catechol-O-methyltransferase Inhibitor Research Articles

Inhibitors of MAO-B and COMT: their effects on brain dopamine levels and uses in Parkinson's disease.

MAO-B and COMT are both enzymes involved in dopamine breakdown and metabolism. Inhibitors of these enzymes are used in the treatment of Parkinson's disease. This review article describes the scientific background to the localization and function of the enzymes, the physiological changes resulting from their inhibition, and the basic and clinical pharmacology of the various inhibitors and their role in treatment of Parkinson's disease.

Inhibition of catechol-O-methyltransferase in the cynomolgus monkey by opicapone after acute and repeated administration

IntroductionThe aim of the study was to clarify the dose response for inhibition of catechol-O-methyltransferase (COMT) by opicapone, a third generation COMT inhibitor, after acute and repeated administration to the cynomolgus monkey with pharmacokinetic evaluation at the higher dose. MethodsThree cynomolgus monkeys were used in the study. In the first experiment, COMT inhibition was evaluated over 24 h after the first and at 24 h after the last of 14 daily oral administrations of vehicle, 1, 10 and 100 mg/kg opicapone using a crossover design. In the second experiment, the effect of the maximally effective dose, 100 mg/kg, was retested under the same conditions with additional monitoring of plasma opicapone levels to explore the relationship between pharmacokinetics and pharmacodynamics. ResultsOpicapone dose-dependently inhibited COMT activity, significantly so at 10 and 100 mg/kg. Maximal inhibition was 13.1%, 76.4% and 93.2% at 1, 10 and 100 mg/kg respectively, and COMT remained significantly inhibited at 24 h after 10 and 100 mg/kg (42.6% and 60.2% respectively). Following repeated administration of opicapone residual COMT inhibition at 24 h was 15–25% greater at all doses. In contrast to its pharmacodynamic effect, opicapone was rapidly absorbed and eliminated, with no accumulation in plasma following repeated administration. ConclusionOpicapone showed sustained and dose-dependent COMT inhibition despite being rapidly eliminated from plasma and with no evidence for accumulation in plasma after 14 days administration. Opicapone fills the unmet need for a compound with sustained COMT inhibition which will improve levodopa bioavailability in patients with Parkinson's disease.

Optimization of 8-Hydroxyquinolines as Inhibitors of Catechol O-Methyltransferase.

A series of 8-hydroxy quinolines were identified as potent inhibitors of catechol O-methyltransferase (COMT) with selectivity for the membrane-bound form of the enzyme. Small substituents at the 7-position of the quinoline were found to increase metabolic stability without sacrificing potency. Compounds with good pharmacokinetics and brain penetration were identified and demonstrated in vivo modulation of dopamine metabolites in the brain. An X-ray cocrystal structure of compound 21 in the S-COMT active site shows chelation of the active site magnesium similar to catechol-based inhibitors. These compounds should prove useful for treatment of many neurological and psychiatric conditions associated with compromised cortical dopamine signaling.

90. Catechol-O-methyltransferase deficiency leads to hypersensitivity on the pressor response against angiotensin II

Catechol-O-methyltransferase (COMT) metabolizes 2-hydroxyestradiol into 2-methoxyestradiol (2-ME); COMT deficiency has been shown to be associated with hypertension in men. Preeclampsia is a disease associated with hypersensitivity of pressor response against angiotensin II (Ang II). Here, we found that COMT deficiency could explain the hypersensitivity of pressor response against Ang II in mice because of the lack of 2-ME-dependent suppression of angiotensin II receptor type 1 (AT1R). Male C57BL/6 mice were subjected to COMT inhibitor (COMTi: 25 mg/kg per day) or oil (control) for 4 weeks, with or without low-dose Ang II infusion (ANGII: 70 ng/kg per minute) for the last 3 weeks. The Ang II-infused mice were treated with 2-ME (10 ng/d) or vehicle for the last 1 week. We obtained the following experimental groups: control, ANGII, COMTi, COMTi + ANGII, and COMTi + ANGII + 2-ME. We performed similar experiments using the in vivo administration of small interfering RNA of COMT instead of COMTi. Neither ANGII nor COMTi exhibited significant alterations in systolic blood pressure. Compared with ANGII or COMTi, COMTi + ANGII displayed significantly higher systolic blood pressure, albuminuria, and glomerular endotheliosis; 2-ME normalized such alterations. Similar phenotypes were observed in COMT small interfering RNA-treated mice. In the aorta of COMT-deficient mice, AT1R expression was increased; 2-ME suppressed AT1R expression. The 2-ME exhibited peroxisome proliferator-activated receptor γ agonistic activity in vitro and ex vivo plasma from pregnant female mice as well. In vitro, 2-ME suppressed both basal and Ang II-induced AT1R levels in a peroxisome proliferator-activated receptor γ-dependent manner. The 2-ME is relevant to combat COMT deficiency-associated hypertensive disorders via suppression of AT1R by its peroxisome proliferator-activated receptor γ activity.

