Real-world evidence on levodopa dose escalation in patients with Parkinson's disease treated with istradefylline.

OBJECTIVE: Istradefylline, a selective adenosine A2A receptor antagonist, is indicated in the US and Japan as adjunctive treatment to levodopa/decarboxylase inhibitors in adults with Parkinson's disease (PD) experiencing OFF time. This study aimed to observe patterns of dose escalation of levodopa over time in patients initiated on istradefylline. METHODS: Using Japanese electronic health record data, interrupted time series analyses were used to compare levodopa daily dose (LDD, mg/day) gradients in patients before and after initiation of istradefylline. Data were analyzed by period relative to istradefylline initiation (Month 1): pre-istradefylline (Months -72 to 0), early istradefylline (Months 1 to 24), and late istradefylline (Months 25 to 72). Subgroup analyses included LDD before istradefylline initiation (<400, ≥400 to <600, ≥600 mg/day) and treatment with or without monoamine oxidase-B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, or dopamine agonists before istradefylline initiation. RESULTS: The analysis included 4026 patients; mean (SD) baseline LDD was 419.27 mg (174.19). Patients receiving ≥600 mg/day levodopa or not receiving MAO-B inhibitors or COMT inhibitors demonstrated a significant reduction in LDD increase gradient for pre-istradefylline vs late-phase istradefylline (≥600 mg/day levodopa, -6.259 mg/day each month, p<0.001; no MAO-B inhibitors, -1.819 mg/day each month, p = 0.004; no COMT inhibitors, -1.412 mg/day each month, p = 0.027). CONCLUSIONS: This real-world analysis of Japanese prescription data indicated that slowing of LDD escalation was observed in patients initiated on istradefylline, particularly in those receiving ≥600 mg/day levodopa, suggesting istradefylline may slow progressive LDD increases. These findings suggest that initiating istradefylline before other levodopa-adjunctive therapies may mitigate LDD increases, potentially reducing occurrence or severity of levodopa-induced complications in long-term istradefylline treatment.

A Pilot Study Exploring the Association of Entacapone, Gut Microbiota, and the Subsequent Side Effects in Patients With Parkinson's Disease.

Background and Aims: Entacapone, one of the most common drugs distributed among patients with Parkinson's disease, is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor that is used in addition to levodopa to control symptoms. However, there have been negative effects reported against entacapone, namely, gastrointestinal (GI) problems and drowsiness. In this pilot study, we aim to examine the hypothesis that the discomfort induced by entacapone might be originated from the shift of microbial composition by adjusting the effect of levodopa. Methods: The population in this pilot study consisted of 13 PD patients treated with levodopa only and 11 with both levodopa and entacapone. The 16S rRNA gene sequence data were processed, aligned, and categorized using the DADA2. Alpha diversity indices for Observed, Chao1, Shannon, and Simpson metrics were calculated with Phyloseq 1.32.0. Dissimilarities were calculated using unweighted unique fraction metrics (Unifrac), weighted Unifrac, and Canberra distance. Functional differences were calculated by PICRUSt2 based on the KEGG database. Results: Results of 16S rRNA sequencing analysis showed that while entacapone did not influence the species richness, the composition of the microbial community shifted considerably. Relative abundances of bacteria related to constipation and other GI disorders also altered significantly. Functional enrichment analysis revealed changes in the metabolic activity of alanine, aspartate, and glutamate. These amino acids are related to common side effects of entacapone such as auditory hallucinations, fatigue, and nightmare. Conclusion: Our findings provide testable hypothesis on the cause of unpleasant side effects of entacapone, which in the long run could possibly be reduced through gut microbiota manipulation.

Pathophysiology and Therapeutic Approaches to Cardiac Amyloidosis.

Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the population and increasing incidence and prevalence of cardiac amyloidosis with advancing age, as well as the advent of noninvasive methods using nuclear scintigraphy to diagnose transthyretin cardiac amyloidosis due to either variant or wild type transthyretin without a biopsy. Perhaps the most important driver of the increased awareness is the elucidation of the biologic mechanisms underlying the pathogenesis of cardiac amyloidosis which have led to the development of several effective therapies with differing mechanisms of actions. In this review, the mechanisms underlying the pathogenesis of cardiac amyloidosis due to light chain (AL) or transthyretin (ATTR) amyloidosis are delineated as well as the rapidly evolving therapeutic landscape that has emerged from a better pathophysiologic understanding of disease development.

COMT-Catalyzed Palmitic Acid Methyl Ester Biosynthesis in Perivascular Adipose Tissue and its Potential Role Against Hypertension.

