Tolcapone

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Tolcapone
Tolcapone.svg
Tolcapone3d.png
Clinical data
Trade names Tasmar
AHFS/Drugs.com Monograph
MedlinePlus a698036
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 65%
Protein binding >99.9%
Metabolism Liver (mainly glucuronidation)
Elimination half-life 2–3 hours
Excretion Urine (60%), feces (40%);
only 0.5% in unmetabolized form
Identifiers
  • (3,4-Dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.222.604 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H11NO5
Molar mass 273.244 g·mol−1
3D model (JSmol)
Melting point 143 to 146 °C (289 to 295 °F)
Solubility in water not soluble
  • [O-][N+](=O)c2cc(C(=O)c1ccc(cc1)C)cc(O)c2O
  • InChI=1S/C14H11NO5/c1-8-2-4-9(5-3-8)13(17)10-6-11(15(19)20)14(18)12(16)7-10/h2-7,16,18H,1H3 Yes check.svgY
  • Key:MIQPIUSUKVNLNT-UHFFFAOYSA-N Yes check.svgY
   (verify)

Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). [5] It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.

Contents

Tolcapone appears to be peripherally selective, but can still cross into the brain in significant amounts and has been found to inhibit COMT centrally as well. [6] [7] In comparison with entacapone, another nitrocatechol COMT inhibitor, tolcapone has a longer half life (2.9 hours vs. 0.8 hours) and can better penetrate into the brain, acting both in the central nervous system and in the periphery. [8] However, entacapone is less toxic for the liver.

Medical uses

Tolcapone is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa or levodopa/benserazide medications. Levodopa is a prodrug for dopamine, which reduces Parkinson symptoms; carbidopa and benserazide are aromatic L-amino acid decarboxylase (AADC) inhibitors. [9]

Without administration of tolcapone, the beneficial effects of levodopa tend to wear off more quickly, resulting in motor fluctuations. [10]

Contraindications

Combining tolcapone with non-selective monoamine oxidase inhibitors such as phenelzine or tranylcypromine is contraindicated. [11] Tolcapone is also contraindicated for people with liver diseases or increased liver enzymes. [12]

Side effects

Tolcapone has demonstrated significant liver toxicity (hepatotoxicity) [13] that limits the drug's utility. Entacapone is an alternative, largely since it has a more favorable toxicity profile.

The hepatotoxicity can be related to elevated levels of transaminases, but studies have shown that minimal risk exists for those without preexisting liver conditions when their enzyme levels were being monitored. No clear mechanism is implicated, but it has been hypothesized that it has something to do with abnormal mitochondrial respiration due to the uncoupling of oxidative phosphorylation. [14]

Other side effects regard the increase in dopaminergic activity, including digestive symptoms. [12] Treatment with tolcapone runs the risk of eliciting or prolonging dyskinesia; this can be counteracted by decreasing the dose of levodopa. This occurs because the administration of tolcapone results in the accumulation of the biological methyl donor S-adenosyl-L-methionine (SAM) in the striatum that induces Parkinson symptoms. [14]

Digestive symptoms include nausea and diarrhea; further dopaminergic side effects include orthostatic hypotension, dry mouth, sweating and dizziness. Tolcapone causes more severe diarrhea than entacapone; this was the most common reason for therapy termination in studies. [11] Urine discoloration comes from yellow tolcapone metabolites being excreted in the urine and is harmless. [12] [14]

Interactions

While increase of dopamine levels is a desired interaction, tolcapone can theoretically also increase the levels of other drugs metabolised by COMT, such as the AADC inhibitors carbidopa and benzerazide, as well as methyldopa, dobutamine, apomorphine, adrenaline, and isoprenaline. In studies, a slight interaction with benzerazide was seen, but not with carbidopa. Other interactions with this group of drugs have not been studied. A related type of theoretical interactions is with drugs that increase catecholamine concentrations, such as monoamine oxidase (MAO) inhibitors and noradrenaline reuptake inhibitors; these also showed only slight effects in practice. Combination with non-selective MAO inhibitors might be dangerous. [11] [12]

