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To: Alan Bonander and Multiple recipients of PARKINSN list From: Brian Collins: <[log in to unmask]> Subject: Sinemet CR. Hi Alan, I'm really enjoying this discussion (and learning a lot also). I'd like to talk about the effect of using Sinemet CR on newly-diagnosed patients. Basically, I'm against it, but I think I have a reasonable explanation of what goes on. Have you ever considered what would happen if you gave a normal non- Parkinsonian a large dose of levodopa ? Based on the way that we react to just a small excess, we might expect a pretty violent reaction from a non-sufferer. In fact, apart from possibly a slight headache, there is no other reaction ! The reason for this (to me) surprising result is that the normally functioning brain operates on a feed-back system to regulate the required level of Dopamine in the brain. When an external source of Dopamine appears, the brain simply shuts down as much of the normal Dopamine production as necessary to maintain the required total flow rate. In a PD sufferer's brain, around 80% to 90% of the normal Dopamine producing cells have died, so the remaining system is limited in the response that it can make to an external dose of Dopamine - too much really will result in an excess of Dopamine and hence dyskinesias. At the same time, some external Dopamine is needed to keep the normal functions going. Now, if we consider a relatively newly- diagnosed PD patient, he still has some production capability, requires less external Dopamine, and can (to a certain degree) regulate this production system to cope with excessive dosage. However, just because the brain can cope with an *overdose* does not mean that it is a good thing to do it on a regular basis with a larger than necessary tablet dosage. It has been suggested that a sort of burn-out could result from contnued larger than necessary doses. I believe that if we operate on the basis of *just enough* we will prolong the useful time that we can extract from Levodopa. I am fascinated (and impressed) by your experience with direct infusion of liquid sinemet. I would imagine that with this system, you would tend to operate on the *just enough* principle. It is interesting that I have also found ( over a 2 to 3 year span, that my just-enough dosage level has also remained at a virtually constant level (using the computer analysis system which I have mentioned previously.) The thing that does progressively decrease is the tolerable overdose level, above which dyskinesias occur. One day this level will be lower than the required mimimum dosage level: Until then, I can cope . ( It's like the man who fell off a skyscraper building - as he passed a second floor window, he was heard to say "So far, I'm coping pretty well". Regards, Brian Collins [log in to unmask]