58Â° Congresso Nazionale SCIVAC: Oncologia veterinaria

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58° Congresso Nazionale SCIVAC • Milano, 7-9 Marzo 2008 • Oncologia veterinaria - Alle soglie del III Millennio phosphamide and has a slower course of action. Gastrointestinal and dermatologic concerns are infrequent. Indications Useful in a variety of neoplastic diseases including chronic lymphocytic leukemia, and as a maintenance agent for treatment of canine and feline lymphosarcoma. Chlorambucil is also used in human medicine for treatment of multiple myeloma, polycythemia vera, macroglobulinemia, and ovarian adenocarcinoma. It may be substituted for cyclophosphamide in those lymphoma patients with sterile hemorrhagic cystitis, or for those patients with excessive adverse effects from cyclophosphamide. Useful as adjunctive therapy for some immune mediated conditions (eg. glomerulonephritis, nonerosive arthritis, or immune-mediated skin disease). Chlorambucil is the drug of choice of some clinicians for the treatment of feline immune-mediated dermatoses such as pemphigus foliaceus and feline eosiniphilic granuloma complex, because of the drug’s efficacy, small tablet size, and lack of severe toxicity. Contraindications Contraindicated in patients that are hypersensitive or who have demonstrated drug resistance. Used with caution in patients with preexisting bone marrow depression or infection. LOMUSTINE The nitrosourea class of alkylating agents was developed in the mid- 1960’s, specifically as potential CNS tumor agents due to the high degree of lipophilicity of these compounds. Mechanism of action Alkylation of DNA results in intrastrand DNA cross-links, with preferential targeting of the O-6 position of guanine in DNA. Upregulation of O6 - alkylguanine-DNA alkyltransferase can repair the DNA lesion and allow the cell to survive. Upregulation of the nucleotide excision repair pathway is also associated with drug resistance. 60
58° Congresso Nazionale SCIVAC • Milano, 7-9 Marzo 2008 • Oncologia veterinaria - Alle soglie del III Millennio Pharmacokinetics Lomustine is administered orally. The standard dose used in small animals ranges from 50 mg/m 2 to 90 mg/m 2 PO on a 3-week basis. Dose for cats has been reported at 60 mg/m 2 PO or as a 10 mg dose per cat every 3 weeks. Lomustine is widely distributed because of its lipid solubility. It penetrates the blood-brain barrier and CSF levels are 15-50% of plasma. Lomustine is extensively metabolized in the liver to both inactive and active metabolites. The half-life of the active metabolites ranges from 16 hours to 2 days. Lomustine’s active and inactive metabolites are excreted primarily in the urine. Prolongation of plasma concentration is thought to reflect a combination of protein binding and enterohepatic recirculation of metabolites. Toxicity The major toxic effect of lomustine therapy is acute and delayed (4-6 weeks post dosing) bone marrow suppression (especially thrombocytopenia and leukopenia). It is recommended that the practitioner monitor the CBC one week after dosing, and again immediately before the next dose is scheduled. Myelosuppression can occur for up to 6 weeks after dosing. Nausea and vomiting are rarely seen with lomustine use. Hepatic toxicity has been described in dogs. While most of the hepatic toxicity seen was manifested as reversible elevation of liver enzymes, a small percentage of dogs had progressive, fatal hepatic failure. Indications Veterinary indications include the treatment of refractory lymphosarcoma in dogs and cats, metastatic mast cell disease in dogs and cats, cutaneous lymphosarcomas, and central nervous system tumors. Contraindications Use with caution in dogs treated with drugs that need microsomal enzyme induction (ie phenobarbital) due to the possible changes in antineoplastic activity. Combination with other myelosuppressive drugs should be carefully monitored. Lomustine has been demonstrated to induce significant and even fatal hepatic toxicity in a limited number of canine patients; its use is therefore contraindicated in patients with pre-existing clinical hepatic dysfunction. Use should be discontinued in the face of elevating liver enzyme levels. 61
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58Â° Congresso Nazionale SCIVAC: Oncologia veterinaria

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