Neurotoxicity vincristine

Jeng MR, Feusner J. Itraconazole-enhanced vincristine neurotoxicity in a child with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2001 18(2) 137-42. 

Sathiapalan RK, El-SoUi H. Enhanced vincristine neurotoxicity from drug interactions case report and review of literature. Pediatr Hematol Oncol 2001 18(8) 543-6. 

In a prospective, double-blind, placebo-controlled study, concurrent oral administration of 500 mg glutamic acid tds with vincristine reduced the incidence of subjective and objective signs of vincristine neurotoxicity (54). There were no differences in constipation, weakness, or loss of knee reflexes. There were no severe gastrointestinal adverse effects. 

Legha SS. Vincristine neurotoxicity. Pathophysiology and management. Med Toxicol 1986 l(6) 421-7. 

Jackson DV, Wells HB, Atkins JN, Zekan PJ, White DR, Richards F 2nd, Cruz JM, Muss HB. Amehoration of vincristine neurotoxicity by glutamic acid. Am J Med 1988 84(6) 1016-22. 

Griffiths JD, Stark RJ, Ding JC, Cooper lA. Vincristine neurotoxicity in Charcot-Marie-Tooth syndrome. Med J Aust 1985 143(7) 305-6. 

Egbelakin A, Ferguson MJ, MacGill E et al (2011) Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 56 361-367... 

The reasons for this interaction are not understood, but among the suggestions are that the itraconazole inhibits the metabolism of vincristine by the cytochrome P450 enzyme system, so that it is cleared from the body less quickly. Another possible explanation is that itraconazole inhibits P-glycoprotein, and increased vincristine neurotoxicity may be the result of the inhibition of this pump in endothelial cells of the blood-brain barri-... 

Ariffin H, Omar KZ, Ang EL, Shekhar K. Severe vincristine neurotoxicity with concomitant use of itraconazole. J Paediatr Child Health (2003) 39, 638-9. 

Muenchow N, Janka G, ErttmannR, Looft G, Bielack S, Winkler K. Increased vincristine neurotoxicity during treatment wifii itraconazole in 3 pediatric patients with acute myelogenous leukaemia. Blood(1999) 94 (Suppl 1, part 2) 234b. 

An isolated case report su ests that vincristine neurotoxicity may possibly have been increased by subsequent asparaginase therapy. The UK manufacturer recommends that vincristine should be given 12 to 24 hours before asparaginase. Regimens including both drugs are commonly used in treating leukaemia. 

Some limited evidence siu esitsi that vincristine neurotoxicity may possibly be increased by isoniazid. 

Eiden C, Palenzuela G, Hillaire-Buys D, Margueritte G, Cociglio M, Hansel-Esteller S, Peyriere H. Posaconazole-increased vincristine neurotoxicity in a child a case report. J Pediatr Hematol Oncol 2009 31 292-5. 

Naumann R, Mohm J, Reuner U, Kroschinsky F, Rautenstrauss B, Ehninger G. Early recognition of hereditary motor and sensory neuropathy type 1 can avoid life-threatening vincristine neurotoxicity. Br J Haematol 2001 115(2) 323-5. 

Cumulative organ toxicity also presents a significant obstacle for effective chemotherapy. In many cases, the severity of the toxicity impedes the broader use of an agent. Other specific toxicities are associated with specific agents, for example cardiotoxicity with adriamycin (32), renal toxicity with i7j -platinum (28), and neurotoxicity with vincristine (49). 

Vinca alkaloids (vincristine, vinblastine, vindesine) are derived from the periwinkle plant (Vinca rosea), they bind to tubulin and inhibit its polymerization into microtubules and spindle formation, thus producing metaphase arrest. They are cell cycle specific and interfere also with other cellular activities that involve microtubules, such as leukocyte phagocytosis, chemotaxis, and axonal transport in neurons. Vincristine is mainly neurotoxic and mildly hematotoxic, vinblastine is myelosuppressive with veiy low neurotoxicity whereas vindesine has both, moderate myelotoxicity and neurotoxicity. 

Vinca alkaloids are derived from the Madagascar periwinkle plant, Catharanthus roseus. The main alkaloids are vincristine, vinblastine and vindesine. Vinca alkaloids are cell-cycle-specific agents and block cells in mitosis. This cellular activity is due to their ability to bind specifically to tubulin and to block the ability of the protein to polymerize into microtubules. This prevents spindle formation in mitosing cells and causes arrest at metaphase. Vinca alkaloids also inhibit other cellular activities that involve microtubules, such as leukocyte phagocytosis and chemotaxis as well as axonal transport in neurons. Side effects of the vinca alkaloids such as their neurotoxicity may be due to disruption of these functions. 

Vinblastine is another vesicant vinca alkaloid that causes myelo-suppression and less neurotoxicity than vincristine. The pharmacokinetics of vinblastine are best described by a three-compartment model, with an a half-life of 25 minutes, a 3 half-life of 53 minutes, and a terminal half-life of 19 to 25 hours.12 Vinblastine has shown activity in the treatment of bladder, breast, and kidney cancer, as well as some lymphomas. The doses of vinblastine tend to be higher on a milligram per meter squared basis than vincristine. Nausea and vomiting are minimal with vinblastine. Other side effects include mild alopecia, rash, photosensitivity, and stomatitis. 

Vincristine—vesicant-avoid extravasation cumulative neurotoxicity—may produce severe constipation -maximum 2 mg per administration... 

Doxorubicin—monitor cumulative dose for cardiac toxicity (not to exceed 550 mg/M2 or 450 mg/M2 with prior chest radiotherapy) vesicant—avoid extravasation use 50% for bilirubin 1.5-3.0 use 25% for bilirubin >3.0 Vincristine—vesicant—avoid extravasation cumulative neurotoxicity—may produce severe constipation maximum 2 mg per administration ... 

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