Due to its affinity to the liver enzyme CYP2C9, interactions with drugs being metabolised by this enzyme are also possible, but unlikely. No interaction with tolbutamide, a 2C9 substrate, was observed in studies. [12]

Pharmacology

Mechanism of action

Rat catechol-O-methyltransferase bound to tolcapone. PDB entry 3s68. 3s68 tcw.png
Rat catechol-O-methyltransferase bound to tolcapone. PDB entry 3s68 .

Tolcapone selectively and reversibly [11] binds to the catalytic site of COMT in both the periphery and the central nervous system (CNS) with greater affinity than any of the three catecholamines, including levodopa. [16] It thereby prevents the 3-O-methylation of levodopa by COMT in the periphery, which produces 3-O-methyldopa, a major metabolite that competes with levodopa to cross the blood–brain barrier. More of the levodopa that is administered reaches the CNS. Additionally, levodopa that has already reached the CNS, after being converted to dopamine, will not be degraded as quickly when tolcapone inhibits COMT activity. Thus, tolcapone improves the bioavailability and reduces the clearance of levodopa and subsequently dopamine from the CNS. [17]

3-O-Methylation of levodopa (3-hydroxy-L-tyrosine) via COMT activity COMT activity.svg
3-O-Methylation of levodopa (3-hydroxy-L-tyrosine) via COMT activity

The strength of the binding affinity of tolcapone, represented by the inhibition constant Ki (2.5 nM), can be thought of as the dissociation constant for enzyme and inhibitor complex kinetics. Maximum catalytic activity denotes the efficacy of tolcapone (Vmax = 58.4 pmol/min·mg). [18]

Pharmacokinetics

Tolcapone is quickly absorbed from the gut to about 85%. It has an absolute bioavailability of 65%, which is only slightly decreased when taken with food. The substance reaches highest blood plasma concentrations after about two hours. When in the bloodstream, it is almost completely (>99.9%) bound to plasma proteins, primarily albumin. The main inactivation step is glucuronidation; other processes are methylation by COMT, hydroxylation by CYP3A4 and CYP2A6 with subsequent oxidation to a carboxylic acid, and possibly a minor path with reduction to an amine with subsequent acetylation. [11] [12]

The half-life of tolcapone is two to three hours, the volume of distribution (Vd) being 0.3 L/kg (21 L in an average 70 kg person). [10] 60% of the metabolites are excreted via the urine and 40% via the feces. Only 0.5% of the drug are excreted in unchanged form via the urine. [11] [12]

Tolcapone and its metabolites. The reduction to the amine and subsequent N-acetylation is putative. Tolcapone metabolism.svg
Tolcapone and its metabolites. The reduction to the amine and subsequent N-acetylation is putative.

99% of tolcapone is in monoanionic form in the body because the physiological pH is 7.4. Tolcapone penetrates the blood–brain barrier much better than two other nitrocatechols, nitecapone and entacapone, because it has higher lipophilicity due to its R-substituent.[ vague ] Partition coefficients quantify the ability of the molecule to cross the blood–brain barrier. LogPIdce= 0.2, –1.4, –0.4 for tolcapone, nitecapone and entacopone respectively. Partition coefficients in this case were measured in 1,2-dichloroethane/H2O solution which caused molecules to be in ionized form. There is no current explanation for how these charged molecules permeate the blood–brain barrier. [19]

Tolcapone has been said to enter the central nervous system only minimally and hence would appear to be peripherally selective. [6] However, tolcapone is more lipophilic than other COMT inhibitors like entacapone and may be more likely to cross the blood–brain barrier (BBB). [7] A imaging study in humans found that tolcapone also inhibited COMT in the brain to a significant degree. [7]

Chemistry

Tolcapone is an intensely yellow, odorless, bitter tasting, non-hygroscopic, crystalline compound with a relative molecular mass of 273.25 g/mol. It melts at 143 to 146 °C (289 to 295 °F), is practically insoluble in water and acids but soluble in 0.1  M aqueous sodium hydroxide solution. The pKa values are 4.5 and 10.6 for the two phenyl groups; and the maximum absorption is at 268  nm (in 0.1 M hydrochloric acid / ethanol). [11] Its chemical name is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone.

