Levodopa in Parkinson’s disease

Block G, Liss C, Reines S, Irr J, Nibbelink D. Comparison of immediate-release and controlled release carbidopa/levodopa in Parkinson s disease a multicenter 5-year study. The CR First Study Group. Eur Neurol 1997 37 23-27. 

Randomized trials and systematic reviews of trials, therefore, provide the most reliable data on the effects of treatment. That is not to say, however, that non-randomized studies cannot sometimes provide reliable evidence on the benefits of intervention. Few people would doubt the validity of the observational data on the benefits of antibiotic treatment in bacterial meningitis or the benefits of treatment with levodopa in Parkinson s disease. Similarly, clinical guidelines have been revised worldwide on the basis of the non-randomized evidence of the substantial reduction in the risk of early recurrent stroke (see Fig. 19.2, p. 245) as a result of the urgent initiation of standard secondary prevention (Rothwell et al. 2007). 

Theoretically, could reduce the efficacy of levodopa in Parkinson s disease Not rational to combine with another cholinesterase inhibitor... 

Resurgence of chronic disease which has progressed in severity although its consequences have been wholly or partly suppressed, i.e. a catching-up phenomenon, is an obvious possible consequence of withdrawal of effective therapy, e.g. levodopa in Parkinson s disease in corticosteroid withdrawal in autoimmune disease there may be both resurgence and rebound. 

Hershey T, Black KJ, Carl JL, McGee-Minnich L, Snyder AZ, Perlmutter JS (2003) Long term treatment and disease severity change brain responses to levodopa in Parkinson s disease. J Neurol Neurosurg Psychiatry 74 844—851. 

Vidailhet MJ, Bonnet AM, Belal S, Dubois B, Marie C, Agid Y. Ropinirole without levodopa in Parkinson s disease. Lancet 1990 336(8710) 316-17. 

In light of the serious side effects of levodopa in Parkinson s disease, Birk-mayer and Hornykiewicz tried to achieve a levodopa-sparing effect by the concurrent administration of levodopa with an MAO inhibitor. As such combinations frequently elicited hypertensive attacks, they were soon compelled to terminate this line of clinical research (Birkmayer and Hornykiewicz 1962). 

Nutt JG, HoRord NHG. The response to levodopa in Parkinson s disease Imposing pharmacological law and order. Ann Neurol 1996 39 561-573. 

Rabey, J.M., Schwartz, M., Graff, E., Harsat, A. and Vered, Y. (1991) The influence of bromocriptine on the pharmacokinetics of levodopa in Parkinson s disease. Clin. Neuro-pharmacol. 14 514-522. 

Table 3 lists the dose and incidence of the hepatotoxicity for various drugs, some of which have been withdrawn as a result of these findings. Some of the drugs show effects on liver function earlier than the actual onset of liver toxicity, with serum aminotransferase levels raised by threefold the upper limit of normal (ULN). The incidence of this is much higher and can show a classical dose response for instance, tolcapone, a catechol-O-methyltransferase inhibitor used as an adjunct to levodopa in Parkinson s disease, produces threefold the ULN in 1-3% of patients receiving 100 mg TID and 3.7% of patients receiving 200 mg TID (Olanow and Watkins 2007). Tolcapone, an o-nitrocatechol, is metabohzed to reactive intermediates - o-quinone or quinoneimine species - by human fiver microsomes (Smith et al. 2003). 

Shindler JS, Finnerty GT, Towlson K, Dolan AL, Davies CL, I rices JD. Donperidone and levodopa in Parkinson s disease. BrJ Clin Pharmacol (1984) 18,959-62. 

Carter JH, Nutt JG, Woodward WR Hatcher LF, Trotman TL. Amount and distribution of dietary protein affects clinical response to levodopa in Parkinson s disease. Neurology (1989)... 

Gerschlager W, Bloem BR. Hiccups associated with levodopa in Parkinson s disease. Movement Dis 2009 24(4) 621-2. 

Hair Hair and beard darkening was recognized as a complication of treatment with levodopa in Parkinson s disease since its earliest introduction, levodopa-dopamine are intermediate metabolites in the production of melanin, therefore, this association is not surprising. After the introduction of decarboxylase inhibitors, this phenomenon, probably related to peripheral effects of levodopa, became strikingly rare. 

Figure 7.8 Dopamine and motor function. When nigrostriatal dopamine activity is normal so is motor function. Any reduction in this DA activity, as in Parkinson s disease, results in reduced motor activity, i.e. akinesia. By contrast, too much DA activity, as in Huntington s Chorea, produces abnormal motor function, i.e. dyskinesia. The latter may be controlled by neuroleptic drugs (DA antagonists) but they can swing the balance in DA activity sufficiently to produce akinesia (Parkinsonism). DA agonists (and levodopa) may overcome akinesia but can induce DA overactivity and dyskinesia (peak dose effect) (see Chapter 15)...