Decreased release of palmitic acid methyl ester (PAME), a vasodilator, from perivascular adipose tissue (PVAT) might contribute to hypertension pathogenesis. However, the PAME biosynthetic pathway remains unclear. In this study, we hypothesized that PAME is biosynthesized from palmitic acid (PA) via human catechol-O-methyltransferase (COMT) catalysis and that decreased PAME biosynthesis plays a role in hypertension pathogenesis. We compared PAME biosynthesis between age-matched normotensive Wistar Kyoto (WKY) rats and hypertensive spontaneously hypertensive rats (SHRs) and investigated the effects of losartan treatment on PAME biosynthesis. Computational molecular modeling indicated that PA binds well at the active site of COMT. Furthermore, in in vitro enzymatic assays in the presence of COMT and S-5'-adenosyl-L-methionine (AdoMet), the stable isotope [13C16]-PA was methylated to form [13C16]-PAME in incubation medium or the Krebs-Henseleit solution containing 3T3-L1 adipocytes or rat PVAT. The adipocytes and PVATs expressed membrane-bound (MB)-COMT and soluble (S)-COMT proteins. [13C16]-PA methylation to form [13C16]-PAME in 3T3-L1 adipocytes and rat PVAT was blocked by various COMT inhibitors, such as S-(5'-adenosyl)-L-homocysteine, adenosine-2',3'-dialdehyde, and tolcapone. MB- and S-COMT levels in PVATs of established SHRs were significantly lower than those in PVATs of age-matched normotensive WKY rats, with decreased [13C16]-PA methylation to form [13C16]-PAME. This decrease was reversed by losartan, an angiotensin II (Ang II) type 1 receptor antagonist. Therefore, PAME biosynthesis in rat PVAT is dependent on AdoMet, catalyzed by COMT, and decreased in SHRs, further supporting the role of PVAT/PAME in hypertension pathogenesis. Moreover, the antihypertensive effect of losartan might be due partly to its increased PAME biosynthesis. SIGNIFICANCE STATEMENT: PAME is a key PVAT-derived relaxing factor. We for the first time demonstrate that PAME is synthesized through PA methylation via the S-5'-adenosyl-L-methionine-dependent COMT catalyzation pathway. Moreover, we confirmed PVAT dysfunction in the hypertensive state. COMT-dependent PAME biosynthesis is involved in Ang II receptor type 1-mediated blood pressure regulation, as evidenced by the reversal of decreased PAME biosynthesis in PVAT by losartan in hypertensive rats. This finding might help in developing novel therapeutic or preventive strategies against hypertension.

Transthyretin stabilization activity of the catechol-O-methyltransferase inhibitor tolcapone (SOM0226) in hereditary ATTR amyloidosis patients and asymptomatic carriers: proof-of-concept study.

Objective: To assess the transthyretin (TTR) stabilization activity of tolcapone (SOM0226) in patients with hereditary ATTR amyloidosis, asymptomatic carriers and healthy volunteers. Methods: A phase IIa proof-of-concept trial included two phases separated by a 6-week washout period. Phase A: single 200 mg dose of tolcapone; phase B: three 100 mg doses taken at 4 h intervals. The primary efficacy variable was TTR stabilization. Results: Seventeen subjects were included (wild type, n = 6; mutation TTR Val30Met, n = 11). TTR stabilization was observed in all participants. Two hours after dosing, 82% of participants in phase A and 93% of those in phase B reached a TTR stabilization value of at least 20%. In phase A, there was an increase of 52% in TTR stabilization vs baseline values 2 h after dosing, which decreased to 22.9% at 8 h. In phase B, there was a significant increase of 38.8% in TTR stabilization 2 h after the first 100 mg dose. This difference was maintained after 10 h and decreased after 24 h. No serious adverse events were observed. Conclusions: The ability of tolcapone for stabilizing TTR supports further development and repositioning of the drug for the treatment of ATTR amyloidosis. EudraCT trial number: 2014-001586-27 ClinicalTrials.gov Identifier: NCT02191826.

Enhancing the Cancer Cell Growth Inhibitory Effects of Table Grape Anthocyanins.

