Levodopa, treatment of Parkinson

Presthus J, Holmsen R. Appraisal of long-term levodopa treatment of parkinsonism with special reference to therapy limiting factors. Acta Neurol Scand 1974 50(6) 774-90. 

Domperidone is a dopamine antagonist similar to metoclopramide. However, since it acts on the dopamine receptors in the stomach wall, and unlike metoclopramide, it does not readily cross the blood-brain barrier, it does not appear to oppose the effects of levodopa within the brain, although some extrapyramidal symptoms have been observed. It may even slightly increase the bioavailability and effects of levodopa (by stimulating gastric emptying). Domperidone can therefore be used to control the nausea and vomiting associated with levodopa treatment of Parkinson s disease. 

Presthus J, Berstad J, Lien K. Selegiline (1-deprenyl) and low-dose levodopa treatment of Parkinson s disease. Acta Neurol Scand (1987) 16, 200-3. 

Sweet RD, Lee JE, McDowell FH. Methyldopa as an adjunct to levodopa treatment of Parkinson s disease. Clin Pharmacol Ther( 912) 13, 23-7. 

While a number of drugs, e.g. a-methyl dopa, inhibit the enzyme they have little effect on the levels of brain DA and NA, compared with inhibition of tyrosine hydroxylase and they also affect the decarboxylation of other amino acids. Some compounds, e.g. a-methyl dopa hydrazine (carbidopa) and benserazide, which do not easily enter the CNS have a useful role when given in conjunction with levodopa in the treatment of Parkinsonism (see Chapter 15) since the dopa is then preserved peripherally and so more enters the brain. 

Monoamine oxidase exists in two forms, MAOa and MAOb. The former is more active against NA and 5-HT than it is against DA, which is a substrate for both, even though, like S-phenylethylamine, it is more affected by MAOb. H seems likely that MAOb is the dominant enzyme in human brain and inhibitors of it, such as selegiline, have some value in the treatment of Parkinson s disease by prolonging the action of the remaining endogenous DA as well as that formed from administered levodopa. 

NG Gillespie, I Mena, GC Cotzias, MA Bell. Diets affecting treatment of parkinsonism with levodopa. J Am Diet Assoc 62 525-528, 1973. 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

Levodopa (L-DOPA), the most reliable and effective drug used in the treatment of parkinsonism, can be con-... 

A recently introduced class of drugs for the treatment of parkinsonism is the catechol-O-methyl transferase (COMT) inhibitors. COMT metabolizes catechol compounds, including dopamine and levodopa (see Chapter... 

Adjunctive treatment of Parkinson s disease PO Initially, 100-200 mg 3 times a day concomitantly with each dose of carbidopa and levodopa. Maximum 600 mg/day Dosage in hepatic impairment Patients with moderate to severe cirrhosis should not receive more than 200 mg tolcapone 3 times a day... 

Presented in Fig. 9.3 is an example of a model used to extrapolate the 6-month trial results of a COMT inhibitor (entacapone) used in combination with levodopa versus levodopa alone in the treatment of Parkinson s disease. This particular model is an example of a Markov model... 

Levodopa is the most effective drug available for the treatment of parkinsonism... 

The treatment of Parkinson s disease is often an exercise in polypharmacy, since no single agent is fully effective over the course of the disease. Most antimuscarinic drugs promoted for this application (see Table 28-1) were developed before levodopa became available. Their use is accompanied by all of the adverse effects described below, but the drugs remain useful as adjunctive therapy in some patients. 

Levodopa, which is converted to dopamine in the body, and dopamine agonists with central actions are of considerable value in the treatment of Parkinson s disease and prolactinemia. These agents are discussed in Chapters 28 and 37. 

There is no clear consensus of which drugs should be used in the initial and subsequent treatment of Parkinson disease. Future research should help clarify whether it is better to begin treatment with dopamine agonists, and to save levodopa and other medications until later in the disease course. Ultimately, the physi-... 

