Side Effects of tolcapone: A Synthesis of Findings from 28 Studies

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Original Abstract of the Article

Main Research Findings

Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor that increases the levels of dopamine, norepinephrine, adrenaline, and total catecholamines in the plasma of Parkinson's disease patients. 23 . Tolcapone has been shown to be effective in treating Parkinson's disease, but it has also been associated with several side effects, including worsening of dyskinesia and psychosis, diarrhea, and elevated liver enzymes. 23 . Entacapone is another COMT inhibitor that has been shown to be more tolerable than tolcapone. 24 . Both tolcapone and entacapone are effective in extending the duration of action of levodopa and improving motor function in Parkinson's disease patients. 26 . However, the risk of liver toxicity is higher with tolcapone than with entacapone. 20 The exact mechanism of tolcapone-induced liver toxicity is still unknown, but it is believed to be related to its off-target binding to a protein called 3-hydroxyisobutyryl-CoA hydrolase (HIBCH). 4 Entacapone does not bind to HIBCH, which may explain its lower risk of liver toxicity.

Reasons for Side Effects

Tolcapone is a COMT inhibitor, and its mechanism of action involves inhibiting COMT activity, which prevents the breakdown of L-DOPA and increases the levels of dopamine and other catecholamines in the body. 23 . This increase in catecholamine levels can lead to excessive adrenergic stimulation, which is believed to be responsible for the higher risk of liver toxicity associated with tolcapone compared to entacapone. 23 Additionally, tolcapone may interact with other proteins in the body, such as HIBCH, which could contribute to its hepatotoxicity. 4

Common Side Effects

Dyskinesia

Both tolcapone and entacapone can worsen dyskinesia. 23 , 24 Dyskinesia is a movement disorder that causes involuntary movements.

Psychosis

Tolcapone can worsen psychosis. 23 Psychosis is a mental state characterized by a loss of contact with reality.

Diarrhea

Tolcapone can cause diarrhea. 23 , 25 Entacapone can also cause diarrhea, but it is less frequent than with tolcapone. 19 , 9

Liver

Tolcapone can cause elevated liver enzymes and liver toxicity. 23 , 20 Entacapone has a lower risk of liver toxicity compared to tolcapone. 19 , 20 , 9 Elevated liver enzymes can indicate a problem with the liver.

Side Effects Management

Dyskinesia

If dyskinesia occurs, reducing the dosage of levodopa may help. 25 Other dopamine agonists or anticholinergics may also be helpful.

Psychosis

If psychosis occurs, the dosage of tolcapone may need to be reduced or stopped. 24 Antipsychotic medications may also be helpful.

Diarrhea

If diarrhea occurs, the dosage of tolcapone may need to be reduced or stopped. 25 Antidiarrheal medications may also be helpful.

Liver

If you are taking tolcapone, you should have regular liver function tests. 20 If abnormal liver function tests occur, the dosage of tolcapone may need to be reduced or stopped. 16

Comparison Across Studies

Similarities in Studies

Both tolcapone and entacapone have been shown to improve the effectiveness of levodopa in treating Parkinson's disease patients in multiple studies. 24 , 26 , 25 , 1

Differences in Studies

Multiple studies have shown that tolcapone has a higher risk of liver toxicity compared to entacapone. 20 , 26 , 25 , 9 , 4 . Studies have also shown that tolcapone is more likely to worsen dyskinesia and psychosis compared to entacapone. 23

Practical Implications

If you are taking tolcapone, you should follow your doctor's instructions carefully and have regular liver function tests. 20 . You should also inform your doctor if you experience any side effects. 16 . Because of the risk of liver toxicity, entacapone is often preferred over tolcapone. 19 , 9 . There are many different medications used to treat Parkinson's disease. Talk to your doctor about the best treatment options for you.

Limitations of Current Research

The exact mechanism of tolcapone-induced liver toxicity is still not fully understood. 4 , , 7 , 17 , 2 . Therefore, there is no proven way to completely prevent this side effect.

Future Research Directions

Research is needed to clarify the mechanism of tolcapone-induced liver toxicity and develop methods to prevent it. 4 , , 7 , 17 , 2 . Additionally, further research is needed to better understand the interactions of tolcapone with other medications.