Henry, B and Brotchie, JM (1996) Potential of opioid antagonists in the treatment of levodopa, induced dyskinesias in Parkinson s disease. Drugs and Ageing 9 149-158. 

MH van Woert. Phenylalanine and tyrosine metabolism in Parkinson s disease treated with levodopa. Clin Pharmacol Ther 12 368-375, 1971. 

Levodopa is the amino precursor of dopamine. It is used to replenish depleted dopamine in Parkinson s disease. Levodopa may cause insomnia, reddish discoloration of urine and headache. 

Bromocriptine is a dopamine agonist acting by direct stimulation of the dopamine receptors. In Parkinson s disease, it is reserved for use in patients who are intolerant to levodopa or in whom levodopa alone is not sufficient. Orphenadrine is an antimuscarinic indicated in Parkinson s disease. Antimuscarinics tend to be more effective than levodopa in targeting tremor rather than rigidity and bradykinesia. Moclobemide is an antidepressant referred to as a reversible monoamine oxidase inhibitor (RIAAA) type A. 

Co-careldopa is a combination of levodopa and the peripheral dopadecar-boxylase inhibitor. Co-careldopa is indicated in Parkinson s disease to improve bradykinesia and rigidity rather than tremor. Orphenadrine is an antimuscarinic agent indicated in patients with Parkinson s disease where tremor predominates. Trifluoperazine is a piperazine antipsychotic that should be used with caution in patients with Parkinson s disease as its use may exacerbate the condition. 

Hallucinations Dopaminergic therapy in Parkinson s disease patients has been associated with hallucinations. In clinical trials, hallucinations developed in approximately 4% of patients treated with 200 mg entacapone or placebo. Dyskinesia Entacapone may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate pre-existing dyskinesia. 

Amantadine is an old drug with several pharmacological properties warranting its (empirical) use in Parkinson s disease facilitation of dopamine release, blockade of dopamine re-uptake, anticholinergic effect, blockade of NMDA receptors. Amantadine is usually employed early in the disease process (monotherapy, 100 mg b.i.d.) and most often in combination with levodopa in more advanced stage disease (anti-dyskinesia effect ). 

Clarke CE, SpeUer JM. Pergolide for levodopa-induced complications in Parkinson s disease. Cochrane Database Syst Rev 1999. 

Kieburtz K, et al. Entacapone improves motor fluctuations in levodopa-treated Parkinson s disease patients. Ann Neurol 1997,52 747-755. 

Adjunct to levodopa/carbidopa in Parkinson s disease longer acting than bromocriptine... 

Modeling is an analytical tool that can be used to extrapolate shorter term clinical results, such as days of improved symptoms in Parkinson s disease patients in a study over 6 months, to longer time periods. A model was developed to extrapolate the results of a 6-month trial in which patients received either levodopa alone or levodopa plus the catechol-o-methyltransferase (COMT) inhibitor entacapone. Comtan (entacapone) is designed to reduce the metabolism of levodopa in peripheral tissue and vessels so that more of the drug is available in the brain at a more constant rate than is seen with levodopa alone. The 6-month clinical trial produced clinical results that allow us to establish entacapone s effect on the OFF time associated with levodopa therapy. OFF time refers to a re-emergence of symptoms prior to the next scheduled levodopa dose. Entacapone reduces the OFF time and increases the ON time of levodopa therapy. 

Dopamine agonists suppress prolactin release very effectively in patients with hyperprolactinemia. GH release is reduced in patients with acromegaly, although not as effectively. Cabergoline and bromocriptine are also used in Parkinson s disease to improve motor function and reduce levodopa requirements (see Chapter 28). Newer, nonergot D2 agonists... 

Lamberti P, Zoccolella S, Iliceto G, Armenise E, Fraddosio A, de Mari M, Livrea P. Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson s disease patients. Mov Disord 2005 20 69-72. 

Olanow CW Stocchi F. COMT inhibitors in Parkinson s disease can they prevent and/or reverse levodopa-induced motor complications Neurology. 2004 62(suppl 1) S72-S81. 

The effect of amantadine on levodopa induced dyskinesias in Parkinson s disease a double-blind, placebo-controlled study. Clin Neuropharmacol. 2000 23 82-85. 

Despite the lack of controlled studies, there is evidence that cannabinoids are of therapeutic value in the treatment of tics in Tourette syndrome, the reduction of levodopa-induced dyskinesia in Parkinson s disease, and some forms of tremor and dystonia. 

Myllyla W, Heinonen EH, Vuorinen JA, Kilkku OI, Sotaniemi KA. Early selegiline therapy reduces levodopa dose requirement in Parkinson s disease. Acta Neurol Scand 1995 91 177-182. 

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