Synthesis

A synthesis of tolcapone proposed in 2008, begins with a Grignard reaction between 3-Benzyloxy-4-methoxybenzaldehyde [20] [21] and p-tolyl magnesium bromide. The alcohol thus produced is then converted to a ketone using sodium t-butoxide. The benzyl protecting group is removed by palladium-catalyzed hydrogenation in the presence of ammonium formate. A nitro group is introduced at the 5-position adjacent to the hydroxyl group unmasked in the cleavage of the benzyl ether. The synthesis ends with cleavage of the methoxy group using aluminum chloride to yield the product alcohol. [22]

Synthesis of tolcapone Tolcapone synthesis.svg
Synthesis of tolcapone

History

Tolcapone was introduced into the European market in August 1997, and subsequently into the United States market in March 1998. Liver toxicity was reported in four people who were administered tolcapone, three people died due to complications. Consequentially, the marketing authorization of tolcapone was suspended from December 1998 until August 2004 when it was lifted. In November 1998, the company that manufactured tolcapone voluntarily [23] removed the drug from the market. The authorization was then renewed in August 2009. [24]

As a result of reported complications, the U.S. Food and Drug Administration (FDA) issued a black box warning for tolcapone and label revisions that aimed to regulate the monitoring of those prescribed tolcapone for Parkinson's disease in November 1998. [25] A number of other countries withdrew tolcapone from the market; Australia in February 1999, Bulgaria in April 1999, Iceland in November 1998, Lithuania in December 1998. [23]

Research

Transthyretin amyloidosis

Because of preliminary data suggesting the drug may have activity, the U.S. FDA in 2013 granted tolcapone "orphan drug status" in studies aiming at the treatment of transthyretin familial amyloidosis (ATTR). [26] However, as of 2015 tolcapone was not FDA approved for the treatment of this disease. [27]

Psychiatric disorders

In animal studies, tolcapone shows antidepressant- and anti-anhedonia-like effects, stimulates exploratory behavior, and enhances the locomotor hyperactivity induced by psychostimulants like amphetamine and nomifensine. [28] [29] [30] Tolcapone has been clinically studied in the treatment of certain psychiatric disorders such as obsessive–compulsive disorder (OCD). [31] [32] There is also interest in brain-penetrant COMT inhibitors like tolcapone for the treatment of schizophrenia [31] [33] as well as disorders of diminished motivation like apathy. [34]

Related Research Articles

Catechol-<i>O</i>-methyltransferase Class of enzymes

Catechol-O-methyltransferase is one of several enzymes that degrade catecholamines, catecholestrogens, and various drugs and substances having a catechol structure. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene. Two isoforms of COMT are produced: the soluble short form (S-COMT) and the membrane bound long form (MB-COMT). As the regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines. COMT was first discovered by the biochemist Julius Axelrod in 1957.

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as l-3,4-dihydroxyphenylalanine and used medically as levodopa, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine.

<span class="mw-page-title-main">Carbidopa</span> Chemical compound

Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–brain barrier for central nervous system effect, instead of being peripherally metabolised into substances unable to cross said barrier.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

Bial is a pharmaceutical company headquartered in São Mamede do Coronado, in Trofa, Porto district, Portugal. It was founded in 1924, being among the largest companies of its kind in Portugal. Its products are sold in pharmacies in more than 58 countries in 4 continents: Europe, America, Africa and Asia.