Conclusion

While tolcapone can improve the effectiveness of levodopa in treating Parkinson's disease, it comes with a risk of liver toxicity. 20 . If you are taking tolcapone, it is important to follow your doctor's instructions carefully and have regular liver function tests. 16 . Because of the risk of liver toxicity, entacapone is often preferred over tolcapone. 19 , 9 It is essential to discuss with your doctor the best treatment options for you based on your individual needs and medical history.

Keywords
Benefit Keywords
Parkinson's disease treatment
1
DILI prediction
3
Parkinson's disease treatment
4
Neurological disorder treatment
5
Parkinson's treatment
6
Detect drug-induced cytotoxicity
7
Parkinson's disease treatment
8
Treat Parkinson's disease
9
Motor symptom control
10
Drug safety assessment
Off-target identification
11
Parkinson's disease
12
Improved safety
Improved tolerability
Reduced dyskinesia
Reduced motor fluctuations
13
Improved safety
14
Prevent ADRs
15
Parkinson treatment
Tolcapone efficacy
16
Drug safety
17
PD treatment
18
Motor Fluctuation Management
Parkinson's Disease Treatment
19
Parkinson disease treatment
20
Parkinson's disease treatment
21
Parkinson's disease treatment
22
Parkinson's disease treatment
23
Effective Parkinson's treatment
24
Effective Parkinson's treatment
Increased 'on' time
25
Effective Parkinson's treatment
Improved motor function
26
Improved quality of life
Prolonged life
Self-dependency
27
Levodopa duration extension
Parkinson's disease treatment
28
Risk Keywords
Diarrhea
Yellow discoloration of urine
1
DILI risk
FXR antagonism
Hepatotoxicity
2
Drug induced liver injury
3
Hepatotoxicity
4
Dopaminergic side effects
Gastrointestinal side effects
5
Liver enzyme elevation
6
Convulsions
Diarrhea
Liver toxicity
9
Unknown
11
Liver problems
12
Liver failure
14
Hepatotoxicity
Liver injury
16
Hepatotoxicity
17
Drug diskinesias
Motor fluctuations
18
Diarrhea
Dyskinesia
Nausea
Urine Discoloration
19
Hepatotoxicity
20
Constipation
Dyskinesias
Hypotension
Urine discoloration
21
Drug side effects
22
Diarrhea
Dyskinesia
Liver enzyme elevation
Psychosis
23
Dyskinesia
Side effects
24
Diarrhea
Dyskinesia
Liver dysfunction
25
Diarrhea
Dyskinesia
Liver enzyme elevation
26
Dyskinesia
Loss of medication efficacy
Motor fluctuations
Psychosis
27
Diarrhea
Dopaminergic effects
Liver function abnormalities
28
Literature analysis of 28 papers
Positive Content
25
Neutral Content
1
Negative Content
2
Article Type
1
1
1
16
28
1.

[Relevance of COMT inhibitors in the treatment of motor fluctuations].

Author: JostWolfgang H, BuhmannCarsten, ClassenJoseph, EggertKarla, KohlZacharias, OuteiroTiago, TöngesLars, WoitallaDirk, ReichmannHeinz

Parkinson's disease treatment
Diarrhea
Yellow discoloration of urine

Catechol O‑methyltransferase (COMT) inhibitors are effective for treating motor fluctuations in Parkinson's disease. This manuscript summarizes the results of a working group that discussed the value of COMT inhibitors in Parkinson's disease treatment.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : German

2.

In vitro assessment of farnesoid X receptor antagonism to predict drug-induced liver injury risk.

Author: NoronaLeah M, FullertonAaron, LawsonChris, LeungLeslie, BrummJochen, KiyotaTomomi, MaherJonathan, KhojastehCyrus, ProctorWilliam R

DILI risk
FXR antagonism
Hepatotoxicity

Drug-induced liver injury (DILI) is a significant problem in drug development. This study investigated the role of farnesoid X receptor (FXR) antagonism in DILI. The study found that FXR antagonism was relatively uncommon among a large set of drugs, and it was not a strong predictor of DILI risk. However, the study identified some novel FXR antagonists among well-known hepatotoxic drugs.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

3.

Safety data and withdrawal of hepatotoxic drugs.

