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Inhibiting The Inhibitors Chapter II of IV The Entacapone Story Carbidopa, Benserazide: Looking for a "decarboxylase inhibitor" (DCI)that would prevent the conversion of levodopa to dopamine outside the brain, but would not itself cross the blood-brain barrier, researchers selected the two named above. Carbidopa and levodopa are combined in the U.S. drugs Sinemet or Atamet, while the benserazide/ levodopa combination is sold in Europe as Madopar or Prolopa. Levodopa is only slightly soluble in water, and is absorbed mostly in the small intestine, competing with proteins in food for the same entry channels. The blood takes it from there to the brain. Experience varies widely in and between individuals, but roughly, the effects of levodopa combined with a DCI are felt in from 20 to 30 minutes, reach a peak in about an hour, then decline to zero after 4 hours or so. Even with a DCI, only a small proportion of a levodopa dose becomes dopamine in the brain, the rest ending in other parts of the body. Since dosage by mouth is periodic, The plasma concentration of levodopa follows a sort of sawtooth profile over time, which leads to corresponding fluctuations of the PD symptoms between the "peak- dose" and "end-of-dose" conditions. These can appear as dyskinesias, dystonia (painful muscle cramps), inappropriate temperature sensation and control, mood swings, immobility, and others. They may be disabling or uncomfortable and (some suspect) harmful to the remaining dopamine pathways in the brain, therefore it's desirable to maintain the concentration of medicinal levodopa as steady as possible. Fight-Or-Flight: An automatic defense of the body during an emergency is to increase production by the adrenal glands of the catecholines norepinephrine and epinephrine (Adrenalin), a powerful stimulant that increases blood pressure and heart pulse rate. The adrenal glands make the final product, epinephrine, by a series of reactions that begin with tyramine, abundant in many foods such as cheese, beer, wine, chicken liver, and so forth. Tyramine is converted to tyrosine, which is changed to dopamine, that becomes norepinephrine, the precursor of epinephrine. As most of us know, Adrenalin is commonly used to treat life- threatening shock in emergency cases, but may itself cause a life-threatening cerebral hemorrhage or other injury due to the increased blood pressure or heart rate. -- J. R. Bruman (818) 789-3694 3527 Cody Road Sherman Oaks, CA 91403-5013