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2.6.10
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2.6.10
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NO RESPONSE. A few patients with parkinsonism will experience no beneficial response to carbidopa-levodopa in any dose. Such patients with parkinsonian symptoms probably do not have PD but rather striatonigral degeneration or some other similar condition in which the pathology is beyond the substantia nigra, involving other portions of the extrapyramidal motor system. An adequate trial of medication must be employed before concluding that the patient is a nonresponder. Management (breakout 13) Patients who fail to respond to lower dosages of carbidopa-levodopa can have the dosage gradually raised, with the standard rather than the CR preparation for the purposes of this trial. Patients should be instructed to take their doses on an empty stomach. to make certain the poor response is not secondary to the inhibitary effects of dietary protein. Once the dosage has been slowly pushed up to approximately 1,200 mg per day (eg, 300 mg four times daily) with no response, it would then be reasonable to conclude that carbidopa-levodopa therapy is not beneficial. Since the long-duration levodopa response takes several days to become fully manifest, patients should be maintained on the higher doses for approximately 1 week to allow the full effects to occur. Certain patients being seen in the office who report no response to levodopa may be challenged with a somewhat larger dose than they have been taking. If there is still no response, however, this strategy should not preclude going ahead with a trial of chronic administration of higher doses of carbidopa-levodopa, since some patients manifest a long-duration effect that will not be seen after one or two doses. Obviously, the aforementioned strategies pertain to patients who simply fail to respond to carbidopa-levodopa rather than those who cannot tolerate this medication, for whom other strategies may apply. Patients who fail to respond to very high doses of carbidopa-levodopa are unlikely to respond to dopamine agonist medications either, although some clinicians choose to try these nonetheless. Patients who fail to respond to levodopa and whose primary problem is tremor or dystonia can he given a trial of anticholinergic therapy {eg, trihexyphenidyl, benztropine).
SUBOPTIMAL PEAK RESPONSE. Patients who experience suboptimal motor control at the time of peak effect of levodopa can have their response potentiated in a variety of ways (breakout 14). The simplest approach is to raise the individual doses of levodopa (with carbidopa) by small and gradual increments until improvement develops. The point of diminishing returns is at approximately 250 mg of levodopa per dose of the standard formulation and 400 mg of the CR formulation. Rare patients may require slightly higher doses for maximum effect. Although no compelling evidence points to levodopa toxicity, some concerns do exist;[114] hence, some clinicians have favored keeping the levodopa dosage lower and instead adding or increasing one of the two available adjunctive dopamine agonist drugs, bromocriptine or pergolide. A minimum total daily dose of 15 mg of bromoctiptine or 1.5 mg of pergolide (divided) is usually necessary to achieve a minimally clinically significant effect. Selegiline also will potentiate the peak effect of levodopa therapy[115] by inhibiting MAO-B, one enzymatic route of dopamine degradation. If tremor is prominent, the addition of an anticholinergic drug, such as trihexyphenidyl or benztropine, may be helpful, if tolerated. Amantadine is also mildly beneficial as an adjunctive drug in this situation. Unfortunately occasional patients experience side effects that limit the dosage of medications that can be administered. These include hallucinations, psychosis, confusion, nightmares, and dyskinesias, which can be induced or exacerbated by levodopa, dopamine agonists, or selegiline. Anticholinergic drugs have their own side-effect spectrum that includes memory impairment, hallucinations, psychosis, constipation, urinary hesitancy, and visual blurring.
OPTIMAL PEAK RESPONSE BUT "WEARING OFF." Adjustment of medications to obtain an optimal peak effect generally is the initial strategy. Subsequently, the focus shifts to the levodopa response duration. Patients with "wearing off" of their levodopa effect before the next dose may respond to one of several strategies (breakout 15). Substituting sustained-release caribidopa-levodopa for the standard formulation typically will add 60 to 90 minutes to the response duration.[116] Although there is not a direct milligram to milligram correspondence between the standard and CR formulations of carbidopa-levodopa, simple dosing guidelines allow a rapid transition. In converting to the CR formulation, the individual doses must be 30 to 50% higher to achieve the same peak effect.[116] The interval between doses is adjusted to correspond with the estimated response duration. Simply shortening the interval between carbidopa-levodopa doses (standard or CR formulation) is a common sense strategy for countering "wearing-off" effects. Optimally, the next dose should be given just before the effects from the last dose have worn off. Patients with short-duration responses often respond well to adjunctive dopamine agonist therapy with bromocriptine[117] or pergolide.[118] The dosage is started at subtherapeutic levels (1.25 mg of bromocriptine or 0.05 mg of pergolide daily), and hence the levodopa dosage should be maintained until a clinical response develops. Subsequently, the levodopa dosage can be gradually lowered as the clinical effects from bromocriptine or pergolide become apparent. The clinically effective range of dosages is approximately 15 to 50 mg of bromocriptine or 1.5 to 5.0 mg of pergolide daily (divided). Occasionally, switching from one dopamine agonist to another (eg, bromocriptine to pergolide using a 10-to-1 potency ratio is helpful). The expense of the highest doses of these drugs may be prohibitive, however, for certain patients. In patients with severe fluctuations, if titration cannot be adequately achieved with the above measures, transition to liquid carbidopa-levodopa may be considered.[119] Very close titration is possible with this strategy, resulting both in less "off" time and potentially fewer dyskinesias (see below) The disadvantages are: a much shorter response duration (60 to 90 minutes), the requirement for the patient to prepare the liquid formulation, and the lack of stability of levodopa in solution. This last problem is countered by adding ascorbic acid for stabilization, but even then, the liquid preparation cannot be carried over from one day to the next. The usual mixture is prepared by pulverizing with mortar and pestle, ten 25/100 standard carbidopa-levodopa tablets and 2 g of ascorbic acid, which are then added to 1 liter of tap water.[119] The transition from tablet to liquid carbidopa-levodopa is made by administering small levodopa doses at 60- to 90-minute intervals, with the total daily dose similar to that given with tablets; further titration is based on the response. Several investigational drugs are under development for treatment of response fluctuations. These include novel dopamine agonists, catechol-O-methyl transferase inhibitors, and selective MAO inhibitors. Patients who experience fluctuations may wish to take advantage of the opportunities for entry into investigational protocols, which are available at many major medical centers.