Author: BabaiSamy, AuclertLaurent, Le-LouëtHervé

DILI prediction
Drug induced liver injury

Predicting drug-induced liver injury (DILI) remains challenging due to limitations in in vitro cytotoxicity screening and animal studies. A comprehensive review of hepatotoxicity data is essential to identify factors that could predict the occurrence of serious DILI.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

6.

Safety and efficacy of tolcapone in the long-term use in Parkinson disease: an observational study.

Author: EggertKarla, OertelWolfgang H, LeesAndrew J,

Parkinson's treatment
Liver enzyme elevation

Tolcapone was found to be safe and effective in patients with Parkinson disease. Significant liver transaminase elevations were rare and generally returned to normal without intervention.

Clinical TrialA clinical trial is a planned study conducted on humans to evaluate the efficacy and safety of pharmaceuticals, medical devices, and treatment methods. It aims to explore the possibilities of new treatments and improve the health of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Multicenter StudyResearch conducted in collaboration with multiple research institutions. It aims to collect a wide range of data and obtain more generalizable results.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

7.

Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation.

Author: HosomiHiroko, FukamiTatsuki, IwamuraAtsushi, NakajimaMiki, YokoiTsuyoshi

Detect drug-induced cytotoxicity

This study constructed a cell-based system to evaluate the cytotoxicity of reactive metabolites produced by CYP3A4. The study found that HepG2 cells showed the highest CYP3A4 protein expression and activity among seven hepatoma cell lines. The cytotoxicity of 23 drugs was evaluated in AdCYP3A4-infected HepG2 cells, with 11 drugs showing significant decrease in cell viability.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

8.

Meta-analysis of the comparative efficacy and safety of adjuvant treatment to levodopa in later Parkinson's disease.

Author: StoweRebecca, IvesNatalie, ClarkeCarl E, HandleyKelly, FurmstonAlexandra, DeaneKatherine, van HiltenJ J, WheatleyKeith, GrayRichard

Parkinson's disease treatment

Levodopa effectively manages Parkinson's disease symptoms initially, but long-term use often leads to movement problems. Other medications, such as dopamine agonists, catechol-O-methyl transferase inhibitors, and monoamine oxidase type B inhibitors, are added to levodopa treatment. This meta-analysis compares the effectiveness and risks of these additional medications in people with Parkinson's disease who have developed movement problems.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Meta-AnalysisA statistical technique that integrates the results of multiple studies to draw more general conclusions about a particular issue.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.
Systematic ReviewA review that systematically collects, evaluates, and integrates relevant research to answer a specific research question.

Language : English

9.

Toxicology and safety of COMT inhibitors.

Author: HaasioKristiina

Treat Parkinson's disease
Convulsions
Diarrhea
Liver toxicity

Catechol-O-methyltransferase (COMT) inhibitors are used to treat Parkinson's disease, but some have been associated with toxic effects, particularly liver toxicity. This review discusses the development, safety, and effectiveness of COMT inhibitors.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

10.

Replacing a dopamine agonist by the COMT-inhibitor tolcapone as an adjunct to L-dopa in the treatment of Parkinson's disease: a randomized, multicenter, open-label, parallel-group study.

Author: RiesVincent, SelzerRoland, EichhornTobias, OertelWolfgang H, EggertKarla,

Motor symptom control

This study evaluated the feasibility, safety, and efficacy of switching from a dopamine agonist to tolcapone as an adjunctive therapy in patients with Parkinson's disease experiencing fluctuating response to levodopa. Two different replacement strategies were compared.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Multicenter StudyResearch conducted in collaboration with multiple research institutions. It aims to collect a wide range of data and obtain more generalizable results.
Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

11.

Capture compound mass spectrometry sheds light on the molecular mechanisms of liver toxicity of two Parkinson drugs.

Author: FischerJenny J, MichaelisSimon, SchreyAnna K, GraebnerOlivia Graebner nee, GlinskiMirko, DregerMathias, KrollFriedrich, KoesterHubert

Drug safety assessment
Off-target identification
Unknown

Capture compound mass spectrometry (CCMS) is a novel technology for identifying a drug's potential off-targets. It revealed a difference in protein interactions between tolcapone and entacapone, providing insights into their distinct side effect profiles.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

13.

New drug delivery strategies for improved Parkinson's disease therapy.

