Nonergot Derivatives

The Parkinson's-Reversing Breakthrough

Cure for Parkinsons

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Pramipexole acts as an agonist at D2 and D3 receptors with greater affinity for D3 than D2 receptors. The compound has no appreciable affinity for D1, D5, 5-HT2A, and 5-HT2B receptors.37 The reduced dyskinesia associated with pramipex-ole compared with cabergoline may be related to its low affinity for the D1 receptor. Ropinirole has about 20-fold selectivity for cloned human D3 receptors compared with D2 receptors. Additionally, ropinirole has low affinity for 5-HT2A, 5-HT2B, and D1-like receptors.37 A recent study suggests that D3-agonists may be able to restore DA neurons and exert a neuroprotective effect.43 These developments could offer exciting new therapeutic options for parkinsonian patients.

Apomorphine Hydrochloride, USP. Apomorphine hydrochloride, (6ar)-6-methyl-5,6,6a,7-tetrahydro-4h-dibenzo [de,g]quinolone-10,11-diol hydrochloride (Apokyn), is a white or off-white powder or crystal soluble in hot water (pKa = 8.92). Apormorphine is an aporphine alkaloid of the benzoquinoline class. Oral apomorphine is poorly absorbed and has a bioavailability of less than 4%. Upon subcutaneous administration, apomorphine is completely absorbed. Within 10 to 20 minutes, the maximum concentration of the drug is distributed from the blood plasma to the CSF. Other potential routes of administration include continuous subcutaneous infusion, intravenous infusion, intranasal spray application, sublingual, and rectal administration.23 The agent is highly lipophilic in nature, allowing for rapid diffusion across the BBB after injection. Apomorphine has a short plasma halflife; however, clinical effects may last from 60 to 90 minutes. Apomorphine displays a significant degree of interpatient variability in its pharmacokinetic profile. Studies of both intravenous and subcutaneous injection routes found this

variation was not attributable to body weight, age, gender, and duration of PD or l-DOPA dose/duration alone. Apomorphine is extensively metabolized. Hypothesized routes include sulfation, n-demethylation, glucuronidation, and oxidation. Subcutaneous injections of apomorphine are renally and hepatically cleared, with the majority appearing to be renally cleared. Dosage adjustments are needed in both liver and renal impairment. The activity of apomorphine is believed to be caused by stimulation of postsynaptic Dr and D2-type receptors within the caudate/putamen in the brain. Apomorphine is indicated for the acute, intermittent treatment of hypomobility, "off" episodes ("end-of-dose wearing off' and unpredictable on/off episodes) associated with advanced PD.23

Pramipexole Dihydrochloride. Pramipexole dihy-drochloride, (s)-2-amino-6-propylamino-dihydrochloride (Mirapex), is a white to off-white powder soluble in water, slightly soluble in methanol and ethanol, and practically insoluble in dichloromethane. Following oral administration, pramipexole is readily absorbed. Pharmacokinetic properties differ between men and women, with area under the curve (AUC) for each dose level being 35% to 43% greater in women, mainly because of a 24% to 27% lower oral clearance. The drug undergoes minimal hepatic biotransformation and is excreted virtually unchanged in the urine by the renal tubular secretion. Pramipexole interacts with drugs excreted by renal tubular secretion (H2-antagonists, diuretics, verapamil, quinidine, quinine), which leads to a decreased clearance of pramipexole.44,45 Pramipexole is indicated for treatment of the signs and symptoms of idiopathic PD, alone or in combination with levodopa. It is also indicated for symptomatic treatment of moderate to severe idiopathic restless legs syndrome (RLS).

Ropinirole Hydrochloride. Ropinirole hydrochloride, 4-(2-(dipropylamino)ethyl)indolin-2-one hydrochloride (Requip), is a white to pale greenish yellow powder that is very soluble in water. Ropinirole is rapidly absorbed after oral administration with maximal plasma concentrations generally reached after about 1.5 hours, and the elimination half-life appears to be approximately 3 hours. Ropinirole is also rapidly and extensively distributed from the vascular compartment and shows low plasma protein binding that is independent of its plasma concentration. This drug is cleared by metabolism in the liver, with only 10% being excreted unchanged. The main metabolite of ropinirole is the n-despropyl metabolite. The glucuronide of this metabolite and the carboxylic acid metabolite, 4-carboxymethylin-dolin-2-one, account only for 10% of the administered dose. None of the metabolites is pharmacologically active, and the excretion of ropinirole-derived products is mainly via the urine. The main CYP450 isozyme involved in the metabolism of ropinirole is CYP1A2. Inhibitors or inducers of this enzyme have been shown to alter the clearance of ropinirole.46,47 Ropinirole is believed to act as an agonist at postsynaptic D2 receptors. Ropinirole is indicated for the treatment of the signs and symptoms of idiopathic PD and moderate to severe primary RLS.

