The initial dosage of lomustine for dogs weighing 20 pounds or less is 30 mg/meter squared once a month. For dogs weighing more than 20 pounds the initial dosage is 50 mg/meter squared once a month. However when the dosage calculation is made the dosage should always be rounded downward to the closest even 2.5 mg increment for dogs weighing 20 pounds or less, and rounded downward to the closest even 10 mg increment for dogs over 20 pounds. Lomustine is supplied as 10 and 40 mg capsules. For small dogs the capsules must be compounded into a smaller size than 10 mg. The capsules should always be handled with gloves by the owner and hospital staff. Some dogs are very sensitive to bone marrow suppression by this drug and others are very resistant. Because of this the first dosage used should be very conservative. A hemogram should be done exactly 6 days after the first treatment. The goal is to have a granulocyte (neutrophil) count nadir of over 1,000 and less than 3,000 cells. The dose should be gradually raised each month until this range is achieved. Each time the lomustine dose is increased a hemogram needs to be done 6 days later. Once the correct dose is found and the same dose is being given each month the hemogram 6 days post treatment is no longer needed. A hemogram should also be done 21 to 29 days after each treatment, and it should reflect a neutrophil count at least over 3000 to safely give the drug again at 30 days. Lomustine therapy is generally used for one year to treat autoimmune CNS disease.
Lomustine is used initially combined with prednisone in all cases of necrotizing encephalitis, and all cases of GME that involve the spinal cord or that cause blindness since these forms of autoimmune CNS disease seem to almost always relapse or not go into remission at all if prednisone only is used. By adding lomustine initially to prednisone in these cases the long-term remission rate is approaching 90 percent.
Cyclosporine is also an effective immunosuppressive drug that can be used in place of, or more often combined with, prednisone and lomustine to achieve maximum immunosuppression.
The microemulsified form (Neoral®), or its generic equivalent (cyclosporine modified), should always be used since its dose is less and the blood level achieved is more uniform due to better intestinal absorption than Cyclosporine USP, Sandimmune® (Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936).9 Cyclosporine acts primarily by strongly suppressing T lymphocyte activation and proliferation. Cyclosporine binds to the cytosol of lymphocytes with cyclosporine-binding proteins and blocks calcium-dependent signal transduction blocking T-cell activation.9 In addition it prevents synthesis of several cytokines such as interleukin-2, which further inhibits T-cell proliferation.9 It has been shown by immunohistochemical studies that the bulk of lymphocytes in GME lesions of the brains of dogs are CD3 antigen positive T lymphocytes.10 The data from these studies strongly suggests that canine GME is a T-cell-mediated delayed-type hypersensitivity, organ-specific autoimmune disease.10 Therefore, cyclosporine's T-cell specificity makes it a good choice to treat GME. Cyclosporine is lipophilic and has poor blood-brain barrier permeability; however it may be trapped in the endothelial cells and the chroid plexuses of the CNS since it concentrates mostly in intracellular compartments including of erythrocytes and leukocytes.11
GME primarily creates perivascular lesions in the CNS; so it is likely that cyclosporine would enter the intracellular compartment of the lymphocytes and macrophages in these perivascular granulomas.6 |