COMT Inhibition Alters Cue-Evoked Oscillatory Dynamics during Alcohol Drinking in the Rat.

Alterations in the corticostriatal system have been implicated in numerous substance use disorders, including alcohol use disorder (AUD). Adaptations in this neural system are associated with enhanced drug-seeking behaviors following exposure to cues predicting drug availability. Therefore, understanding how potential treatments alter neural activity in this system could lead to more refined and effective approaches for AUD. Local field potentials (LFPs) were acquired simultaneously in the prefrontal cortex (PFC) and nucleus accumbens (NA) of both alcohol preferring (P) and Wistar rats engaged in a Pavlovian conditioning paradigm wherein a light cue signaled the availability of ethanol (EtOH). On test days, the catechol-o-methyl-transferase (COMT) inhibitor tolcapone was administered prior to conditioning. Stimulus-evoked voltage changes were observed following the presentation of the EtOH cue in both strains and were most pronounced in the PFC of P rats. Phase analyses of LFPs in the θ band (5–11 Hz) revealed that PFC-NA synchrony was reduced in P rats relative to Wistars but was robustly increased during drinking. Presentation of the cue resulted in a larger phase reset in the PFC of P rats but not Wistars, an effect that was attenuated by tolcapone. Additionally, tolcapone reduced cued EtOH intake in P rat but not Wistars. These results suggest a link between corticostriatal synchrony and genetic risk for excessive drinking. Moreover, inhibition of COMT within these systems may result in reduced attribution of salience to reward paired stimuli via modulation of stimulus-evoked changes to cortical oscillations in genetically susceptible populations.

Effectiveness and safety of safinamide as add-on to levodopa in patients with parkinson's disease: non-interventional study

Safinamide (Xadago®) is a newly approved selective MAO-B inhibitor for the treatment of Parkinson's Disease (PD). The X-TRA study investigated the efficacy and tolerability of the substance under clinical practice conditions. Prospective, observational study in unselected patients in line with safinamide product specifications. Of the 299 patients included (65.9 % males, age 72.7 ± 9.0 years, duration of disease 7.8 ± 5.9 years), at the beginning of the documentation 229 patients (81.2 %) received L-dopa, 108 (39.3 %) combination drugs containing L-dopa, 172 (59.3 %) a dopamine agonist and 23 (8.3 %) a COMT inhibitor. Of these, 203 patients were followed-up over a period of 6 months. The MDS-UPDRS Part III score for motor symptoms decreased from a baseline value of 48.2 ± 22.1 points by 6.8 ± 14.5 points at the end of the study. The Non-Motor Symptoms Scale score indicating the presence or absence of motor symptoms decreased from a baseline value of 57.6 ± 42.1 by 9.3 ± 2.1 points, the Abnormal Involuntary Movement Score from 4.6 ± 5.8 points by 0.9 ± 2.7 points.The Parkinson's Disease Score (PDQ-8) for assessing quality of life decreased from a baseline value of 39.4 ± 18.2 points by 4.3 ± 13.7 points, reflecting an improvement. In total, 300 adverse events were classified as related to safinamide in 132 patients (44.1 %). Fifty-three events were serious (in 15 patients; 5 %). Seventy-four patients (24.7 %) discontinued safinamide therapy because of adverse drug reactions. Safinamide therapy improved the motor and non-motor symptoms as well as the quality of life in PD. Most patients tolerated the therapy well. The only side effects that occurred are those described in the patient information leaflet.