<span class="mw-page-title-main">Entacapone</span> Chemical compound

Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of Parkinson's disease. Entacapone together with levodopa and carbidopa allows levodopa to have a longer effect in the brain and reduces Parkinson's disease signs and symptoms for a greater length of time than levodopa and carbidopa therapy alone.

<span class="mw-page-title-main">Rasagiline</span> Chemical compound

Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases. The drug is taken by mouth.

In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.

Catechol-<i>O</i>-methyltransferase inhibitor Medication

A catechol-O-methyltransferase inhibitor is a drug that inhibits the enzyme catechol-O-methyltransferase. This enzyme methylates catecholamines such as dopamine, norepinephrine and epinephrine. It also methylates levodopa. COMT inhibitors are indicated for the treatment of Parkinson's disease in combination with levodopa and an aromatic L-amino acid decarboxylase inhibitor. The therapeutic benefit of using a COMT inhibitor is based on its ability to prevent the methylation of levodopa to 3-O-methyldopa, thus increasing the bioavailability of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.

<span class="mw-page-title-main">Droxidopa</span> Synthetic amino acid/norepinephrine prodrug

Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS) and sold under the brand names Northera and Dops among others, is sympathomimetic medication which is used in the treatment of hypotension and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Levodopa</span> Dopaminergic medication

Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor like carbidopa or benserazide. Levodopa is taken by mouth, by inhalation, through an intestinal tube, or by administration into fat.

<span class="mw-page-title-main">Levoamphetamine</span> CNS stimulant and isomer of amphetamine

Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination with dextroamphetamine in varying ratios under brand names like Adderall and Evekeo. The drug is known to increase wakefulness and concentration in association with decreased appetite and fatigue. Pharmaceuticals that contain levoamphetamine are currently indicated and prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy in some countries. Levoamphetamine is taken by mouth.

<span class="mw-page-title-main">Carbidopa/levodopa/entacapone</span> Anti Parkinson medicine

Carbidopa/levodopa/entacapone, sold under the brand name Stalevo among others, is a dopaminergic fixed-dose combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease.

3-<i>O</i>-Methyldopa Chemical compound

3-O-Methyldopa (3-OMD) is one of the most important metabolites of L-DOPA, a drug used in the treatment of the Parkinson's disease.

Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).

<span class="mw-page-title-main">Opicapone</span> Chemical compound

Opicapone, sold under the brand name Ongentys, is a medication which is administered together with levodopa in people with Parkinson's disease. Opicapone is a catechol-O-methyltransferase (COMT) inhibitor.

Disorders of diminished motivation (DDM) are a group of disorders involving diminished motivation and associated emotions. Many different terms have been used to refer to diminished motivation. Often however, a spectrum is defined encompassing apathy, abulia, and akinetic mutism, with apathy the least severe and akinetic mutism the most extreme.

<span class="mw-page-title-main">Melevodopa/carbidopa</span> Combination dopaminergic medication

Melevodopa/carbidopa, sold under the brand name Sirio, is a combination of melevodopa, a prodrug of the dopamine precursor and hence non-selective dopamine receptor agonist levodopa (L-DOPA), and carbidopa, a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor, which is used in the treatment of Parkinson's disease in Italy. It is taken orally in the form of tablets.

<span class="mw-page-title-main">Nebicapone</span> Abandoned COMT inhibitor

Nebicapone is a catechol O-methyltransferase (COMT) inhibitor which was under development for the treatment of Parkinson's disease but was never marketed. It is a nitrocatechol and is structurally related to entacapone, nitecapone, and tolcapone. The drug shows peripheral selectivity and does not significantly act in the brain. In contrast to the centrally penetrant tolcapone, nebicapone does not potentiate the psychostimulant-like effects of amphetamine in animals. Nebicapone was found to be effective for Parkinson's disease in clinical trials. However, it also showed hepatotoxicity, including elevated liver enzymes. As a result, its development was discontinued by 2014. Nebicapone was first described in the scientific literature by 2000.

