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The Parkinson's-Reversing Breakthrough

Medication for Parkinson Disease

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Jl Jh3C NHNHo Carbidopa

Carbidopa, USP. Carbidopa, (S)-3-(3,4-dihydroxy-phenyl)-2-hydrazinyl-2-methylpropanoic acid, is a white crystalline powder, slightly soluble in water (pKa = 7.8). Carbidopa is absorbed slower than levodopa and is 36% plasma protein bound.23 Carbidopa is metabolized to two main metabolites (a-methyl-3-methoxy-4-hydroxyphenyl-propionic acid and a-methyl-3,4-dihydroxyphenylpropionic acid). These two metabolites are primarily eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa accounts for 30% of the total urinary excretion. No drug interactions have been described.

MAO-B Inhibitors

MAO inhibitors are utilized to prolong the plasma half-life of levodopa or block the striatal metabolism of DA. Initially, the use of nonselective MAO inhibitors led to serious adverse effects caused by peripheral inhibition of monoamines. The use of selective MAO-B inhibitors decreases the risk of a hypertensive crisis that is associated with nonselective MAO inhibitors. The addition of a selective MAO-B inhibitor to levodopa therapy decreases both the metabolism of DA that is produced from levodopa and DA that is already present in the striatum.

Selegiline is an irreversible MAO-B inhibitor. Unlike compounds that inhibit MAO-A, selegiline does not produce the so-called cheese effect. This is a hypertensive crisis of the cardiovascular system caused by elevated levels of p-tyramine and other indirectly acting sympathomimetic amines that are found in certain foods (e.g., red wine, cheese, and herring).24 Selegiline potentiates the effects of levodopa by blocking its metabolism by MAO. When administered with levodopa, selegiline allows for a reduction in the daily dosage and appears to improve the wearing-off effect of levodopa. However, whether selegiline is able to exert a neuroprotective effect in PD is inconclusive.25 Selegiline is extensively first-pass metabolized to yield N-desmethylselegi-line, l-methamphetamine, and l-amphetamine. These metabolites have been implicated in some of the psychomo-tor and cardiovascular adverse effects of selegiline.26

Rasagiline is a selective irreversible inhibitor of MAO-B that is approximately five times more potent than selegiline. The R-isomer is the active enantiomer whereas the ^-isomer demonstrates only weak inhibition of MAO-B. Similar to selegiline, rasagiline does not produce the characteristic cheese effect that is observed for nonselective MAO in-hibitors.27 The neuroprotective effect of rasagiline is inferred by the propargyl group. This effect is observed at drug concentrations well below those necessary to cause MAO-B inhibition. Several mechanisms have been proposed for the neuroprotective effect of rasagiline including (a) a decrease in proapoptotic proteins (Bax and Bad), (b) an increase in antiapoptotic proteins (Bcl-2 and Bcl-xL), and (c) stabilization of mitochondrial membrane potential, thus preventing subsequent release of proapoptotic proteins.28,29

Selegiline Hydrochloride, USP. Selegiline hydrochloride, (R)-N-methyl-N-(1-phenylpropan-2-yl)prop-2-yn-1-amine hydrochloride (Eldepryl), is an off-white powder, freely soluble in water and methanol (pKa = 7.4).30 Selegiline is readily absorbed from the GI tract. It is well distributed in the body and it penetrates the CNS. Selegiline has a high apparent volume of distribution, short half-life, and a very high oral clearance, indicating an extensive metabolism not only in the liver but also through extrahepatic biotransformation. Transdermal delivery reduces the first-pass metabolism and provides higher and more prolonged plasma levels of unchanged selegiline and lower levels of metabolites compared with the oral administration.31 Selegiline transdermal system (EMSAM) has recently been approved for the treatment of depression.23 Selegiline administered with fluoxetine may produce a "serotonin" syndrome (CNS irritability, increased muscle tone, altered consciousness), and with meperidine could result in agitation, seizures, diaphoresis, and fever, which may progress to coma, apnea, and death. Drug reactions may occur several weeks following withdrawal of selegiline. The use of selegiline as monotherapy is limited to younger patients with early disease and without disabling symptoms.

Rasagiline Mesylate. Rasagiline mesylate, (R)-N-(prop-2-ynyl)-2,3-dihydro-1H-inden-1 -amine methanesulfonate (Azilect), belongs to the propargylamine family and is a white to off-white powder, soluble in water or ethanol, slightly soluble in isopropanol. Rasagiline is rapidly absorbed. Plasma protein binding for rasagiline ranges from 88% to 94%, with specific binding to serum albumin being 61% to 63%. It undergoes complete biotransformation before excretion, mainly via N-dealkylation and hydroxylation, to yield three major metabolites: 1(R)-aminoindan, 3-hydroxy-N-propargyl-1-aminoindan, and 3-hydroxy-1-aminoindan. Both oxidative pathways are catalyzed by cytochrome P450 (CYP) enzymes, mainly the 1A2 isozyme. Rasagiline and its metabolites undergo glucuronide conjugation with subsequent urinary excretion.29 Inhibitors of the CYP1A2 may increase plasma concentrations of rasagiline up to twofold.32,33 Because rasagiline is a selective and irreversible inhibitor of MAO-B, its duration of action is independent of the drug's half-life and is instead determined by the regeneration rate of MAO-B. This characteristic is potentially beneficial in PD, where rasagi-line's prolonged effect may be able to limit the fluctuating responses that are characteristic of long-term drug treatment with levodopa.34

Dopamine Agonists

The addition of DA agonists to levodopa therapy has gained widespread popularity in the treatment of PD.35 DA agonists not only produce less dyskinesia, but also have been hypothesized to slow the progressive degeneration of DA neu-rons.36 DA agonists are classified into ergot derivatives (pergolide, cabergoline, and bromocriptine) and nonergot derivatives (apomorphine, pramipexole, ropinirole, and rotigotine).

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