Dopamine agonists, for parkinsonism

Zanetti, R., Antonini, A., Gatto, G., Gentile, R., Tesei, S. and Pezzoli, G. (2007) Valvular heart disease and the use of dopamine agonists for Parkinson s disease. The New England Journal of Medicine, 356, 39-46. 

A number of azetidine-based compounds have been disclosed in patent applications from Aventis Pharma for CBi-modulated treatment of diseases such as obesity, Parkinson s disease, schizophrenia, respiratory and neurological diseases [330-334]. Compound (556) was specifically claimed for use in two formulation patent applications [330, 331] for a stable semi-solid composition and oral emulsion composition, respectively. The optional coadministration of an agent that activates norepinephrinergic and se-rotoninergic neurotransmission (for example, sibutramine) or dopaminergic neurotransmission was also claimed for the treatment of obesity. The optional use of a dopamine agonist (for example, levodopa) was claimed... 

Bennett JP, Piercey MF (1999) Pramipexole-new dopamine agonist for the treatment of Parkinson s disease. J Neurol Sci 163 25-32. 

A more recent application of oxime derivatives as prodrugs is the design of cascade prodmgs of dopamine agonists for the treatment of Parkinson s disease. As shown in Scheme 16, enones such as S-(-)-6-(Af,Af-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2//-naphthalen-l-one (103) can be oxidized in vivo to catecholamines... 

The pathology of Parkinson s disease is associated with a substantial reduction in neurotransmitters such as dopamine, 5-hydroxytryptamine, GABA, in the brain. Treatment is based on the use of replacement of dopamine or dopamine agonists which relieve the rigidity but do not affect a cure. Currently, there is no laboratory-based diagnostic test for PD and so diagnosis is based on clinical presentation alone. 

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. 

The antihistamine diphenhydramine (Benadry/), because it has anticholinergic properties, is used for mild parkinsonism and with the elderly, who may not be able to tolerate the more potent anticholinergics, levodopa, or the dopamine agonists. 

Consistent with its most potent known mechanism of action, bupropion is an indirect dopamine agonist via its inhibition of the neuronal uptake pump for dopamine (503, 504). Hence, bupropion can potentiate the effects of other dopamine agonists. This interaction does not typically cause serious problems and may even be advantageous in specific instances such as patients with Parkinson s disease plus a depressive disorder. Because of its ability to inhibit NE uptake, bupropion would be prone to the same interactions as NSRIs such as desipramine and reboxetine. 

Bromocriptine is a D2 agonist its structure is shown in Table 16-6. This drug has been widely used to treat Parkinson s disease in the past, but is now rarely used for this purpose, having been superseded by the newer dopamine agonists. Bromocriptine is absorbed to a variable extent from the gastrointestinal tract peak plasma levels are reached within 1-2 hours after an oral dose. It is excreted in the bile and feces. The usual daily dose of bromocriptine for parkinsonism varies between 7.5 and 30 mg. To minimize adverse effects, the dose is built up slowly over 2 or 3 months from a starting level of 1.25 mg twice daily after meals the daily dose is then increased by 2.5 mg every 2 weeks, depending on the response or the development of adverse reactions. 

The dopamine agonist rotigotine, delivered daily through a skin patch, was approved in 2007 by the FDA for treatment of early Parkinson s disease. It supposedly provides more continuous dopaminergic stimulation than oral medication in early disease its efficacy in more advanced disease is less clear. Benefits and side effects are similar to those of other dopamine agonists but reactions may also occur at the application site and are sometimes serious. The product was recalled in 2008 because of crystal formation on the patches, affecting the availability and efficacy of the agonist. 

Preclinical and clinical results indicate that both entacapone and tolcapone are orally active, nontoxic and well-tolerated drugs. The adjuvant L- dopa therapy with DDC inhibitor + COMT-inhibitor (+ possible MAO inhibitor) may substitute for the present double therapy in the treatment of Parkinson s disease [27-40]. Together with the development of dopamine agonists and MAO inhibitors, the inhibition of COMT will constitute major progress in the treatment of Parkinson s disease in the near future. 

Schwarz J. Rationale for dopamine agonist use as monotherapy in Parkinson s disease. Curr Opin Neurol. 2003 16(suppl 1) S27—S33. 

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