<span class="mw-page-title-main">Neluxicapone</span> COMT inhibitor

Neluxicapone is a catechol O-methyltransferase (COMT) inhibitor which has not been marketed as of 2024. The drug is a nitrocatechol and is structurally related to other catechol COMT inhibitors like entacapone, tolcapone, and nebicapone. COMT inhibitors are used in conjunction with levodopa in the treatment of Parkinson's disease. Neluxicapone was first described in the literature by 2018. Its INNTooltip International Nonproprietary Name was designated by the World Health Organization (WHO) in 2019.

References

  1. ↑ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  2. ↑ "Tasmar 100 mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). 9 October 2020. Retrieved 28 November 2022.
  3. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  4. ↑ "Tasmar- tolcapone tablet, film coated". DailyMed. U.S. National Library of Medicine. 2 October 2020. Retrieved 28 November 2022.
  5. ↑ Antonini A, Abbruzzese G, Barone P, Bonuccelli U, Lopiano L, Onofrj M, et al. (February 2008). "COMT inhibition with tolcapone in the treatment algorithm of patients with Parkinson's disease (PD): relevance for motor and non-motor features". Neuropsychiatric Disease and Treatment. 4 (1): 1–9. doi: 10.2147/NDT.S2404 . PMC   2515921 . PMID   18728767.
  6. 1 2 Keating GM, Lyseng-Williamson KA (2005). "Tolcapone: a review of its use in the management of Parkinson's disease". CNS Drugs. 19 (2): 165–184. doi:10.2165/00023210-200519020-00006. PMID   15697329. The efficacy of tolcapone as an adjunct to levodopa in patients with Parkinson's disease has primarily been attributed to its ability to inhibit peripheral it is thought that tolcapone enters the CNS to a minimal extent only.[16] However, results [17] of a study in patients with Parkinson's disease, as well as results of animal studies,[18-21] suggest that tolcapone also has central activity.
  7. 1 2 3 Fabbri M, Ferreira JJ, Lees A, Stocchi F, Poewe W, Tolosa E, et al. (October 2018). "Opicapone for the treatment of Parkinson's disease: A review of a new licensed medicine". Mov Disord. 33 (10): 1528–1539. doi:10.1002/mds.27475. PMID   30264443. The possible central effect of tolcapone, which is more lipophilic than entacapone and may be more likely to cross the blood-brain barrier (BBB), has been under debate for many years.26 An (18)F-dopa positron emission tomography study showed its effect as a central COMT inhibitior.27 However, this effect was not translated into clinical benefit in L-dopa-naive patients, in whom tolcapone alone or added to selegiline was compared with placebo.28 Tolcapone is more efficacious than entacapone, as it reduces total OFF time by an average of 98 minutes daily.
  8. ↑ Forsberg M, Lehtonen M, Heikkinen M, Savolainen J, Järvinen T, Männistö PT (February 2003). "Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat". The Journal of Pharmacology and Experimental Therapeutics. 304 (2): 498–506. doi:10.1124/jpet.102.042846. PMID   12538800. S2CID   24863335.
  9. ↑ Dingemanse J, Jorga K, Zürcher G, Schmitt M, Sedek G, Da Prada M, et al. (September 1995). "Pharmacokinetic-pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa". British Journal of Clinical Pharmacology. 40 (3): 253–62. doi:10.1111/j.1365-2125.1995.tb05781.x. PMC   1365105 . PMID   8527287.
