Cyclosporine is a very rapidly acting immune suppressor. Effective steady state blood levels can be measured in 24 to 48 hours after starting therapy.9 In most cases a dosage of 6 mg/kg every 12 hours of Neoral will achieve serum concentrations high enough to be therapeutic for GME.6 Whole blood concentrations should be measured soon after starting therapy since there is considerable biological variation in absorption of this drug from one patient to the other. Ideally cyclosporine concentrations of 400 - 600 ng/ml would be achieved 12 hours post pill.9 However it has been shown serum concentrations of only 200 - 400 ng/ml are often effective for GME.6 It appears from blood level testing the half-life of cyclosporine is short in dogs. Generally blood levels 2 to 3 hours post pill are in the 400 - 600 ng/ml range, but 4 to 8 hours post pill the levels are often 200 - 400 ng/ml and 8-12 hours post pill are often less than 200 ng/ml. When this is found it is sometimes necessary to use 6 mg/kg every 8 hours to achieve consistent serum concentrations of cyclosporine over 200 ng/ml throughout the treatment period in dogs.
In general cyclosporine is a safe drug in dogs with few adverse effects. The most common adverse effect is diarrhea, anorexia or vomiting if the dose is too high for a given individual.12 Dividing the dose more evenly throughout the day often resolves this. However, on occasion other adverse effects have been seen such as gingival hyperplasia, papillomatosis, hirsutism, excessive shedding, and insulin resistance or inhibition of insulin release which my require the drug to be discontinued.12 Unlike in humans, the drug is not nephrotoxic or hepatotoxic unless blood levels greater than 3,000 ng/ml are achieved,9 which would be very difficult to do in dogs. Cyclosporine is metabolized by cytochrome P-450. Since phenobarbital induces this enzyme phenobarbital will decrease cyclosporine blood levels.12 However, ketoconazole significantly lowers the dose of cyclosporine needed to achieve an effective blood level and seems to make the blood level more even throughout the day.12 A dose of 10 mg/kg once a day of ketoconazole often allows a 50 to 80 percent reduction in the cyclosporine dose which can result in considerable financial savings since cyclosporine is quite expensive.12 However, it must be kept in mind that ketoconazole has several adverse effects in some dogs. The most common adverse effects are anorexia, vomiting and diarrhea. On occasion the drug can be hepatotoxic. It is teratrogenic; so it should never be given to pregnant dogs. It also lowers gonadal and steroid hormone levels. For these reasons ketoconazole administration with Neoral should only be considered for an owner that cannot possibly afford Neoral therapy any other way.
Generally Neoral is only used in the most resistant cases such as necrotizing encephalitis and spinal cord or blindness form of GME. It may also be used for GME cases that relapse when steroids are withdrawn or when steroids cause too severe adverse effects. Most commonly Neoral is used in combination with prednisone and lomustine. In this situation the prednisone is used for 6 months, the lomustine for one year and the Neoral for 1.5 years. Used this way the permanent remission rate of autoimmune CNS disease of all types approaches 99 percent. |