Comtess - Entacapone

Comtess (Entacapone). Orion Pharma (UIQ Ltd. UK Sinmnaiy of product characteristics, February 2007. 

Second generation COMT inhibitors were developed by three laboratories in the late 1980s. Apart from CGP 28014, nitrocatechol is the key structure of the majority of these molecules (Fig. 3). The current COMT inhibitors can be classified as follows (i) mainly peripherally acting nitrocatechol-type compounds (entacapone, nitecapone, BIA 3-202), (ii) broad-spectrum nitrocatechols having activity both in peripheral tissues and the brain (tolcapone, Ro 41-0960, dinitrocatechol, vinylphenylk-etone), and (iii) atypical compounds, pyridine derivatives (CGP 28014,3-hydroxy-4-pyridone and its derivatives), some of which are not COMT inhibitors in vitro but inhibit catechol O-methylation by some other mechanism. The common features of the most new compounds are excellent potency, low toxicity and activity through oral administration. Their biochemical properties have been fairly well characterized. Most of these compounds have an excellent selectivity in that they do not affect any other enzymes studied [2,3]. 

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]. 

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. 

A newer classification of antiparkinson drugs is the catechol-O-methyltransferase (COMT) inhibitors. Examples of the COMT inhibitors are entacapone (Comtan) and tolcapone (Tasmar). 

The deamination of DA to DOPAC can be prevented by MAOb inhibitors such as selegiline while COMT inhibitors stop its further o-methylation to HVA and the conversion of dopa to OMD. COMT inhibitors can act just peripherally (entacapone) or in the CNS as well (tolcapone). DD — dopa decarboxylase MAO—monoamine oxidase COMT—catechol-o-methyl transferase... 

Entacapone (Comtan ) Peripherally blocks COMT metabolism of DA Take a 200-mg tab with each Sinemet dose up to 8 tabs daily usual MD is 200 mg 3-4 times daily decrease dose by 50% with hepatic impairment... 

L-dopa is not bound to plasma proteins, and the elimination half-life is about 1 hour. The addition ofcarbidopa can extend the half-life to 1.5 hours, and the addition of a COMT inhibitor (e.g., entacapone) can extend it to about 2 to 2.5 hours. 

Inhibitors of catechoI-O-methyl-transferase (COMT). L-Dopa and dopamine become inactivated by methyla-tion. The responsible enzyme can be blocked by entacapone, allowing higher levels of L-dopa and dopamine to be achieved in corpus striatum. 

Pharmacology Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), which alters the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor (such as carbidopa), plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. 

Monoamine oxidase (MAO) inhibitors MAO and COMT are the 2 major enzyme systems involved in the metabolism of catecholamines. Do not treat patients concomitantly with entacapone and a nonselective MAO inhibitor. 

Drugs metabolized by COMT Administer drugs known to be metabolized by COMT (ie, isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, methyidopa, apomorphine, isoetherine, bitolterol) with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, arrhythmias, and excessive changes in blood pressure. 

Entacapone and tolcapon are selective and reversible catechol-O-methyltransferase (COMT) inhibitors which also inhibit the break down of levodopa to 3-methoxy-4-hydroxy-L-phenylalanine. 

Entacapone is a reversible inhibitor of peripheral catechol-O-methyltransferase (COMT). It is given at the dose of 200 mg with each dose of levodopa. It prolongs the action of levodopa and reduces synthesis of 3-O-methyldopa which is presumed to antagonize dopa passage through the blood-brain barrier. 

The two COMT inhibitors in clinical use are tol-capone (Tasmar) and entacapone fComtan). They are used in combination with levodopa-carbidopa. In patients with motor fluctuations, they increase the on time. Adverse effects are similar to those observed with levodopa-carbidopa alone. Tolcapone therapy can cause fatal hepatotoxicity and so should be used only in patients who do not respond to other therapies. Patients taking tolcapone require close monitoring of liver enzymes for signs of hepatic changes. 