  10. 1 2 Jorga KM, Fotteler B, Heizmann P, Zürcher G (July 1998). "Pharmacokinetics and pharmacodynamics after oral and intravenous administration of tolcapone, a novel adjunct to Parkinson's disease therapy". European Journal of Clinical Pharmacology. 54 (5): 443–7. doi:10.1007/s002280050490. PMID   9754991. S2CID   19203574.
  11. 1 2 3 4 5 6 7 Dinnendahl V, Fricke U, eds. (1998). Arzneistoff-Profile (in German). Vol. 10 (13 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN   978-3-7741-9846-3.
  12. 1 2 3 4 5 6 7 8 "Tasmar: EPAR – Product Information" (PDF). European Medicines Agency. 3 August 2016. Archived from the original (PDF) on 15 April 2017. Retrieved 15 April 2017.
  13. ↑ Olanow CW, Watkins PB (2007). "Tolcapone: an efficacy and safety review (2007)". Clinical Neuropharmacology. 30 (5): 287–94. doi:10.1097/wnf.0b013e318038d2b6. PMID   17909307. S2CID   19148461.
  14. 1 2 3 Truong DD (2009). "Tolcapone: review of its pharmacology and use as adjunctive therapy in patients with Parkinson's disease". Clinical Interventions in Aging. 4: 109–13. doi: 10.2147/CIA.S3787 . PMC   2685232 . PMID   19503773.
  15. ↑ Ellermann M, Lerner C, Burgy G, Ehler A, Bissantz C, Jakob-Roetne R, et al. (March 2012). "Catechol-O-methyltransferase in complex with substituted 3'-deoxyribose bisubstrate inhibitors". Acta Crystallographica. Section D, Biological Crystallography. 68 (Pt 3): 253–60. doi:10.1107/S0907444912001138. PMID   22349227.
  16. ↑ Deleu D, Northway MG, Hanssens Y (2002). "Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease". Clinical Pharmacokinetics. 41 (4): 261–309. doi:10.2165/00003088-200241040-00003. PMID   11978145. S2CID   39359348.
  17. ↑ Jorga K, Fotteler B, Heizmann P, Gasser R (October 1999). "Metabolism and excretion of tolcapone, a novel inhibitor of catechol-O-methyltransferase". British Journal of Clinical Pharmacology. 48 (4): 513–20. doi:10.1046/j.1365-2125.1999.00036.x. PMC   2014389 . PMID   10583021.
  18. ↑ Forsberg MM, Huotari M, Savolainen J, Männistö PT (April 2005). "The role of physicochemical properties of entacapone and tolcapone on their efficacy during local intrastriatal administration". European Journal of Pharmaceutical Sciences. 24 (5): 503–11. doi:10.1016/j.ejps.2005.01.005. PMID   15784340.
  19. ↑ Novaroli L, Bouchard Doulakas G, Reist M, Rolando B, Fruttero R, Gasco A, et al. (2006). "The Lipophilicity Behavior of Three Catechol-O-methyltransferase (COMT) Inhibitors and Simple Analogues". Helvetica Chimica Acta. 89 (1): 144–152. doi:10.1002/hlca.200690007.
  20. ↑ "3-Benzyloxy-4-methoxybenzaldehyde". PubChem. U.S. National Library of Medicine.
  21. ↑ Manikumar G, Jin C, Rehder KS (2008). "Convenient Synthesis of Tolcapone, a Selective Catechol-O-methyltransferase Inhibitor". Synthetic Communications. 38 (5): 810–815. doi:10.1080/00397910701821077. S2CID   94242335.
  22. 1 2 Manikumar G, Jin C, Rehder KS (2008). "Convenient Synthesis of Tolcapone, a Selective Catechol-O-methyltransferase Inhibitor". Synthetic Communications. 38 (5): 810–815. doi:10.1080/00397910701821077. S2CID   94242335.
  23. 1 2 "2001 Pharmaceuticals: Restrictions in Use and Availability". World Health Organization. Archived from the original on 12 June 2011. Retrieved 31 October 2012.
  24. ↑ "Tasmar tolcapone EPAR summary for the public" (PDF). European Medicine Agency. Archived from the original (PDF) on 22 May 2013. Retrieved 31 October 2012.
  25. ↑ Press Office UD. "FDA Talk Paper". New Warnings for Parkinson's Drug, Tasmar. Food and Drug Administration.
  26. ↑ "Tolcapone". FDA: Search Orphan Drug Designations and Approvals. 1 January 2013.