Levodopa in Parkinson's Disease: Current Status and Future Developments.

BackgroundEver since the pioneering reports in the 60s, L-3,4-Dioxyphenylalanine (levodopa) has represented the gold standard for the treatment of Parkinson’s Disease (PD). However, long-term levodopa (LD) treatment is frequently associated with fluctuations in motor response with serious impact on patient quality of life. The pharmacokinetic and pharmacodynamic properties of LD are pivotal to such motor fluctuations: discontinuous drug delivery, short half-life, poor bioavailability, and narrow therapeutic window are all crucial for such fluctuations. During the last 60 years, several attempts have been made to improve LD treatment and avoid long-term complications.MethodsResearch and trials to improve the LD pharmacokinetic since 1960s are reviewed, summarizing the progressive improvements of LD treatment.ResultsInhibitors of peripheral amino acid decarboxylase (AADC) have been introduced to achieve proper LD concentration in the central nervous system reducing systemic adverse events. Inhibitors of catechol-O-methyltransferase (COMT) increased LD half-life and bioavailability. Efforts are still being made to achieve a continuous dopaminergic stimulation, with the combination of oral LD with an AADC inhibitor and a COMT inhibitor, or the intra-duodenal water-based LD/ carbidopa gel. Further approaches to enhance LD efficacy are focused on new non-oral administration routes, including nasal, intra-duodenal, intrapulmonary (CVT-301) and subcutaneous (ND0612), as well as on novel ER formulations, including IPX066, which recently concluded phase III trial.ConclusionNew LD formulations, oral compounds as well as routes have been tested in the last years, with two main targets: achieve continuous dopaminergic stimulation and find an instant deliver route for LD.

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

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.

Dopamine, time perception, and future time perspective

RationaleImpairment in time perception, a critical component of decision-making, represents a risk factor for psychiatric conditions including substance abuse. A therapeutic that ameliorates this impairment could be advantageous in the treatment of impulsivity and decision-making disorders.ObjectivesHere we hypothesize that the catechol-O-methyltransferase (COMT) inhibitor tolcapone, which increases dopamine tone in frontal cortex (Ceravolo et al Synapse 43:201–207, 2002), improves time perception, with predictive behavioral, genetic, and neurobiological components.MethodsSubjects (n = 66) completed a duration estimation task and other behavioral testing in each of two sessions after receiving a single oral dose of tolcapone (200 mg) or placebo in randomized, double-blind, counterbalanced, crossover fashion. Resting state fMRI data were obtained in a subset of subjects (n = 40). Subjects were also genotyped for the COMT (rs4680) polymorphism.ResultsTime perception was significantly improved across four proximal time points ranging from 5 to 60 s (T(524) = 2.04, p = 0.042). The degree of this improvement positively correlated with subjective measures of stress, depression, and alcohol consumption and was most robust in carriers of the COMT Val158 allele. Using seed regions defined by a previous meta-analysis (Wiener et al Neuroimage 49:1728–1740, 2010), we found not only that a connection from right inferior frontal gyrus (RIFG) to right putamen decreases in strength on tolcapone versus placebo (p < 0.05, corrected), but also that the strength of this decrease correlates inversely with the increase in duration estimation on tolcapone versus placebo (r = − 0.37, p = 0.02).ConclusionsCompressed time perception can be ameliorated by administration of tolcapone. Additional studies should be conducted to determine whether COMT inhibitors may be effective in treating decision-making disorders and addictive behaviors.

Nitrocatechol Derivatives of Chalcone as Inhibitors of Monoamine Oxidase and Catechol-O-Methyltransferase

