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Inhibiting The Inhibitors Chapter IV of IV The Entacapone Story Tasmar vs Comtan (cont.): Makers of both drugs warn that since MAO and COMT are the two major enzymes that regulate catecholamines (norepinephrine and epinephrine), nonselective inhibitors of MAO (e.g., certain antidepressants) should not be taken concurrently with a COMT inhibitor such as Tasmar or Comtan. In the required tests of renal (kidney) toxicity on rat subjects, both drugs at excessive dosage caused some damage, with Comtan apparently somewhat less toxic than Tasmar, but extension of the effect to human subjects is not established for either drug. In the controlled trials of Tasmar, 1% to 3% (depending on dose) of subjects developed AST or ALT levels more than 3 times the upper limit of normal range. Some dropped out at that point and the levels eventually returned to baseline. AST and ALT are enzymes normally confined within living cells of various organs including the liver, and enter the bloodstream only after a cell's outer wall is destroyed when the cell dies. Of the two, ALT is the more specific indicator of liver damage. Since the enzymes don't remain long in the blood, they can only indicate the rate of current or recent cell deaths and not the long-term cumulative condition of the liver. The first death from fulminant liver failure occurred after taking Tasmar for 60 days, suspiciously like the 8-to-9-week incubation of fulminant liver failure that is caused by other drugs or by hepatitis B. But no AST or ALT monitoring was done in that case, so there is no clear connection. Other adverse effects reported by test subjects taking either Tasmar or Comtan seem mainly attributable to the excess of levodopa, if its dosage is not reduced while taking the COMT inhibitor. A possible exception is nausea, the most frequent complaint after dyskinesia, in 14% of Comtan users (vs 8% placebo) and 30%-35% of Tasmar users (vs 18% placebo). Dosage strategy recommendations for Tasmar and Comtan are quite different. Tasmar, in 100mg or 200mg tablets, is started at 100mg twice a day, up to a maximum of 400mg/day, which is only a little more effective but more than twice as likely to raise the level of ALT. It nearly doubles the half-life (and AUC) of a levodopa/carbidopa dose. Elimination half-life of Tasmar is 2 to 3 hours. In trials, over 70% of those taking more than 600mg of levodopa/carbidopa per day were able to reduce that by 30%. Comtan comes only in 200mg tablets, taken with each levodopa/carbidopa dose up to a maximum of 8 (1600mg) per day. Its elimination half-life is basically 25 to 40 minutes, although a small proportion persists longer. In trials, 58% of those taking more than 800mg of levodopa/carbidopa per day were able to reduce that by about 25%. A 200mg dose increases the AUC of levodopa/carbidopa about 35%. -- J. R. Bruman (818) 789-3694 3527 Cody Road Sherman Oaks, CA 91403-5013