的比较

中药瑞香狼毒抗癌活性的主成分，二萜化合物尼地吗啉（ｇｎｉｄｉｍａｃｒｉｎ），在体外对小鼠白血病Ｌ─１２１０的细胞增殖及克隆形成均呈现浓度依赖性抑制作用，其５０％细胞增殖抑制浓度和５０％克隆形成抑制浓度（ＩＣ５０）较长春新碱低。对人白血病Ｋ５６２和胃癌Ｋａｔｏ─Ⅲ的５０％细胞增殖抑制浓度和５０％克隆形成抑制浓度（ＩＣ５０）均较阿霉素为低。     

Chemotherapy-evoked neuropathic pain: Abnormal spontaneous discharge in A-fiber and C-fiber primary afferent neurons and its suppression by acetyl-l-carnitine

Cancer patients treated with antimitotic drugs in the taxane and vinca alkaloid classes sometimes develop a chronic painful peripheral neuropathy whose cause is not understood. In animal models of painful peripheral neuropathy due to nerve trauma or diabetes there is obvious axonal degeneration accompanied by an abnormal incidence of spontaneous discharge in A-fiber and C-fiber nociceptors. But animals with paclitaxel- and vincristine-evoked neuropathic pain do not have axonal degeneration at the level of the peripheral nerve. However, recent data show that they do have a partial degeneration of the primary afferent neurons’ terminal arbors in the epidermis. It is not clear as to whether this relatively minor degeneration is accompanied by abnormal spontaneous discharge. We surveyed primary afferent axonal activity in the sural nerve of rats with the paclitaxel- and vincristine-evoked pain syndromes at the time of peak pain severity. Compared to vehicle-injected controls, we find a significant increase in spontaneously discharging A-fibers and C-fibers. Moreover, we show that prophylactic treatment with acetyl-l-carnitine (ALC), which blocks the development of the paclitaxel-evoked pain, causes a significant decrease (ca. 50%) in the incidence of A-fibers and C-fibers with spontaneous discharge. These results suggest that abnormal spontaneous afferent discharge is likely to be a factor in the pathogenesis of chemotherapy-evoked painful peripheral neuropathy, and that the therapeutic effects of ALC may be due to the suppression of this discharge.     

Phase II clinical trial of arsenic trioxide with liposomal doxorubicin, vincristine, and dexamethasone in newly diagnosed multiple myeloma

In patients with multiple myeloma, there is preclinical justification to combine arsenic trioxide (ATO and As₂O₃) with DVd (Doxil™, vincristine, and dexamethasone) for newly diagnosed patients. Eleven patients on this phase II trial received 0.15 mg/kg of ATO for five consecutive days followed by four cycles of DVd plus ATO with the ATO at 0.25 mg/kg IV twice per week. The most common grade 3 toxicities were hyperglycemia, hyponatremia, and hypocalcemia. There were four partial and no complete responses. We could not demonstrate that the addition of ATO with this schedule improved the response rate of MM to DVd.     

Vincristine,an efficacious alternative for diffuse neonatal haemangiomatosis

Diffuse neonatal haemangiomatosis (DNH) is an uncommon condition characterized by multiple cutaneous and visceral haemangiomas frequently causing severe complications. Corticosteroids constitute the first therapeutic line; however, when they fail, other alternatives are available, provided possible side effects are closely monitored during and after treatment. We present a case of life‐threatening DNH, non‐responsive to corticosteroids, successfully treated with Vincristine with minor side effects. We conclude that Vincristine is a valid alternative in corticosteroid‐resistant DNH.     

PDP—PEG2000-DSPE修饰的长春新碱脂质体的制备及其包封率测定

目的研制载有长春新碱并用PDP-PEG2000-DSPE对脂质体膜修饰的脂质体并且测定其包封率。方法采用薄膜蒸发超声分散法制备长春新碱脂质体,并用PDP-PEG2000-DSPE对脂质体膜修饰。应用激光电位粒度仪Zeta3000,以去离子水为分散介质测定样品的体积平均粒径。以高效液相色谱法测定其含量和包封率。结果长春新碱脂质体的平均体积粒径大约150nm左右,包封率40%。结论薄膜蒸发超声分散法适用于制备长春新碱脂质体;高效液相色谱法操作简单,准确,重复性好,可用于测定长春新碱脂质体的含量和包封率。     

Characterization of highly stable liposomal and immunoliposomal formulations of vincristine and vinblastine

Purpose  Liposome and immunoliposome formulations of two vinca alkaloids, vincristine and vinblastine, were prepared using intraliposomal triethylammonium sucroseoctasulfate and examined for their ability to stabilize the drug for targeted drug delivery in vivo. Methods  The pharmacokinetics of both the encapsulated drug (vincristine or vinblastine) and liposomal carrier were examined in Sprague Dawley rats, and the in vivo drug release rates determined. Anti-HER2 immunoliposomal vincristine was prepared from a human anti-HER2/neu scFv and studied for targeted cytotoxic activity in cell culture, and antitumor efficacy in vivo. Results  Nanoliposome formulations of vincristine and vinblastine demonstrated similar pharmacokinetic profiles for the liposomal carrier, but increased clearance for liposome encapsulated vinblastine (t _1/2 = 9.7 h) relative to vincristine (t _1/2 = 18.5 h). Immunoliposome formulations of vincristine targeted to HER2 using an anti-HER2 scFv antibody fragment displayed a marked enhancement in cytotoxicity when compared to non-targeted liposomal vincristine control; 63- or 253-fold for BT474 and SKBR3 breast cancer cells, respectively. Target-specific activity was also demonstrated in HER2-overexpressing human tumor xenografts, where the HER2-targeted formulation was significantly more efficacious than either free vincristine or non-targeted liposomal vincristine. Conclusions  These results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized.     

长春新碱致神经病理性疼痛模型中胶质细胞及IL-1β、GDNF 表达的变化

 目的 研究长春新碱致神经病理性疼痛中胶质细胞是否活化及其作用机制。方法 大鼠腹腔内重复注射长春新碱建立模型。免疫组化检测脑及脊髓中星形胶质细胞和小胶质细胞特异性活化标志物GFAP和OX-42的表达。RT-PCR测定IL-1β和GDNF mRNA在脊髓腰段的表达。结果 给药大鼠分别在第8天和第5天出现机械痛闽降低和热痛耐受时间降低。给药大鼠中脑导水管周围灰质及脊髓灰质中见明显胶质细胞的活化。给药组较对照组IL-1β表达增加，GDNF表达减少。结论 胶质细胞在长春新碱致神经病理性疼痛中明显活化。IL-1β及GDNF与长春新碱引起的神经病理性疼痛有关。     

硫酸长春新碱脂质体的质量评价研究

目的：评价硫酸长春新碱脂质体的质量。方法采用pH梯度法制备硫酸长春新碱脂质体。透射电镜观察脂质体的外观形态,阳离子交换树脂柱法测定包封率,并考察其pH值、粒径、Zeta电位、稳定性及体外释放规律。结果形态学观察结果显示,脂质体均匀圆整度良好。硫酸长春新碱脂质体粒径为120 nm左右,Zeta电位约为10 mV,包封率均在90%以上。光照、4℃、18℃、25℃条件下,脂质体各项指标无显著变化。40℃条件下,包封率明显降低。结论本法准确,操作简便,可用于硫酸长春新碱脂质体的质量评价。