The efficacy of L-dopa in the treatment of Parkinson's disease depends on its metabolic conversion to dopamine in the brain, however extensive peripheral metabolism of L-dopa diminishes its availability for uptake into the brain. L-Dopa is extensively decarboxylated in the gastrointestinal tract and peripheral tissues by Aromatic L-Amino Acid Decarboxylase (AADC), and AADC inhibitors are thus frequently combined with L-dopa therapy. When AADC is inhibited, 3-Omethylation Catalysed by Catechol-O-Methyltransferase (COMT) becomes a dominant metabolic pathway for L-dopa, and COMT inhibitors may thus also be used as adjuncts to L-dopa in Parkinson's disease. Monoamine Oxidase (MAO), in turn, metabolises dopamine in the brain, and MAO-B inhibitors may exert a dopamine sparing effect in the brain. Based on the roles of COMT and MAO in the metabolism of L-dopa and dopamine, the present study attempts to discover novel dual inhibitors of these enzymes. For this purpose, nitrocatechol derivatives of chalcone were synthesised and evaluated as inhibitors of COMT and MAO. The chalcone class of compounds is well known to potently inhibit MAO-B, while nitrocatechol derivatives (e.g. tolcapone and entacapone) are clinically used COMT inhibitors. The results document that all of the derivatives are high potency in vitro inhibitors of rat liver COMT with IC50 values ranging from 0.07 to 0.29 μM. Under these experimental conditions, tolcapone and entacapone display IC50 values of 0.26 µM and 0.25 µM, respectively. The chalcones are less potent as inhibitors of MAO with the most potent inhibitor possessing a Ki of 4.6 µM for the in vitro inhibition of human MAO-B. This study shows that nitrocatechol derivatives of chalcone may act as COMT and MAO-B inhibitors, and proposes a general strategy for further enhancing MAO-B inhibition while retaining the potent COMT inhibition activity of this class.

Acupuncture Resolves Persistent Pain and Neuroinflammation in a Mouse Model of Chronic Overlapping Pain Conditions

Patients with chronic overlapping pain conditions have decreased levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. Consistent with clinical syndromes, we previously demonstrated that COMT inhibition in rodents produces persistent pain and heightened immune responses. Here, we sought to determine the efficacy of manual acupuncture in resolving persistent pain and neuroinflammation in the classic inbred C57BL/6 strain and the rapid-wound healing MRL/MpJ strain. Mice received subcutaneous osmotic minipumps to deliver the COMT inhibitor OR486 or vehicle for 13 days. On day 7 after pump implantation, acupuncture was performed at the Zusanli (ST36) point or a non-acupoint for 6 consecutive days. Behavioral responses to mechanical stimuli were measured throughout the experiment. Immunohistochemical analysis of spinal phosphorylated p38 mitogen-activated protein kinase, a marker of inflammation, and glial fibrillary acidic protein, a marker of astrogliosis, was performed on day 13. Results demonstrated that ST36, but not sham, acupuncture resolved mechanical hypersensitivity and reduced OR486-dependent increases in phosphorylated p38 and glial fibrillary acidic protein in both strains. The magnitude of the analgesic response was greater in MRL/MpJ mice. These findings indicate acupuncture as an effective treatment for persistent pain linked to abnormalities in catecholamine signaling and, furthermore, that analgesic efficacy may be influenced by genetic differences. PerspectiveChronic overlapping pain conditions remain ineffectively managed by conventional pharmacotherapies. Here, we demonstrate that acupuncture alleviates persistent pain and neuroinflammation linked to heightened catecholaminergic tone. Mice with superior healing capacity exhibit greater analgesic efficacy. Findings indicate acupuncture as an effective treatment for chronic overlapping pain conditions and provide insight into treatment response variability.

Sustained stimulation of β2- and β3-adrenergic receptors leads to persistent functional pain and neuroinflammation

Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, our lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites and pain-related volitional behaviors. The onset of COMT-dependent functional pain is mediated by peripheral β2- and β3-adrenergic receptors (β2- and β3ARs) through the release of the pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Here, we first sought to investigate the role of β2- and β3ARs and downstream mediators in the maintenance of persistent functional pain. We then aimed to characterize the resulting persistent inflammation in neural tissues (neuroinflammation), characterized by activated glial cells and phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK). Separate groups of rats were implanted with subcutaneous osmotic mini-pumps to deliver OR486 (15 mg/kg/day) or vehicle for 14 days. The β2AR antagonist ICI118551 and β3AR antagonist SR59230A were co-administrated subcutaneously with OR486 or vehicle either on day 0 or day 7. The TNFα inhibitor Etanercept, the p38 inhibitor SB203580, or the ERK inhibitor U0126 were delivered intrathecally following OR486 cessation on day 14. Behavioral responses, pro-inflammatory cytokine levels, glial cell activation, and MAPK phosphorylation were measured over the course of 35 days. Our results demonstrate that systemic delivery of OR486 leads to mechanical hypersensitivity that persists for at least 3 weeks after OR486 cessation. Corresponding increases in spinal TNFα, IL-1β, and IL-6 levels, microglia and astrocyte activation, and neuronal p38 and ERK phosphorylation were observed on days 14–35. Persistent functional pain was alleviated by systemic delivery of ICI118551 and SR59230A beginning on day 0, but not day 7, and by spinal delivery of Etanercept or SB203580 beginning on day 14. These results suggest that peripheral β2- and β3ARs drive persistent COMT-dependent functional pain via increased activation of immune cells and production of pro-inflammatory cytokines, which promote neuroinflammation and nociceptor activation. Thus, therapies that resolve neuroinflammation may prove useful in the management of functional pain syndromes.

Are There Benefits in Adding Catechol-O Methyltransferase Inhibitors in the Pharmacotherapy of Parkinson’s Disease Patients? A Systematic Review

A qualified consensus suggests that a combination of levodopa with a peripherally acting dopa decarboxylase inhibitor continues to present the gold standard treatment of Parkinson's disease (PD). However, as the disease progresses the therapeutic window of levodopa becomes narrowed. Pharmacological strategies for motor fluctuations are focused on providing less pulsatile and more continuous dopaminergic stimulation. Peripheral catechol-O-methyltransferase (COMT) inhibition improves the bioavailability of levodopa and results in a prolonged response. The primary aim of this study was to investigate the efficacy and safety of the two available COMT inhibitors; entacapone and tolcapone and the recently introduced opicapone. Electronic databases were systematically searched for original studies published within the last 37 years. In addition, lists of identified studies, reviews and their references were examined. Twelve studies fulfilled the inclusion criteria. 3701 patients with PD were included in this systematic review. Adjuvant treatment of PD patients experiencing motor fluctuations with entacapone resulted in improvement of motor function and was well tolerated. Therefore, entacapone presented an acceptable benefit to risk ratio. Tolcapone appeared to result in a greater therapeutic effect. However, this was not consistent across all motor variables and studies, and thus would not support its use, given the current onerous monitoring that is required. Opicapone was not associated with adverse reactions in a phase III trial but did not present a greater efficacy than entacapone, and thus further studies are required in order to illustrate its cost effectiveness.

Improved Bioavailability of Levodopa Using Floatable Spray-Coated Microcapsules for the Management of Parkinson’s Disease

Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations. To achieve a prolonged release of LD with the aim of improving its bioavailability, floatable spray-coated microcapsules containing all three PD drugs were developed. This gastro-retentive delivery system showed sustained release of all PD drugs, at similar release kinetics. Pharmacokinetics study was conducted and this newly developed formulation showed a more plateaued delivery of LD that is void of the plasma concentration fluctuations observed for the control (commercial formulation). At the same time, measurements of LD and dopamine of mice administered with this formulation showed enhanced bioavailability of LD. This study highlights a floatable, sustained-releasing delivery system in achieving improved pharmacokinetics data compared to a commercial formulation.

MAO-B and COMT Genetic Variations Associated With Levodopa Treatment Response in Patients With Parkinson's Disease.

The most commonly used Parkinson's disease (PD) treatment is the replacement of dopamine by its levodopa precursor (l-dopa). Monoamine oxidase-B (MAO-B) and catechol-o-methyl transferase (COMT) are enzymes involved in the metabolism and regulation of dopamine availability. In our study we investigated the possible relation among selected single-nucleotide polymorphisms (SNPs) in the MAO-B (rs1799836) and COMT (rs4680) genes and the therapeutic response to levodopa (l-dopa). A total of 162 Brazilian patients from the Pro-Parkinson service of Clinics Hospital of Pernambuco diagnosed with sporadic PD and treated with levodopa were enrolled. PD patients were stratified into 2 groups according to the daily levodopa dose. MAO-B and COMT SNP genotyping was conducted by polymerase chain reaction-restriction fragment length polymorphism. After multivariate analysis, we observed a significant difference between PD groups for the following variables: sex (P=.02), longer duration of disease (P=.02), longer levodopa therapy duration (P=.01), younger onset of PD (P = .01), and use of COMT inhibitor (P=.02). We observed that patients carrying MAO-B (rs1799836) A and AA genotypes and COMT (rs4680) LL genotype suffered more frequently from levodopa-induced-dyskinesia. In addition, we found an increased risk of 2.84-fold for male individuals carrying the MAO-B G allele to be treated with higher doses of levodopa (P=.04). We concluded that before beginning PD pharmacological treatment, it is important to consider the genetic variants of the MAO-B and COMT genes and the sex, reinforcing the evidence that sexual dimorphism in the genes related to dopamine metabolism might affect PD treatment.

