INTRODUCTION: ND0612 is being investigated as a continuous, subcutaneous levodopa/carbidopa infusion, in combination with oral levodopa/carbidopa, for motor fluctuations in Parkinson's disease (PD). One-year data from the ongoing BeyoND study (NCT02726386) showed that the ND0612 regimen was safe and well tolerated and provided a sustained ≥2-h improvement in daily Good ON-time through 12 months of treatment. METHODS: We describe 3-year safety and efficacy outcomes for participants who completed 12 months of ND0612 treatment in the core study period and entered the extension phase. RESULTS: Of the 214 enrolled participants, 120 completed the core 1-year period, and 114 participants continued into the extension phase. Of these, 95/114 (83.3 %) completed 2 years and 77/114 (67.5 %) completed 3 years of study treatment. Key reasons for discontinuation were treatment-emergent adverse events (TEAEs) (n = 5 and n = 11 after 2 and 3 years, respectively) and withdrawal of consent (n = 9 and n = 5, respectively). TEAEs were reported by 105/114 (92.1 %) participants in Year 1, 77/114 (67.5 %) in Year 2, and 73/95 (76.8 %) in Year 3. While most participants experienced infusion site reactions, these led to discontinuation in only five participants during this extension. At Month 36, the mean reduction in OFF-time from baseline was 2.81 h and the increase in Good ON-time was 2.79 h. CONCLUSIONS: Three-year results from this open-label study support the long-term safety, tolerability, and efficacy of ND0612. For participants who entered the extension phase, the high rate of retention supports a favorable benefit-risk ratio of the ND0612 regimen for patients with PD experiencing motor fluctuations.
- Klíčová slova
- Infusion, Levodopa, Motor complications, ND0612, Parkinson's disease,
- MeSH
- antiparkinsonika * aplikace a dávkování škodlivé účinky MeSH
- fixní kombinace léků * MeSH
- karbidopa * aplikace a dávkování MeSH
- levodopa * aplikace a dávkování škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- Parkinsonova nemoc * farmakoterapie MeSH
- senioři MeSH
- subkutánní infuze * MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Názvy látek
- antiparkinsonika * MeSH
- carbidopa, levodopa drug combination MeSH Prohlížeč
- fixní kombinace léků * MeSH
- karbidopa * MeSH
- levodopa * MeSH
The human body gets exposed to a variety of toxins intentionally or unintentionally on a regular basis from sources such as air, water, food, and soil. Certain toxins can be synthetic, while some are biological. The toxins affect the various parts of the body by activating numerous pro-inflammatory markers, like oxidative stresses, that tend to disturb the normal function of the organs ultimately. Nowadays, people use different types of herbal treatments, viz., herbal drinks that contain different spices for detoxification of their bodies. One such example is turmeric, the most commonly available spice in the kitchen and used across all kinds of households. Turmeric contains curcumin, which is a natural polyphenol. Curcumin is a medicinal compound with different biological activities, such as antioxidant, antineoplastic, anti-inflammatory, and antibacterial. Hence, this review gives a comprehensive insight into the promising potential of curcumin in the detoxification of heavy metals, carbon tetrachloride, drugs, alcohol, acrylamide, mycotoxins, nicotine, and plastics. The review encompasses diverse animal-based studies portraying curcumin's role in nullifying the different toxic effects in various organs of the body (especially the liver, kidney, testicles, and brain) by enhancing defensive signaling pathways, improving antioxidant enzyme levels, inhibiting pro-inflammatory markers activities and so on. Furthermore, this review also argues over curcumin's safety assessment for its utilization as a detoxifying agent.
- Klíčová slova
- curcumin, detoxification, health, herbal drugs, in vivo, toxicity,
- MeSH
- akrylamid toxicita MeSH
- antioxidancia farmakologie MeSH
- Curcuma chemie MeSH
- kurkumin * farmakologie chemie MeSH
- lidé MeSH
- metabolická inaktivace MeSH
- mykotoxiny toxicita MeSH
- nikotin MeSH
- oxidační stres účinky léků MeSH
- těžké kovy toxicita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- akrylamid MeSH
- antioxidancia MeSH
- kurkumin * MeSH
- mykotoxiny MeSH
- nikotin MeSH
- těžké kovy MeSH
This study assessed the potential of dried Cayenne pepper (CP; Capsicum annuum L.) as a natural additive to rice bran oil (RBO), grape seed oil (GSO), and virgin olive oil (OO). Key analyses included peroxide and acid values, oxidative stability (Rancimat method), the composition of fatty acids (FAs) (GC-FID method), antioxidant activity (AA; DPPH method), and antimicrobial properties (disc diffusion method). Capsaicin and the dihydrocapsaicin contents in CP were quantified (HPLC-DAD method) as 1499.37 ± 3.64 and 1449.04 ± 5.14 mg/kg DW, respectively. Oleic acid (C18:1cis n9) dominated in OO (69.70%), OO-CP (69.73%), and RBO-CP (38.97%), while linoleic acid (C18:2cis n6) prevailed in RBO (41.34%), GSO (57.93%), and GSO-CP (58.03%). The addition of CP influenced the FA profile, particularly linoleic acid in OO and RBO, and all FAs in GSO. Peroxide and acid values increased significantly in RBO and GSO upon CP addition, but induction times remained unaffected. The strongest AA (77.00 ± 0.13%) was observed in OO-CP. Cayenne pepper significantly enhanced the antioxidant profiles of all oils compared to the counterparts. However, the antimicrobial activity was weak (≤5.0 mm inhibition zones) against tested microorganisms. These findings support CP as a functional additive for enhancing the nutritional and functional properties of gourmet oils, while highlighting the need for further optimization to improve stability and bioactivity.