  27. ↑ Reig N, Ventura S, Salvadó M, Gámez J, Insa R (2015). "SOM0226, a repositioned compound for the treatment of TTR amyloidosis". Orphanet J Rare Dis. 10 (Suppl 1): P9. doi: 10.1186/1750-1172-10-s1-p9 . PMC   4642128 .
  28. ↑ Guay DR (January 1999). "Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson's disease". Pharmacotherapy. 19 (1): 6–20. doi:10.1592/phco.19.1.6.30516. PMID   9917075. It also enhances locomotor hyperactivity induced by amphetamine and nomifensine and stereotypy induced by amphetamine, and stimulates exploratory activity in the open field test in rats and mice.14 Tolcapone potentiates levodopa antagonism of haloperidol-induced catalepsy in MPP+-lesioned mice (murine model of Parkinson's disease) and potentiates and prolongs levodopa-induced circling behavior in rats with 6-hydroxydopamine-induced nigrostriatal pathway lesions (another animal model of Parkinson's disease).23, 24 [...] The effect of tolcapone on animal models of depression was evaluated in two studies. In rats with chronic mild stress-induced anhedonia, tolcapone 10 or 30 mg/kg twice/day by intraperitoneal injection prevented the stress-induced anhedonic state compared with vehicle-treated controls.28 Another rat study using the forced swimming test and learned helplessness paradigm, found no significant antidepressant activity of the agent.29 The relevance of these findings to the management of depression in humans with both parkinsonian and nonparkinsonian disease is unknown.
  29. ↑ Maj J, Rogóz Z, Skuza G, Sowińska H, Superata J (1990). "Behavioural and neurochemical effects of Ro 40-7592, a new COMT inhibitor with a potential therapeutic activity in Parkinson's disease". J Neural Transm Park Dis Dement Sect. 2 (2): 101–112. doi:10.1007/BF02260898. PMID   1977408.
  30. ↑ Parada A, Soares-da-Silva P (October 2000). "POSTER COMMUNICATIONS: 49P. BIA 3-202 does not potentiate locomotor hyperactivity during increased dopaminergic stimulation". British Journal of Pharmacology. 131 (Suppl). Wiley: 38P–129P. PMC   1910551 . Tolcapone administered 6 h before amphetamine challenge was found to significantly increase locomotor activity in rats treated with 0.5 and 2.0 mg kg-1 amphetamine. In rats given 4.0 mg kg-1 amphetamine, tolcapone produced a marked decrease in locomotor activity and increased two-fold the duration of the stereotyped behaviour.
  31. 1 2 Kings E, Ioannidis K, Grant JE, Chamberlain SR (June 2024). "A systematic review of the cognitive effects of the COMT inhibitor, tolcapone, in adult humans". CNS Spectr. 29 (3): 166–175. doi:10.1017/S1092852924000130. PMID   38487834.
  32. ↑ Grant JE, Hook R, Valle S, Chesivoir E, Chamberlain SR (September 2021). "Tolcapone in obsessive-compulsive disorder: a randomized double-blind placebo-controlled crossover trial". Int Clin Psychopharmacol. 36 (5): 225–229. doi:10.1097/YIC.0000000000000368. PMC   7611531 . PMID   34310432.
  33. ↑ Apud JA, Weinberger DR (2007). "Treatment of cognitive deficits associated with schizophrenia: potential role of catechol-O-methyltransferase inhibitors". CNS Drugs. 21 (7): 535–557. doi:10.2165/00023210-200721070-00002. PMID   17579498.
  34. ↑ Costello H, Husain M, Roiser JP (January 2024). "Apathy and Motivation: Biological Basis and Drug Treatment". Annu Rev Pharmacol Toxicol. 64: 313–338. doi:10.1146/annurev-pharmtox-022423-014645. PMID   37585659.
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