L-Dopa dosing

Selegiline (deprenyl Eldepryl) is an irreversible MAO-B inhibitor that blocks dopamine breakdown and can modestly extend the duration of action of L-dopa (up to 1 hour). It often permits reduction of L-dopa dose by as much as one-half. 

Because entacapone has a shorter half-life, 200 mg is given with each dose of carbidopa/L-dopa up to eight times a day. Dopaminergic adverse effects may occur and are managed easily by reducing the carbidopa/L-dopa dose. Brownish-orange urine discoloration may occur (as with tolcapone), but there is no evidence of hepatotoxicity from entacapone. 

Today, L-dopa is used almost exclusively as a combination product with decarboxylase inhibitors. Starting L-dopa doses of 200-300 mg/day often are adequate for relief of disability. Some patients require larger amounts on a daily basis however, the usual maximal dose of L-dopa needed by patients even with severe parkinsonism is 800 mg/day. Slow buildup of dose (e.g., increments of 100 mg L-dopa per week) can help to assess the lowest effective dose and minimizes the risk for adverse effects, such as postural hypotension, nausea, vomiting, sedation, and vivid dreams. 

With advancement of IPD, a single carbidopa/L-dopa dose may produce benefits for as little as 1.5 to 2 hours. As a result, carbidopa/ L-dopa needs to be given more frequently in order to prevent the wearing off of its benefits. Alternatively, a controlled-release product is available (Sinemet CR, Bristol-Myers Squibb various generic brands) that can extend the duration of L-dopa effect thus there is a more gradual wearing off of L-dopa effect and a need for fewer daily doses. Some patients will require an increase in L-dopa intake when switched to the sustained-release form because of its decreased bioavailability. Patients maintained on the sustained-release product also may require a conventional carbidopa/L-dopa dose in the morning for its more rapid absorption and response. 

Fig, 14.12 Hypothelical L-dopa dose increase if indefinite doses were tolerated. 

COMT inhibitors rescue l-dopa and improve the brain entry of L-dopa by decreasing 3-OMD formation in peripheral tissues. The dose of L-dopa could be decreased, compared with the present combination therapy. Dose interval of L-dopa could also be prolonged. Further, COMT inhibitors should decrease fluctuations of dopamine formation in the brain. 

Clinical studies, available only for entacapone and tolcapone, support preclinical findings. A dose-dependent (100-800 mg) inhibition of the COMT activity of the erythrocytes can be seen after nitrocatechols. However, effective and sufficient dose levels of both entacapone and tolcapone, given concomitantly with L-dopa and DDC inhibitors to patients with Parkinson s disease, appear to be 100-200 mg. However, the treatment strategies of entacapone and tolcapone differ entacapone is a short-acting compound that is given with each dose of L-dopa, and COMT activity may even... 

L-DOPA/Levodopa Dopa Decarboxylase Dopamine System Dopamine- 3-hydroxylase Dopaminergic Neurotoxicity Dose... 

SJ Tye, NM Rupniak, T Narase, M Miyaji, SD Iversen. NB-355 A novel prodrug for L-dopa with reduced risk for peak-dose dyskinesias in MPTP-treated squirrel monkeys. Clin Neuropharm 12(5) 393-403, 1989. 

The answer is c. (idardman, p 510.) Carbidopa is an inhibitor of aromatic L-amino acid decarboxylase. It cannot readily penetrate the central nervous system (CNS) and, thus, decreases the decarboxylation of L-clopa in the peripheral tissues. This promotes an increased concentration of L-clopa in the nigrostriatum, where it is converted to dopamine. In addition, the effective dose of L-dopa can be reduced... 

The answer is a. (Hardman, p 510. Katzung, p 467J Fluctuations in clinical response to L-dopa may or may not be related to drug levels (time of last dose). The likelihood of both kinds of fluctuation increases with longer duration of treatment. When these fluctuations are unrelated to... 

Starting L-dopa at 300 mg/day (in divided doses) in combination with carbidopa often achieves adequate relief of disability. The usual maximal dose of L-dopa is 800 to 1,000 mg/day. 

Provide smaller doses of carbidopa/L-dopa add amantadine consider surgeiy... 

The starting and recommended dose of tolcapone is 100 mg three times daily as an adjunct to carbidopa/L-dopa. Its use is limited by the potential for fatal liver toxicity. Strict monitoring of liver function is required, and tolcapone should be discontinued if liver function tests are above the upper limit of normal or any signs or symptoms suggestive of hepatic failure exist. It should be reserved for patients with fluctuations that have not responded to other therapies. 

Six patients with Parkinson s disease were withdrawn from their antiparkinsonian medications (L-DOPA/carbidopa, bromocriptine, or lisuride) (Rabey et al. 1992, 1993). After 12 hours off medication, the subjects ate 250 g of cooked fava beans. Significant improvements in motor symptoms were noted, comparable to those seen with 125 mg of L-DOPA and 12.5 mg of carbidopa. In fact, three subjects developed severe dyskinesias after fava ingestion, akin to those seen after larger doses of pharmaceutical L-DOPA. Plasma levels of L-DOPA increased after fava ingestion in a manner comparable to that seen with administration of oral L-DOPA. These results suggest that the L-DOPA contained in fava beans was transported into the CNS and converted to dopamine. In five nonparkinsonian, healthy volunteers, a similar increase in plasma L-DOPA was observed after fava ingestion, although much lower. The difference in plasma L-DOPA between normal volunteers and parkinsonian patients is apparently due to a residual effect of carbidopa in the subjects with Parkinson s disease. Without carbidopa, the L-DOPA from fava is rapidly converted to dopamine in the blood stream and never crosses the blood-brain barrier. 

L-DOPA can be initiated at 50 mg taken at bedtime and increased stepwise over a few weeks until the symptoms are relieved. Bromocriptine can be initiated at 7.5 mg at bedtime, pramipexole is often dosed at 0.125-0.375 mg at night, and ropinirole, which has an indication for RLS, is typically administered at 0.25-3 mg at bedtime. These medications are not without side effects. They may cause nausea and, over time, insomnia. Less commonly, these medications can cause hallucinations or involuntary movements called dyskinesias. These side effects usually resolve rapidly upon discontinuing the medication. 

Acetylcholine Precursors. Your nerve cells produce acetylcholine from certain dietary precursors (choline and lecithin). Many early studies tried dietary supplements of these precursors. A precedent for this approach was established using the dopamine precursor, L-DOPA, a well-established treatment for Parkinson s disease. Unfortunately, this approach is ineffective in dementia. It appears that the daily doses of these fatty acid precursors needed to have any discernible impact on acetylcholine levels far exceed what an individual can reasonably take in a day. This approach has therefore been abandoned. 

The powdered seeds of Mucuna pruriens L. have been used in Ayurvedic medicine for diseases of the nervous system and have shown to reduce adverse effects in PD patients. HP-200, a commercial extract of M. pruriens was shown to be twice as effective as the equivalent dose of L-DOPA in rats, although a later study showed that when the same preparation was given to rats over a 52 weeks period, it did not elevate DA levels in the striatum nigrum, but in the cortex. This calls into question whether the observed improvements in parkinsonian symptoms were due to the hypothesis originally proposed i.e. that the L-DOPA in the Mucuna extract was converted to DA and reached the parts of the brain where a deficiency is associated with PD. ... 

Dyskinetic activity. A 4-week dose escalation study was performed to assess the safety and tolerability of cannabis in six patients with Parkinson s disease (PD) with levodopa (L-DOPA)-induced dyskinesia. 

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