- Klíčová slova
- Cayenne pepper red, antimicrobial activity, antioxidant activity, fatty acids, health benefits, technological profile, vegetable oils,
- MeSH
- antiinfekční látky farmakologie chemie MeSH
- antioxidancia * farmakologie chemie MeSH
- Capsicum * chemie MeSH
- kapsaicin analogy a deriváty farmakologie analýza MeSH
- mastné kyseliny analýza MeSH
- oleje rostlin chemie farmakologie MeSH
- olivový olej chemie MeSH
- rýžový olej chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antiinfekční látky MeSH
- antioxidancia * MeSH
- dihydrocapsaicin MeSH Prohlížeč
- kapsaicin MeSH
- mastné kyseliny MeSH
- oleje rostlin MeSH
- olivový olej MeSH
- rýžový olej MeSH
New voltammetric and flow amperometric methods for the determination of guaifenesin (GFE) using a perspective screen-printed sensor (SPE) with boron-doped diamond electrode (BDDE) were developed. The electrochemical oxidation of GFE was studied on the surface of the oxygen-terminated BDDE of the sensor. The GFE provided two irreversible anodic signals at a potential of 1.0 and 1.1 V (vs. Ag|AgCl|KCl sat.) in Britton-Robinson buffer (pH 2), which was chosen as the supporting electrolyte for all measurements. First, a voltammetric method based on differential pulse voltammetry was developed and a low detection limit (LOD = 41 nmol L-1), a wide linear dynamic range (LDR = 0.1-155 μmol L-1), and a good recovery in the analysis of model and pharmaceutical samples (RSD <3.0 %) were obtained. In addition, this sensor demonstrated excellent sensitivity and reproducibility in the analysis of biological samples (RSD <3.2 %), where the analysis took place in a drop of serum (50 μL) without pretreatment and additional electrolyte. Subsequently, SP/BDDE was incorporated into a flow-through 3D printed electrochemical cell and a flow injection analysis method with electrochemical detection (FIA-ED) was developed, resulting in excellent analytical parameters (LOD = 86 nmol L-1, LDR = 0.1-50 μmol L-1). Moreover, the mechanism of electrochemical oxidation of GFE was proposed based on calculations of HOMO spatial distribution and spectroelectrochemical measurements focused on IR identification of intermediates and products.
- Klíčová slova
- Boron-doped diamond electrode, Flow injection analysis with electrochemical detection, Guaifenesin, Screen-printed sensor, Spectroelectrochemistry, Voltammetry,
- MeSH
- bor * chemie MeSH
- diamant * chemie MeSH
- elektrochemické techniky * metody přístrojové vybavení MeSH
- elektrody * MeSH
- guaifenesin * analýza chemie MeSH
- lidé MeSH
- limita detekce MeSH
- oxidace-redukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- bor * MeSH
- diamant * MeSH
- guaifenesin * MeSH
The pungency of chili peppers, the most popular hot spice used worldwide, is caused by capsaicinoids (CPDs), the content of which can vary greatly due to varietal differences and growing conditions. For the first time, a novel simple method for the fast determination of CPDs in chili peppers and chili products was developed based on adsorptive transfer cyclic square-wave voltammetry (AdTCSWV), using adsorption of lipophilic CPDs on an unmodified glassy carbon electrode surface from methanolic extracts of chili pepper samples. The CSWV is based on short oxidation of adsorbed CPDs to quinoid products, and their subsequent reduction and re-oxidation to provide specific analytical signals with a linear range from 0.05 to 1.00 mg L-1. This principle was also implemented in tandem coulometric and amperometric detection of CPDs after HPLC separation. The two-step electrochemical detection provides increased selectivity for CPDs in case of CPDs co-elution with other electrochemically oxidizable components that cannot be reversibly reduced.
