L-dopa effects

Dyskinesias are involuntary choreiform movements, usually involving the neck, trunk, and extremities. They are usually associated with peak striatal dopamine levels. Less commonly, dyskinesias also can develop during the rise and fall of L-dopa effects (the dyskinesias-improvement-dyskinesias or diphasic pattern of response. 

Rasagiline, another MAO-B inhibitor, has similar effects as selegiline in enhancing L-dopa effects and modest beneficial effect as monotherapy. Early initiation is associated with better long-term outcomes. 

However, these dopaminergic medications are very effective treatments for the nighttime movement disorders, PLMD and RLS. L-DOPA effectively relieves the symptoms of RLS and PLMD, and unlike the benzodiazepines, patients do not develop tolerance to its effects. 

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. 

Dyskinesias. Another complication of L-dopa therapy is dyskinesias (choreiform abnormal involuntary movements involving usually the neck, trunk, and upper extremities). These involuntary movements usually are associated with peak antiparkinsonian benefit (peak-effect dyskinesia or improvement-dyskinesia/dystonia-improvement), although they also can develop during the rise and fall of L-dopa effects (the dyskinesia-improvement-dyskinesia or diphasic pattern of response). In the case of peak-effect dyskinesias or dystonias, smaller, more frequent doses of L-dopa, use of the sustained-release preparations, or addition of dopamine agonists sometimes can be beneficial. The optimal treatment for the dyskinesia-improvement-dyskinesia pattern is unknown and actually can worsen with strategies useful for extending L-dopa effect. 

Selegiline (Eldepryl, Somerset various generic brands), an irreversible MAO-B inhibitor, also known as deprenyl, is marketed for extending L-dopa effects. By its central action, it modestly extends the duration of action from each dose of L-dopa. This can provide up... 

A variety of dopaminergic agents mimicking L-DOPA effects are available, all with a smaller efficacy than L-DOPA, but with varying beneficial features like long half-life, better tolerability or modified, but not principally different, side-effect profiles [32]. 

Duvoisin RC, Yahr MD, Cote LD. lyridoxine reversal of L-dopa effects in parkinsonism. Trans Am Neurol Assoc (1969) 94, 81-4. 

A number of other approaches to enhancing the effectiveness of L-dopa is possible. One suggestion is to replace it by a derivative which is more easily able to penetrate to the brain [205, 206]. Inhibition of dopamine- 3-oxidase, the enzyme converting DA to NA does not increase L-dopa effectiveness [207] which is understandable as brain NA formation from administered L-dopa is probably quantitatively relatively unimportant [208]. 

Catecholamines. The catecholamines, epinephrine (EPl adrenaline) (85), norepinephrine (NE noradrenaline) (86) (see Epinephrine and norepinephrine), and dopamine (DA) (2), are produced from tyrosine by the sequential formation of L-dopa, DA, NE, and finally EPl. EPl and NE produce their physiological effects via CC- and -adrenoceptors, a-Adrenoceptors can be further divided into CC - and a2-subtypes which in turn are divided... 

Research for an antidepressant among non-tricyclic compounds with pharmacological effects qualitatively different from those of the conventional tricyclic compounds led to the preparation and testing of a series of indazole derivatives for reserpine-like activity in mice. l-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-l//-indazole (FS-32 692) antagonizes reserpine-induced effects and potentiates amphetamine-induced self-stimulation and l-Dopa-induced increase in motor activity. FS-32 produces an anticholinergic action mainly on the central nervous System, while the action of imipramine occurs centrally as well as peripherally (79AF511). 

An early success story in the field of catalytic asymmetric synthesis is the Monsanto Process for the commercial synthesis of l-DOPA (4) (see Scheme 1), a rare amino acid that is effective in the treatment of Parkinson s disease.57 The Monsanto Process, the first commercialized catalytic asymmetric synthesis employing a chiral transition metal complex, was introduced by W. S. Knowles and coworkers and has been in operation since 1974. This large-scale process for the synthesis of l-DOPA (4) is based on catalytic asymmetric hydrogenation, and its development can be... 

Antagonists of muscarinic acetylcholine receptors had widely been used since 1860 for the treatment of Parkinson s disease, prior to the discovery of l-DOPA. They block receptors that mediate the response to striatal cholinergic interneurons. The antiparkinsonian effects of drugs like benzatropine, trihexyphenidyl and biper-iden are moderate the resting tremor may sometimes respond in a favorable manner. The adverse effects, e.g., constipation, urinary retention, and mental confusion, may be troublesome, especially in the elderly. 

Low affinity use-dependent NMDA recqrtor antagonists meet the criteria for safe administration into patients. Drugs like amantadine and memantine have modest effects on Parkinson s disease and are used as initial therapy or as adjunct to l-DOPA. Their adverse effects include dizziness, lethargy and sleep disturbance. 

Antipsychotic medications are indicated in the treatment of acute and chronic psychotic disorders. These include schizophrenia, schizoaffective disorder, and manic states occurring as part of a bipolar disorder or schizoaffective disorder. The co-adminstration of antipsychotic medication with antidepressants has also been shown to increase the remission rate of severe depressive episodes that are accompanied by psychotic symptoms. Antipsychotic medications are frequently used in the management of agitation associated with delirium, dementia, and toxic effects of both prescribed medications (e.g. L-dopa used in Parkinson s disease) and illicit dtugs (e.g. cocaine, amphetamines, andPCP). They are also indicated in the management of tics that result from Gilles de la Tourette s syndrome, and widely used to control the motor and behavioural manifestations of Huntington s disease. 

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... 

In patients having Parkinson s disease, both entacapone and tolcapone potentiate the therapeutic effect of L-dopa and prolong the daily ON time by 1-2 h. In the clinic, COMT inhibitors have been well tolerated, and the number of premature terminations has been low. In general, the incidence of adverse events has been higher in tolcapone-treated patients than in entacapone-treated patients. The main events have comprised of dopaminergic and gastrointestinal problems [2,3]. 

Torn wall M, Mannisto PT (1993) The effect of three types of COMT inhibitors on L-dopa-induced circling behaviour in rats. Eur J Pharmacol 250 77-84... 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

Finally, as an old example of kinetic resolution of racemic mixtures, mention must be made on the report of Kise and Tomiuchi on the significant effect of acetonitrile on the enantioselectivity of different proteases toward the kinetic resolution of aromatic amino acid ethyl esters (5-8). For instance, (l)-DOPA (8) was obtained with 99% ee in the presence of 90% v/v acetonitrile [9]. 

This soluble enzyme requires pyridoxal phosphate for the conversion of L-dopa to 3,4-dihydroxyphenylethyl-amine (dopamine). Compounds that resemble L-dopa, such as a-methyldopa, are competitive inhibitors of this reaction. a-Methyldopa is effective in treating some kinds of hypertension. 

Treseder, SA, Jackson, M and Jenner, P (2000) The effects of central aromatic amino acid (dopa) decarbosylase inhibition on the motor actions of L-dopa and dopamine agonists in MPTP-treated primates. Brit. J. Pharmacol. 129 1355-1366. 

Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include L-3,4-dihydroxyphenylalanine (L-dopa) to the brain [56], dipivaloyl derivative of epinephrine to the eye [57], /-glutamyl-L-dopa to the kidney [58], fi-n-glucoside dexamethasone and prednisolone derivatives to the colon [59], thiamine-tetrahydrofuryldisulfide to red blood cells, and various amino acid derivatives of antitumor agents such as daunorubicin [61,62], acivicin [63], doxorubicin [63], and phenylenediamine [63] to tumor cells. 

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