Rotigotine. Rotigotine, (6s)-6-{propyl[2-(2-thienyl) ethyl]amino}-5,6,7,8-tetrahydro-1-naphthalenol (Neupro), is a nonergoline that is available as a silicone-based, self-adhesive matrix, transdermal system for continuous delivery over a 24-hour period. Approximately 45% of the drug is released within 24 hours. The terminal half-life of rotigotine is 5 to 7 hours after removal of the patch. Rotigotine is 90% bound to plasma proteins. The compound undergoes extensive metabolism and has low bioavailability by the oral route. The major metabolites of rotigotine are the glu-curonide and sulfate conjugates of rotigotine and sulfate conjugates of n-despropylrotigotine and n-desthienylethyl rotigotine. Rotigotine is excreted in the urine (71%) and feces (11%).23 Studies using human liver microsomes did not find any interactions with CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates.48 Rotigotine transdermal system contains sodium metabisulfite, and individuals sensitive to sulfite could be at risk for allergic reactions. Additionally, somnolence is a common adverse reaction with individuals on rotigotine, and patients should be closely monitored during therapy.23 In transfected Chinese hamster ovary (CHO) cells, rotigotine binds with high affinity at D3 and D2L receptors (variants in the D2 receptor subtype are caused by insertion of the 29 amino acids into the third loop to give D2s and D2L).49 Using rat CHO cells, rotigotine shows over 30-fold selectivity at D3 versus D2 receptors.48 Rotigotine was approved in May 2007 for the treatment of early-stage PD.

COMT Inhibitors

When administered with an AADC inhibitor, circulating levodopa is mainly metabolized by COMT. In the presence of a COMT inhibitor, the peripheral metabolism of levodopa is therefore decreased.

Tolcapone is a selective and reversible inhibitor of COMT in the CNS and periphery. Inhibition of COMT in the periphery reduces the formation of 30MD in tissues that have significant COMT activity. It has been speculated that 30MD may compete with the uptake of levodopa into the CNS and thereby contributes to the wearing-off effect of levodopa. Administration of levodopa in combination with a dopa decarboxylase inhibitor (carbidopa) and a COMT inhibitor (tolcapone) increases CNS delivery of levodopa. Therefore, more continuous levels of levodopa and DA are maintained.50 Unlike tolcapone, entacapone does not penetrate the BBB to any extent. Thus, the compound only inhibits peripheral COMT. When combined with levodopa and carbidopa, entacapone provides less motor fluctuations in parkinsonian patients. Another advantage of entacapone over tolcapone is its lack of hepatotoxicity.51

Tolcapone Entacapone

Tolcapone Entacapone

Tolcapone. Tolcapone, 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Tasmar), is a yellow, odorless, nonhy-groscopic, crystalline compound (pKa = 4.78). Tolcapone is rapidly absorbed after oral administration. Tolcapone is highly bound to plasma albumin (>98%), and its distribution is therefore restricted. Tolcapone has low first-pass metabolism. It is almost completely metabolized in the liver before excretion, and 60% is excreted by the kidney. The major metabolite of tolcapone is an inactive glucuronide conjugate. COMT inhibitors increase chronotropic and arrhythmogenic effects of epinephrine.52,53 Tolcapone is indicated as an adjunct to levodopa/carbidopa for the management of signs and symptoms of PD.

Entacapone. Entacapone, (E>2-cyano-3-(3,4-dihy-droxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (Comtan), is a nitrocatechol that is practically insoluble in water (pKa = 4.50). Entacapone is rapidly absorbed after oral administration and does not cross the BBB. Entacapone does not distribute widely into tissues because of its high plasma protein binding and it is completely metabolized before excretion. The main metabolic pathway is by isomerization to the cisisomer followed by direct glucuronidation of the parent and the cis-isomer. The glucuronide conjugates are inactive. Entacapone is eliminated in the feces (90%) and urine (10%). Entacapone is indicated as an adjunct to levodopa/carbidopa to treat patients with idiopathic PD who experience the signs and symptoms of end-of-dose wearing off.

Carbidopa/Levodopa/Entacapone. Levodopa, car-bidopa, and entacapone (Stalevo) are formulated together to take advantage of each compound's mechanism of action. When entacapone is coadministered with levodopa and carbidopa, plasma levels of levodopa are greater and more sustained.23 For absorption, distribution, metabolism, and excretion (ADME) properties and drug interactions, refer to the preceding monograph.

Other Antiparkinsonian Drugs

Anticholinergic agents have been used in the early stages of PD, frequently with amantadine and selegiline. The most commonly employed anticholinergics are benztropine, trihexyphenidyl, orphenadrine, and procyclidine. These compounds are most useful for treating the tremor aspect of PD. Because most individuals with PD are elderly, anticholinergics may impair cognitive function. Additionally, anticholinergics may produce various side effects through blockade of peripheral muscarinic receptors.21,26

Amantadine has demonstrated beneficial effects in the treatment of PD, especially in attenuating dyskinesias.26 Although amantadine has DA-releasing properties, other pharmacological mechanisms appear to be involved in its antiparkinsonian effect. The compound is a weak noncompetitive N-methyl d-aspartate (NMDA) antagonist, yet it differs in its action from the NMDA antagonist MK-801 in a rodent model of PD.54 Additionally, amantadine potently inhibits nicotinic acetylcholine function in the hippocampus.55

Trihexyphenidyl Benztropine Amantadine

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