P.2.034 - Genotype-dependent deterioration of sustained attention by the COMT inhibitor tolcapone after sleep deprivation

Introduction Elevated sleepiness and impaired vigilance due to medical disorders, is often treated by drugs that enhance dopaminergic neurotransmission, including modafinil, caffeine or cocaine [1]. Tolcapone is a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties that leads to relatively specific increases in prefrontal cortex (PFC) dopamine signaling [2,3]. Because it hardly affects striatal domapinergic transmission, tolcapone may mitigate subjective and behavioral consequences of sleep deprivation without unwanted psychostimulant adverse effects [2]. Tolcapone also improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT [3]. The impact of this common genetic variant for efficient treatment of hypersomnolence and behavioral markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of human sleep homeostasis. Methods We first quantified the impact of COMT genotype (SNP-Id: rs4680) on the evolution of attentional lapses during two days of extended wakefulness in a non-tolcapone treated group of 73 volunteers. Subsequently, in an independent group of 30 healthy male study participants, we tested whether selective inhibition of COMT activity by tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a COMT genotype-dependent manner. 2 x 100 mg tolcapone were administered after 11 and 23 hours, in a randomized, double-blind, placebo-controlled, cross-over design. The psychomotor Vigilance Test (PVT) and objective electroencephalogram (EEG) recordings were carried out in three-hour intervals among all 103 volunteers across the 40 hours of prolonged wakefulness. Repeated measure linear mixed-models were applied, followed by multiple comparison corrected post-hoc testing when appropriate. Results Both COMT genotype and tolcapone modulated the sleep-loss induced impairment of vigilant attention. More specifically, data from the non-tolcapone treated group revealed that Val/Met heterozygotes produced twice as many lapses after a night without sleep compared to Met/Met homozygotes (p Conclusions The current results demonstrate that PFC dopaminergic neurotransmission regulates attentional lapses during sleep deprivation without changing neurophysiological markers of sleep homeostasis. Intriguingly, selective inhibition of COMT can even reverse the expected beneficial effects of pharmacologically enhanced dopaminergic tone after prolonged wakefulness. These findings may have important implications, given the increased use of stimulants in healthy people aimed at improving vigilance and cognitive functions [1,4].

Real life evaluation of safinamide effectiveness in Parkinson's disease.

In this retrospective study, we evaluated both efficacy and effectiveness of safinamide 50 and 100mg in the treatment of motor fluctuations and disabling dyskinesias in a cohort of patients with idiopathic Parkinson's disease (PD). Ninety-one PD patients were evaluated during the first year of commercialization of the drug, both prior to starting safinamide and at the last available follow-up. Evaluations were based on the Unified Parkinson's Disease Scale part III (UPDRS III), Hoehn & Yahr (HY), Unified Dyskinesia Rating Scale (UDysRS) walking and balance item 9 score, daily time spent in OFF and in ON with disabling dyskinesias (1week diary), mean daily dose of levodopa (LD), dopamine-agonists (DA), catechol-O-methyl transferase inhibitor (COMT-I), monoamine oxidase B inhibitor (MAOB-I), and their LD equivalent dose (LEDD). Eight patients withdrew safinamide within the first month for minor side effects. At the follow-up evaluation, after a mean time with safinamide of 7.5months ± 3.4, all patients showed a significant improvement of all the scale scores, except for HY, and of the daily dosages of the drugs and the LEDD. The same results were shown by PD patients treated with safinamide 50mg and patients who started safinamide without switching from a previous MAOBI. PD patients with safinamide 100mg and patients who started safinamide switching from a previous MAOBI significantly improved in time spent in OFF and LEDD. In conclusion, safinamide is safe and effective in improving motor complications in patients with idiopathic PD and can be considered a useful levodopa sparing strategy.

