Vincristine
Vincristine is a cell-cycle specific (M-phase) antineoplastic agent derived from the periwinkle plant (*Catharanthus roseus*). It is a cornerstone in veterinary oncology, primarily utilized in combination chemotherapy protocols (such as CHOP) for lymphoid and hematopoietic neoplasms like lymphoma. Key clinical highlights: * **Bone Marrow Sparing**: Unlike many other chemotherapeutics (e.g., its analog vinblastine), vincristine is notably sparing to the bone marrow at standard doses, making it highly valuable in combination protocols. * **Transmissible Venereal Tumors (TVT)**: It is highly efficacious as a single agent for TVT in dogs. * **Immune-Mediated Thrombocytopenia (IMT)**: Vincristine is uniquely used to treat refractory IMT. It promotes the fragmentation of megakaryocytes, leading to a rapid release of platelets into circulation. * **Vesicant**: It is a severe tissue vesicant; strict intravenous administration via a perfectly placed catheter is mandatory to prevent devastating extravasation injuries.
Mecanismo: Vincristine is a cell-cycle specific agent that acts during the **M-phase** (mitosis). * **Antineoplastic Action**: It binds specifically to **tubulin** dimers → inhibits microtubule polymerization → prevents the formation of the mitotic spindle → arrests cell division in **metaphase**, ultimately leading to apoptosis. * **Metabolic Effects**: It interferes with amino acid metabolism by inhibiting glutamic acid utilization and preventing purine synthesis, citric acid cycle, and urea formation. * **Thrombocytosis**: The exact mechanism is unknown, but it is believed to stimulate megakaryocyte fragmentation, accelerating the release of platelets into the peripheral blood. * **Immunosuppression**: Exhibits mild immunosuppressive activity, which may contribute to its efficacy in immune-mediated conditions.
Dosificación por especie
- Neoplastic diseases · 0.5-0.75 mg/m2 · IV · every 1-3 weeks · Dosed in mg/m2, NOT mg/kg. Consultation with an oncologist recommended.
- Neoplastic diseases (particularly lymphoproliferative disorders) · See Appendix for chemotherapy protocols and conversion of body weight to body surface area. · IV · Not specified · Not specified · Must be administered i.v. through a carefully pre-placed catheter.
- Neoplastic diseases · 0.5 mg/m2 (usually 2.5-3 mg total dose per horse) · IV · weekly · Often used in CAP protocol with cytarabine and cyclophosphamide.
- Neoplastic diseases (usually in combination protocols) · 0.5-0.75 mg/m2 · IV · every 1-2 weeks · Dosed in mg/m2, NOT mg/kg. Consultation with an oncologist recommended.
- Transmissible venereal tumor (TVT) · 0.5 mg/m2 (maximum dose 1 mg) · IV · once weekly · for 4-6 weeks · Used as sole therapy.
- Adjunctive treatment of immune-mediated thrombocytopenia (IMT) · 0.5 mg/m2 · IV · once · If platelet count <10-20,000 cells/mcL or bleeding; consider bone marrow aspiration to document megakaryocytes.
- Adjunctive treatment of immune-mediated thrombocytopenia (IMT) refractory to prednisone · 0.5-0.7 mg/m2 · IV · once · Given as an IV bolus or as an infusion over 4-6 hours.
- Adjunctive treatment of immune-mediated thrombocytopenia (IMT) · 0.02 mg/kg · IV · once · Generally single use.
Vías de administración
Contraindicaciones
- Preexisting neuromuscular disease
- Severe leukopenia
- Uncontrolled infection
- No specific absolute contraindications listed, but requires extreme caution in specific disease states
Efectos adversos
- Peripheral neuropathy (proprioceptive deficits, spinal hyporeflexia)
- Paralytic ileus and severe constipation
- Mild leukopenia
- Tissue necrosis and sloughing (if extravasated)
- Anorexia, vomiting, diarrhea
- Impaired platelet aggregation
- Increased liver enzymes
- Syndrome of inappropriate ADH secretion (SIADH)
- Jaw pain
- Alopecia
- Stomatitis
- Seizures
- Pulmonary edema (rare, reported in cats)
- Peripheral neuropathy
- Ileus
- GI tract toxicity
Interacciones farmacológicas
- Asparaginase · Additive neurotoxicity may occur; less common if asparaginase is administered after vincristine.
- Mitomycin · Severe bronchospasm has occurred in humans receiving mitomycin-C with Vinca alkaloids.
- Amiodarone · Inhibits P-glycoprotein; may increase vincristine toxicity, especially in MDR1/ABCB1 mutant dogs.
- Azole Antifungals (e.g., ketoconazole) · Inhibits P-glycoprotein; may increase vincristine toxicity.
- Carvedilol · Inhibits P-glycoprotein; may increase vincristine toxicity.
- Cyclosporine · Inhibits P-glycoprotein; may increase vincristine toxicity.
- Diltiazem · Inhibits P-glycoprotein; may increase vincristine toxicity.
- Erythromycin · Inhibits P-glycoprotein; may increase vincristine toxicity.
- Clarithromycin · Inhibits P-glycoprotein; may increase vincristine toxicity.
- Quinidine · Inhibits P-glycoprotein; may increase vincristine toxicity.
- Spironolactone · Inhibits P-glycoprotein; may increase vincristine toxicity.
- Tamoxifen · Inhibits P-glycoprotein; may increase vincristine toxicity.
Monitorización
- Efficacy (tumor burden reduction or platelet count)
- Peripheral neuropathic clinical signs (e.g., gait abnormalities, constipation)
- Complete blood counts (CBC) with platelets
- Liver function tests (prior to therapy and repeated as necessary)
- Serum uric acid
- Complete Blood Count (CBC) prior to each dose
- IV catheter site for any signs of extravasation during administration
- Gastrointestinal signs (monitoring for ileus or severe constipation)
- Neurological exams (monitoring for peripheral neuropathy, e.g., dragging paws, loss of reflexes)
Sobredosis
Vincristine has a narrow therapeutic index. * **Dogs**: The maximally tolerated dose is reported as 0.06 mg/kg every 7 days for 6 weeks. Toxicity signs include slight anemia, leukopenia, increased liver enzymes, and neuronal shrinkage in the peripheral and central nervous systems. * **Cats**: The lethal dose is reportedly 0.1 mg/kg. Toxic signs include weight loss, seizures, leukopenia, and general debilitation. A reported 10X overdose (5 mg/m2) resulted in death within 72 hours despite intensive care (including calcium folinate). * **Treatment**: Primarily supportive. Includes cardiovascular and hematologic monitoring, anticonvulsants for seizures, and prevention of ileus. Fluid restriction and loop diuretics may be needed to manage SIADH. Leucovorin calcium has been used in humans, but efficacy is unconfirmed.
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