The risk for breast and colon cancer may be lowered in part by high intake of fruits and vegetables. Fruits such as grapes are abundant in bioactive compounds such as anthocyanins. The potential anticancer activity of anthocyanins may be limited by their metabolism in the gut and liver. One metabolic transformation is due to the enzyme catechol-O-methyltransferase (COMT), which methylates polyphenols such as anthocyanins. Entacapone is a clinically used inhibitor of COMT, and has been shown to modulate the methylation of food-derived polyphenols. In this study, we compared the effect of entacapone on the cell viability of colon (Caco-2 and HT-29) and breast (MDA-MB-231) cancer cell lines treated with anthocyanins. Cells were treated with either cyanidin-3-glucoside, delphinidin-3-glucoside, or an anthocyanin-rich grape extract, in the absence or presence of entacapone. Cell viability was assessed using the thiazolyl blue tetrazolium bromide (MTT) assay. Entacapone in combination with the anthocyanins had a greater than additive effect on growth inhibition of the Caco-2 cells. In the MDA-MB-231 cell line, entacapone similarly enhanced the growth inhibitory activity of the anthocyanin extract. Entacapone also had antiproliferative effects when used as a single treatment. Total hydroperoxides was quantified in the cell culture media. Greater concentrations of the treatments resulted in higher levels of total hydroperoxides, indicating that oxidative stress may be an important mechanism for growth inhibition. In conclusion, the antiproliferative activity of fruit-derived anthocyanins was improved in human cancer cell lines by the clinically used drug entacapone. The efficacy and mechanisms of entacapone/anthocyanin combinations should be carefully studied in vivo. PRACTICAL APPLICATION: Chemical components of grapes are good for our health and have been shown to lower risk for certain cancers. Their beneficial health effects could also be enhanced by consuming other molecules that improve their bioavailability.

Tolcapone induces oxidative stress leading to apoptosis and inhibition of tumor growth in Neuroblastoma.

Catechol-O-methyltransferase (COMT) is an enzyme that inactivates dopamine and other catecholamines by O-methylation. Tolcapone, a drug commonly used in the treatment of Parkinson's disease, is a potent inhibitor of COMT and previous studies indicate that Tolcapone increases the bioavailability of dopamine in cells. In this study, we demonstrate that Tolcapone kills neuroblastoma (NB) cells in preclinical models by inhibition of COMT. Treating four established NB cells lines (SMS-KCNR, SH-SY5Y, BE(2)-C, CHLA-90) and two primary NB cell lines with Tolcapone for 48 h decreased cell viability in a dose-dependent manner, with IncuCyte imaging and Western blotting indicating that cell death was due to caspase-3-mediated apoptosis. Tolcapone also increased ROS while simultaneously decreasing ATP-per-cell in NB cells. Additionally, COMT was inhibited by siRNA in NB cells and showed similar increases in apoptotic markers compared to Tolcapone. In vivo xenograft models displayed inhibition of tumor growth and a significant decrease in time-to-event in mice treated with Tolcapone compared to untreated mice. These results indicate that Tolcapone is cytotoxic to neuroblastoma cells and invite further studies into Tolcapone as a promising novel therapy for the treatment of neuroblastoma.

Interventions in Parkinson's disease: Role of executive function.

The cortico-striatal network plays a major role in executive functions (EF), and is believed to play a role in the pathophysiology of Parkinson's disease (PD). However, the tools to assess EF are limited. This review assesses the impact of all PD interventions, namely, pharmacotherapy, physical exercise and Deep Brain Stimulation (DBS) surgery on EF. The effect of PD pharmacotherapy varies with the drug class, neuropsychological test used and the affected dopamine receptor family. There appears to be a benefit of aerobic exercise on EF, including judgment and attention. The effect of Deep Brain Stimulation on EF might vary with site of brain stimulation, the neuropsychological test performed and the pre-operative cognitive state. The effect of EF on underlying manifestations and as a factor in the pathway to the motor benefit needs to be better assessed with more accurate tests that focus on motor component of EF.

Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity.

Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists.

Development of an HTRF Assay for the Detection and Characterization of Inhibitors of Catechol-O-Methyltransferase.

Catechol-O-methyltransferase (COMT) plays an important role in the deactivation of catecholamine neurotransmitters and hormones. Inhibitors of COMT, such as tolcapone and entacapone, are used clinically in the treatment of Parkinson's disease. Discovery of novel inhibitors has been hampered by a lack of suitable assays for high-throughput screening (HTS). Although assays using esculetin have been developed, these are affected by fluorescence, a common property of catechol-type compounds. We have therefore evaluated a new homogenous time-resolved fluorescence (HTRF)-based assay from CisBio (Codolet, France), which measures the production of S-adenosyl-L-homocysteine (SAH). The assay has been run in both HTS and medium-throughput screening (MTS) modes. The assay was established using membranes expressing human membrane-bound COMT and was optimized for protein and time to give an acceptable signal window, good potency for tolcapone, and a high degree of translation between data in fluorescence ratio and data in terms of [SAH] produced. pIC50 values for the hits from the HTS mode were determined in the MTS mode. The assay also proved suitable for kinetic studies such as Km,app determination.