Geriatric Considerations - Summary Entacapone inhibits peripheral COMT and increases levodopa s effects. Itsprimary role is as adjunctive therapy to prolong the beneficial effects of levodopa and to decrease end-of-dose fluctuations in response to treatment. Concurrent use of levodopa is necessary for entacapone to be effective and unlike tolcapone, hepatic monitoring is not required. 

Another approach to the therapy of Parkinson s disease involves the use of enzyme inhibitors. For example, inhibition of the enzyme monoamine oxidase B (MAO-B) by selegiline (4.105) improves the duration of L-DOPA therapy because it inhibits the breakdown of dopamine but not of NE. Likewise, inhibitors of catechol-O-methyl-transferase (COMT) can also be exploited as agents for the treatment of Parkinson s disease. L-DOPA and dopamine become inactivated by methylation the COMT enzyme responsible for this metabolic transformation can be clocked by agents such as entacapone (4.106) or tolcapone (4.107), allowing higher levels of L-DOPA and dopamine to be achieved in the corpus striamm of the brain. 

This approach is also applied successfully in Parkinson s disease. Drugs such as entacapone inhibit the activity of the enzyme catechol-omethyltransferase (COMT), which is involved in degradation of the neurotransmitter dopamine, and thus increase and prolong the availability of dopamine in the synaptic cleft. Inhibition of COMT and substitution of L-Dopa are often combined in the therapy of Parkinson patients. 

Modeling is an analytical tool that can be used to extrapolate shorter term clinical results, such as days of improved symptoms in Parkinson s disease patients in a study over 6 months, to longer time periods. A model was developed to extrapolate the results of a 6-month trial in which patients received either levodopa alone or levodopa plus the catechol-o-methyltransferase (COMT) inhibitor entacapone. Comtan (entacapone) is designed to reduce the metabolism of levodopa in peripheral tissue and vessels so that more of the drug is available in the brain at a more constant rate than is seen with levodopa alone. The 6-month clinical trial produced clinical results that allow us to establish entacapone s effect on the OFF time associated with levodopa therapy. OFF time refers to a re-emergence of symptoms prior to the next scheduled levodopa dose. Entacapone reduces the OFF time and increases the ON time of levodopa therapy. 

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 + carbidopa + entacapone (Stalevo) Entacapone is a catechol-O-methyltransferase (COMT) inhibitor (see below)... 

Entacapone Inhibits COMT in periphery does not enter CNS Reduces metabolism of levodopa and prolongs its action Parkinson s disease Oral Toxicity Increased levodopa toxicity nausea, dyskinesias, confusion... 

Structures of second-generation COMT inhibitors discussed in this paper nitecapone (OR-462), entacapone (OR-611), tolcapone (RO-40-7592), and 2-((3, 4-dihy-droxy-2-nitrophenyl) vinyl) phenylketone. 

The tenfold higher inhibitory activity of entacapone compared with vinylphenylketone against human COMT can be accounted for by the electron- withdrawing effect of the side-chain substitution. In the case of entacapone, the side chain at position C5 has a more beneficial electronic influence on the 2-hydroxyl of the inhibitor producing a better inhibition (see Section VI). 

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. 

COMT inhibitors Entacapone Tolcapone Help prevent breakdown of dopamine in peripheral tissues allows more levodopa to reach the brain. Useful as an adjunct to levodopa/carbidopa administration may improve and prolong effects of levodopa. 

Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea, and confusion. It is often necessary to lower the daily dose of levodopa by about 30% in the first 48 hours to avoid or reverse such complications. Other side effects include diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine. Tolcapone may cause an increase in liver enzyme levels and has been rarely associated with death from acute hepatic failure accordingly, its use in the USA requires signed patient consent (as provided in the product labeling) plus monitoring of liver function tests every 2 weeks during the first year and less frequently thereafter. No such toxicity has been reported with entacapone. 

Entacapone and tolcapone are peripheral inhibitors of catechol-O-methyl-transferase (COMT). COMT metabolises levodopa to an inactive product so their use enables greater amounts of levodopa to reach the brain. They are licensed for use as an adjunct to co-beneldopa and co-careldopa for patients who experience end-of-dose deterioration and cannot be stabilised on the combined preparations alone. 

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