Olanow CW Agid Y, Mizuno Y, et al. Levodopa in the treatment of Parkinson s disease current controversies. Mov Disord. 2004 19 997-1005. 

Tyrosine is converted to dopa by the rate-limiting enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin, and is inhibited by a-methyltyrosine. Dopa is decarboxylated to dopamine by L-aromatic amino acid decarboxylase, which requires pyridoxal phosphate (vitamin B6) as a coenzyme. Carbidopa, which is used with levodopa in the treatment of parkinsonism, inhibits this enzyme. Dopamine is converted to norepinephrine by dopamine P-hydroxylase, which requires ascorbic acid (vitamin C), and is inhibited by diethyldithiocarbamate. Norepinephrine is converted to epinephrine by phenylethanolamine A -methyltransferase (PNMT), requiring S-adeno-sylmethionine. The activity of PNMT is stimulated by corticosteroids. 

Levodopa (L-dopa) is a natural intermediate in the biosynthesis of catecholamines in the brain and peripheral adrenergic nerve terminals. In the biologic sequence of events it is converted to dopamine, which in turn serves as a substrate of the neurotransmitter norepinephrine. Levodopa is used successfully in the treatment of Parkinson s syndrome, a disease characterized by dopamine deficiency. When levodopa is administered to an individual with this syndrome, the symptoms of Parkinson s disease are ameliorated, presumably because the drug is converted to dopamine and thereby counteracts the deficiency. Individuals treated with levodopa, especially older men, have been observed to experience a sexual rejuvenation. This effect has led to the belief that levodopa stimulates sexual powers. Consequently, studies with younger men complaining of decreased erectile ability have shown that levodopa increases libido and the incidence of penile erections. Overall, however, these effects are short lived and do not reflect continued satisfactory sexual function and potency. Thus, levodopa is not a true aphrodisiac. The increased sexual activity experienced by parkinsonian patients treated with levodopa may reflect improved well-being and partial recovery of normal sexual functions that were impaired by Parkinson s disease. 

The following are new, non-ergot dopamine agonists that have been approved for the treatment of Parkinson s disease. Pramipexole and ropinirole are effective as first-line and adjunctive therapy, whereas tolcapone should only be used as an adjunct in patients on levodopa/carbidopa. 

Dose. Usually the equivalent of 50 mg of benserazide daily, increasing to 100 to 250 mg daily (given in combination with levodopa in the treatment of parkinsonism). 

Selegiline is a relatively selective and irreversible inhibitor of monoamine oxidase type B, which has been used in the treatment of Parkinson s disease. It was originally suggested that selegiline may be neuroprotective. However, in a prospective double-blind study no such action was seen (1). On the other hand, selegiline does delay the start of disability, determined by the need for levodopa and progression of parkinsonian signs and symptoms (2). 

Adjunctive to levodopa/carbidopa in treatment of Parkinson s disease... 

Papavasiliou, P.S. Cotzias, G. Rosal, V.L.F. Miller, S.T. (1978) Treatment of parkinsonism with N-//-propyl norapomorphine and Levodopa (with or without Carbidopa). Arch. Neurol. 35, 787-791. 

There are several promising opportunities in the treatment of Parkinson s disease 1. to slow the progress of the disease and delay the timepoint at which levodopa is needed in de novo patients with Parkinson s disease by administering (-)-BPAP, a much more potent and selective enhancer substance than (-)-deprenyl 2. to administer a carefully adjusted dose of (-)-deprenyl when levodopa is already needed and 3. to make a safe use of the levodopa-sparing effect of (-)-deprenyl. 

Parkinson Study Group (1996) Impact of deprenyl and tocopherol treatment of Parkinson s disease in DATATOP patients requiring levodopa. Ann Neurol 39 37-45... 

Levodopa is a prodrug for the neurotransmitter dopamine and as such has been used in the treatment of Parkinson s disease—a condition due primarily to a deficiency of the neurotransmitter dopamine. Dopamine itself cannot be used since it is too polar to cross the blood-brain barrier. 

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