The expression and activation of sex steroid receptors in the preeclamptic placenta.

Estrogen and progesterone are the main pregnancy hormones produced by the placenta. It is well understood that estrogen stimulates angiogenesis in the uterus during the reproductive cycle. Although the estrogen and progesterone signaling pathways are assumed to be associated with placental vascularization and preeclampsia, expression of estrogen receptors (ESRs) and progesterone receptor (PGR) in the placenta have not been well studied. The present study examined the expression patterns of steroid hormone receptors in placentas. Human placenta samples were collected and divided into normal and preeclampsia groups. Results revealed that expression levels of ESR1 were reduced, whereas ESR2 and PGR were elevated in preeclamptic placentas. To generate an invitro preeclampsia environment, human placenta‑derived BeWo cells were incubated under hypoxic conditions, or treated with catechol‑O‑methyl transferase inhibitor (COMT‑in) or L‑NG‑nitroarginine methyl ester (L‑NAME). Expression levels of ESR1, ESR2 and PGR in hypoxic cells demonstrated similar regulation as those in placentas from women with preeclampsia. Although COMT‑in and L‑NAME did not significantly regulate the expression levels of the receptors, COMT‑in translocated ESR2 and PGR from the nucleus to the cytoplasm, indicating that these receptors were inactivated. These results suggested that ESRs and PGR are associated with symptoms of preeclampsia in the placenta. The expression of ESR1 was reduced in preeclamptic placenta and hypoxic BeWo cells. In addition, the activation of ESR2 and PGR was blocked in placenta cells subjected to COMT‑in treatment. The reduced ESR1 expression and inactivation of ESR2 and PGR proteins may affect the physiological complications of preeclampsia in the placenta.

The launch of opicapone for Parkinson’s disease: negatives versus positives

ABSTRACTIntroduction: Opicapone is a novel, third generation COMT inhibitor approved for the treatment of Parkinson’s disease. Safety and tolerability data is critical to determine the benefit-harm balance and anticipate therapeutic adherence.Areas covered: This review evaluates the tolerability and safety profile of opicapone. These data were extracted from all published clinical trials, including preclinical, phase I, phase II and phase III studies as well as postmarketing data. Opicapone was safe and well tolerated, with frequencies of treatment-emergent adverse events similar to placebo.Expert opinion: Opicapone have shown a good safety and tolerability profile. This adds to its proven efficacy and convenient once-daily administration, supporting a role of opicapone as a first-line therapy for motor complications in Parkinson’s disease patients.

Pharmacokinetic drug evaluation of opicapone for the treatment of Parkinson’s disease

ABSTRACT Introduction: Opicapone (OPC) is a novel, potent, reversible, and purely peripheral third-generation COMT inhibitor, which provides an enhancement in levodopa (L-Dopa) availability. It represents adjunctive therapy for L-Dopa treated patients with PD and motor fluctuations. Areas covered: The purpose of this study was to evaluate pharmacokinetic of OPC for the treatment of PD. Expert commentary: Oral OPC exhibits linear, dose-dependent absorption. However, following concomitant ingestion of a high-fat, high-calorie meal, the maximum plasma concentration will be decreased. A once-daily bedtime administration of OPC 1 h after the last daily L-Dopa/AADCi, are considered to avoid any interaction during the L-Dopa absorption phase. There are no clinically relevant effects of age (in adults), renal impairment or race on the pharmacokinetics of OPC. OPC dose adjustment is not needed in patients with mild to moderate chronic hepatic impairment. Opicapone exhibits the lowest potential for cytotoxicity in comparison with other COMT inhibitors. It significantly decreases COMT activity, with half-life of COMT inhibition in human erythrocytes of 61.6 h and increases systemic exposure to L-Dopa. This provides an enhancement in L-Dopa availability that translates into clinical benefit for PD patients in terms of significant decrease of OFF periods and increase in ON-time without troublesome dyskinesia.