Clinical pharmacology and therapeutic use of COMT inhibition in Parkinson's disease

Gordin, A.; Brooks, David J.

doi:10.1007/s00415-007-4007-9

Cited by 12 publications

(7 citation statements)

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“…Levodopa (L-DOPA), a metabolic precursor of dopamine (DA), has been the gold standard treatment for decades . Other strategies used to elevate or maintain DA brain levels involve the use of DA agonists, inhibitors of DA reuptake, or inhibitors of DA metabolizing enzymes such as monoamine oxidase B (MAO-B) and catechol- O -methyltransferase (COMT) . However, with long-term treatment, these dopamine-targeted drugs carry the risk of undesirable side effects, including motor fluctuations (e.g., wearing-off, “on–off” phenomena, dyskinesia) and hallucinations .…”

Section: Therapeutic Applications Of A2a Receptor Antagonistsmentioning

confidence: 99%

Adenosine A_2A Receptor as a Drug Discovery Target

2013

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The adenosine A2A receptor is a G-protein-coupled receptor (GPCR) that has been extensively studied during the past few decades because it offers numerous possibilities for therapeutic applications. Herein we describe adenosine A2A receptor distribution, signaling pathways, pharmacology, and molecular structure, followed by a summary and SAR discussion of the most relevant series of adenosine A2A agonists and antagonists. This review also provides an update of the A2A ligands that are undergoing or have undergone clinical studies, including the two currently marketed agonists adenosine and regadenoson.

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Section: Therapeutic Applications Of A2a Receptor Antagonistsmentioning

confidence: 99%

Adenosine A_2A Receptor as a Drug Discovery Target

2013

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“…As a COMT inhibitor, tolcapone affects central metabolism of l -dopa and would cause compensatory effects on the metabolism of other neurotransmitters . Perturbed tryptophan metabolism and phenylalanine metabolism were observed, which most likely correspond to altered tetrahydrobiopterin BH 4 cycle (Figure S-4).…”

Section: Resultsmentioning

confidence: 99%

“…Theoretically, COMT inhibitors that are active in the CNS would also reduce central metabolism of both levodopa and dopamine (Figure S-1). , …”

Section: Introductionmentioning

confidence: 99%

“…Theoretically, COMT inhibitors that are active in the CNS would also reduce central metabolism of both levodopa and dopamine (Figure S-1). 12,13 Tolcapone, as a potent, selective reversible inhibitor of COMT, improves clinical parameters of levodopa, such as the increase in duration of "on" and decrease of "off" time; and prolongs the half-life from approximately 2 to 3.5 h. 14 These result in a doubling of levodopa relative bioavailability. The tolcapone adjunctive therapy has been effective for patients who do not obtain optimal response to levodopa-based therapy.…”

Section: ■ Introductionmentioning

confidence: 99%

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Analysis of an Integrated Human Multiorgan Microphysiological System for Combined Tolcapone Metabolism and Brain Metabolomics

et al. 2019

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Human-on-a-chip systems are rapidly advancing due to the availability of human stem cells from a variety of tissues, but publications have utilized mostly simple methods of biochemical analysis.Here, we apply mass spectrometry to a sophisticated multi-organ human-on-a-chip system for the comprehensive study of tolcapone metabolite profiling and metabolomics. The developed humanon-a-chip includes seven interacting microphysiological systems (MPSs): brain, pancreas, liver, lung, heart, gut, endometrium, with a mixer chamber for systemic circulation and tolcapone dose.We investigated tolcapone metabolism by analyzing the circulating medium using mass spectrometry. Twelve tolcapone metabolites were identified, three of which are newly reported.These metabolites demonstrated that oxidation, reduction, and conjugation reactions were the most important routes of tolcapone metabolism. In parallel, metabolomics in brain MPS evaluated the tolcapone influences on endogenous pathways in human brain. Untargeted metabolomics identified 18 key biomarkers significantly changed in human brain MPS after tolcapone dosing, which were mainly associated with perturbation of tryptophan and phenylalanine metabolism (BH4 cycle), glycerophospholipid metabolism, energy metabolism, and aspartate metabolism. This is the first example of successfully combining drug metabolism, metabolomics and cell engineering to capture complex human physiology and the multi-organ interactions; the results we present here could be a step toward using analytical chemistry to advance the utilization of human-on-a-chip for testing both drug efficacy and toxicity in a single system.

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“…The current therapy of PD is targeted at dopamine replacement, thereby decreasing the motor symptoms. It includes precursor of dopamine (levodopa), dopamine agonists [15,16] monoamine oxidase type B (MAO-B) inhibitors [17], and catechol-O-methyltransferase (COMT) inhibitors [17,18]. These agents produce undesirable side effects such as on-off effects, hallucinations, and dyskinesia.…”

Section: The Role Of Adenosine a 2a In Parkinson's Diseasementioning

confidence: 99%

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease

Aryati¹,

Salamah²,

Syahdi³

et al. 2019

Neuroprotection

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Adenosine is a neuromodulator that regulates the body's response to dopamine and another neurotransmitter in the brain that is responsible for motoric, emotion, learning, and memory function. Adenosine is a G-protein-coupled receptor and has four subtypes, which are A 1, A 2A , A 2B , and A 3. Adenosine A 2A is located in the striatum of the brain. Antagonist interferes with GABA releasing, modulates acetylcholine and releases dopamine, and also facilitates dopamine receptor's signaling. Therefore, it can reduce motoric symptoms in Parkinson's disease. Adenosine A 2A antagonist is also believed to have neuroprotective effects. Several compounds have been reported and have undergone clinical test as selective adenosine A 2A antagonists, including istradefylline, preladenant, tozadenant, vipadenant, ST-1535, and SYN-115. Nonselective adenosine A 2A antagonists from natural compounds are caffeine and theophylline.

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Clinical pharmacology and therapeutic use of COMT inhibition in Parkinson's disease

Cited by 12 publications

References 68 publications

Adenosine A_2A Receptor as a Drug Discovery Target

Adenosine A_2A Receptor as a Drug Discovery Target

Analysis of an Integrated Human Multiorgan Microphysiological System for Combined Tolcapone Metabolism and Brain Metabolomics

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease

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Clinical pharmacology and therapeutic use of COMT inhibition in Parkinson's disease

Cited by 12 publications

References 68 publications

Adenosine A2A Receptor as a Drug Discovery Target

Adenosine A2A Receptor as a Drug Discovery Target

Analysis of an Integrated Human Multiorgan Microphysiological System for Combined Tolcapone Metabolism and Brain Metabolomics

The Role and Development of the Antagonist of Adenosine A2Ain Parkinson’s Disease

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Product

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Adenosine A_2A Receptor as a Drug Discovery Target

Adenosine A_2A Receptor as a Drug Discovery Target

The Role and Development of the Antagonist of Adenosine A_2Ain Parkinson’s Disease