Author: Di StefanoAntonio, SozioPiera, IannitelliAntonio, CerasaLaura Serafina

Improved safety
Improved tolerability
Reduced dyskinesia
Reduced motor fluctuations

This review explores the progress in anti-Parkinson therapy, focusing on delivery strategies and codrug approaches for continuous dopaminergic stimulation (CDS), aiming to reduce motor fluctuations, dyskinesia, and improve long-term safety and tolerability.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

14.

Real-life evaluations of compliance with mandatory drug safety monitoring exemplified with tolcapone in Parkinson's disease.

Author: UngerMarcus M, ReeseJens P, OertelWolfgang H, EggertKarla M

Improved safety
Liver failure

Tolcapone, a drug for Parkinson's disease, was withdrawn from the market due to safety concerns but relaunched with mandatory liver enzyme monitoring. This study evaluated the compliance with this monitoring in real-life conditions.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

15.

Knowledge creation about ADRs--turning the perspective from the rear mirror to the projector?

Author: AagaardLise, SoendergaardBirthe, StenverDoris I, HansenEbba Holme

Prevent ADRs

The study highlights the importance of thoroughly investigating potential adverse drug reactions before drug marketing to prevent unexpected and serious cases after release.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

18.

[A comparative study of efficacy of dopamine receptors agonists and catechol-O-methyltransferase in the treatment of late stages of Parkinson's disease].

Author: KrivonosO V, FedorovaN V, Chigir'I P

PD treatment
Drug diskinesias
Motor fluctuations

This review discusses the use of dopamine receptor agonists and catechol-O-methyltransferase (COMT) inhibitors in treating Parkinson's disease (PD) at both early and late stages, highlighting their role in improving pharmaco-therapeutic efficacy and patient quality of life.

Clinical TrialA clinical trial is a planned study conducted on humans to evaluate the efficacy and safety of pharmaceuticals, medical devices, and treatment methods. It aims to explore the possibilities of new treatments and improve the health of patients.
Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : Russian

19.

Safety and tolerability of COMT inhibitors.

Author: BrooksDavid J

Motor Fluctuation Management
Parkinson's Disease Treatment
Diarrhea
Dyskinesia
Nausea
Urine Discoloration

Combining levodopa with the COMT inhibitor entacapone is a safe and effective treatment for Parkinson's disease (PD) patients with motor fluctuations. The most common side effects are dyskinesia and nausea, which can be managed.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

20.

Hepatotoxic profile of catechol-O-methyltransferase inhibitors in Parkinson's disease.

Author: BenabouReina, WatersCheryl

Parkinson disease treatment
Hepatotoxicity

Entacapone and tolcapone are selective catechol-O-methyltransferase (COMT) inhibitors used to treat Parkinson's disease. They extend the duration of action of levodopa. Tolcapone is associated with a risk of hepatotoxicity, while entacapone is generally well-tolerated and safe.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

21.

Entacapone in the management of Parkinson's disease.

Author: HenchcliffeClaire, WatersCheryl

Parkinson's disease treatment
Constipation
Dyskinesias
Hypotension
Urine discoloration

Entacapone is a new drug that helps extend the effects of levodopa for Parkinson's disease patients. It can improve motor fluctuations, but it can also worsen dyskinesias, cause low blood pressure, constipation, and urine discoloration. Entacapone does not require liver function monitoring unlike the similar drug tolcapone.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

24.

A comparison of dopamine agonists and catechol-O-methyltransferase inhibitors in Parkinson's disease.

Author: InzelbergR, CarassoR L, SchechtmanE, NisipeanuP

Effective Parkinson's treatment
Dyskinesia
Side effects

This study compared the efficacy and tolerability of three dopamine agonists (pergolide, pramipexole, ropinirole) and two COMT inhibitors (tolcapone, entacapone) for Parkinson's disease. Pramipexole and entacapone showed the best efficacy and tolerability profile. However, all drugs caused more dyskinesias than placebo.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

28.

Catechol-O-methyltransferase (COMT) inhibitors in Parkinson's disease.

Author: WatersC

Levodopa duration extension
Parkinson's disease treatment
Diarrhea
Dopaminergic effects
Liver function abnormalities

COMT inhibitors, such as tolcapone, are used in conjunction with levodopa to improve the duration of action of levodopa in Parkinson's disease. While they can augment dopaminergic effects and require levodopa dose adjustment, monitoring for liver function abnormalities is crucial.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

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