The efficacy of oral adenosine A(2A) antagonist istradefylline for the treatment of moderate to severe Parkinson's disease.

The moderate and severe stages of Parkinson's disease (PD) are marked by motor and non-motor complications that still remain difficult to control with the currently available therapy. Adenosine A(2A) receptor antagonists target non-dopaminergic systems, and have emerged as promising add-on therapy in the management of PD, a little more than a decade ago. While the development of this new drug class was slower than initially expected, istradefylline was recently registered in Japan, because it provides reduction of the off-time, when given in association with levodopa. Effects on some non-motor features have also been suggested, and preliminary studies further suggest a potential neuroprotective effect. Associations of A(2A) receptor antagonists with dopaminergic agents, as well as enzyme blockers like catechol-O-methyltransferase (COMT) and monoamine oxidase-B (MAO-B) inhibitors, should provide even greater benefit in advanced PD patients, and, thus, a more individualized treatment approach would be at hand.

Trends in inpatient antiparkinson drug use in the USA, 2001-2012.

PURPOSE: Although therapeutic options and clinical guidelines for Parkinson's disease (PD) have changed significantly in the past 15 years, prescribing trends in the USA remain unknown. The purpose of this population-based cohort study was to examine patterns of inpatient antiparkinson drug use between January 2001 and December 2012 in relation to clinical guideline publication, drug introduction/withdrawal, and emerging safety concerns. METHODS: A total of 16,785 inpatients receiving pharmacological treatment for PD were identified in the Cerner Health Facts database. Our primary outcome was standardized (age, sex, race, and census region) annual prevalence of antiparkinson drug use. We also examined antiparkinson medication trends and polypharmacy by age and sex. RESULTS: The most frequently prescribed antiparkinson drugs between 2001 and 2012 were levodopa (85%) and dopamine agonists (28%). Dopamine agonist use began declining in 2007, from 34 to 27% in 2012. The decline followed publication of the American Academy of Neurology's practice parameter refuting levodopa toxicity, pergolide withdrawal, and pramipexole label revisions. Despite safety concerns for cognitive impairment and falls, individuals ≥80 years of age demonstrated stable rates of dopamine agonist use from 2001 to 2012. Polypharmacy was most common in younger patients. CONCLUSIONS: Dopamine agonist use declined from 2007 to 2012, suggesting that increased awareness of safety issues and practice guidelines influenced prescribing. These events appear to have minimally influenced treatment provided to older PD patients. Antiparkinson prescribing trends indicate that safety and best practice information may be communicated effectively.

[Medical treatment of Parkinson's disease in elderly and multimorbid patients]. / Pharmakotherapie des Morbus Parkinson beim älteren, multimorbiden Patienten.

BACKGROUND: Parkinson's disease is a frequent neurodegenerative disease, which typically occurs in older age. With progression of the disease, therapeutic complications, such as dyskinesias and fluctuations in the response to medication are common. To embed the medication of Parkinson's disease into a complex treatment plan of a patient suffering from multimorbidity can be challenging. OBJECTIVES: Not only the cardinal motor symptoms have to be treated properly but also the non-motor symptoms e.g. depression, dementia, autonomic dysregulations and gastrointestinal disorders. Pharmacological treatment and their risks are presented. CONCLUSION: Especially in older patients the symptoms need to be treated with regard to multimorbidity and the risks of polypharmacotherapy. The therapeutic strategy needs to be carefully planned in order to achieve a high quality of life and social interaction.

Inhibitors of catechol-O-methyltransferase in the treatment of neurological disorders.

Catechol-O-methyltransferase (COMT) is the enzyme which catalyzes the transfer of a methyl group from S-adenosylmethionine to catechols and catecholamines, like the neurotransmitters dopamine, epinephrine and norepinephrine. COMT has implications in many neurological and psychiatric disorders like schizophrenia, Parkinson's disease (PD), bipolar disorders, etc. and therefore, it serves as an important drug target. Since its characterization in 1957, many inhibitors were designed where the first generation inhibitors were found to be highly toxic, short acting and had poor bioavailability. Currently, two of the second generation inhibitors, tolcapone and entacapone have been used for treatment of PD but are associated with various dopaminergic and gastro-intestinal side-effects. There have been several approaches for the design of novel COMT inhibitors with a good and safe therapeutic profile. The focus of this article is to review the current knowledge on COMT and the role of COMT inhibitors in the treatment of neurological disorders. The inhibitors have been classified into six different classes based on the structural framework. A historical overview of the discovery and development of COMT inhibitors is presented with a special emphasis on new generation of inhibitors till date.