- Klíčová slova
- Adsorptive transfer cyclic square-wave voltammetry, Capsaicinoids, Chili peppers, HPLC with tandem electrochemical detection,
- MeSH
- adsorpce MeSH
- Capsicum * chemie MeSH
- elektrochemické techniky * metody MeSH
- elektrody MeSH
- kapsaicin * analýza chemie MeSH
- limita detekce MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kapsaicin * MeSH
AIM OF STUDY: To determine whether a high dose of levodopa-carbidopa intestinal gel (LCIG), expressed as levodopa equivalent daily dose (LE daily dose), is a risk factor for acute polyneuropathy in patients treated with LCIG. CLINICAL RATIONALE FOR STUDY: Treatment with LCIG is an effective device-assisted therapy in the advanced stages of Parkinson's Disease (PD). Polyneuropathy is a well-known complication of PD treatment. Patients treated with oral levodopa usually suffer from sub-clinical or mild chronic sensory polyneuropathy. However, severe acute polyneuropathy occurs in patients treated with LCIG, which is causally related to the treatment and leads to its immediate discontinuation. The etiology is not yet clear, but some patients with acute polyneuropathy have been given high doses of LCIG. MATERIAL AND METHODS: A retrospective multicentre study of patients treated with LCIG was performed. Patients with acute polyneuropathy were subjected to a detailed analysis including statistical processing. RESULTS: Of 183 patients treated with LCIG in seven centres, six patients (five females, median age 63 years) developed acute polyneuropathy with LCIG discontinuation. The median (interquartile range) initial and final LE daily dose in patients with and without acute polyneuropathy was 3,015 (2,695-3,184) and 1,898 (1,484-2,167) mg, respectively. The final LE daily dose of 2,605 mg cut-off had 83% sensitivity and 93% specificity for the prediction of acute polyneuropathy. CONCLUSIONS AND CLINICAL IMPLICATIONS: The risk of acute polyneuropathy in LCIG-treated patients was associated with a daily LE dose of greater than 2,605 mg or with more than a 62% increase in the daily LE dose during LCIG treatment.
- Klíčová slova
- Parkinson’s Disease, acute polyneuropathy, levodopa equivalent daily dose, levodopa/carbidopa intestinal gel,
- MeSH
- antiparkinsonika * škodlivé účinky aplikace a dávkování MeSH
- fixní kombinace léků * MeSH
- gely * MeSH
- karbidopa * aplikace a dávkování škodlivé účinky MeSH
- levodopa * aplikace a dávkování škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- Parkinsonova nemoc * farmakoterapie MeSH
- polyneuropatie * chemicky indukované farmakoterapie MeSH
- retrospektivní studie MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Názvy látek
- antiparkinsonika * MeSH
- carbidopa, levodopa drug combination MeSH Prohlížeč
- fixní kombinace léků * MeSH
- gely * MeSH
- karbidopa * MeSH
- levodopa * MeSH
G protein-coupled estrogen receptor 1 (GPER-1) has gained recognition for its role in conferring cardioprotection. However, the extent to which GPER-1 exerts equally important effects in both sexes remains unclear. The study found similar expressions of GPER-1 in rat heart apex in both sexes. In male rats, administering epinephrine (Epi) at a dose of 31.36 microg/100 g resulted in a rapid decline in cardiac function, accompanied by a sharp increase in bax/bcl-2 levels. In contrast, female rats did not display significant changes in cardiac function under the same conditions. Additionally, compared to the injection of Epi alone (at a dose of 15.68 microg/100 g), the administration of G15 (GPER-1 antagonist) further decreased cardiac function in both male and female rats. However, it only increased mortality and lung coefficient in male rats. Conversely, G1 (GPER-1 agonist) administration improved cardiac function in both sexes. Notably, the apex of the male heart exhibited lower levels of inhibitory G protein (Galphai). Furthermore, female and male rats treated with Epi displayed elevated phosphorylated protein kinase B (p-Akt). Compared to their respective Epi groups, the administration of G15 increased p-Akt levels in female rat hearts but decreased them in male rat hearts. Conversely, the administration of G1 decreased p-Akt levels in females but rapidly increased them in male rats. Our study uncovers the vital role of GPER-1 in protecting against stress-induced heart injuries in a sex-specific manner. These findings hold immense potential for advancing targeted cardiac therapies and enhancing outcomes for both females and males.
- MeSH
- adrenalin MeSH
- fyziologický stres fyziologie MeSH
- krysa rodu Rattus MeSH
- pohlavní dimorfismus MeSH
- potkani Sprague-Dawley * MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- receptory pro estrogeny metabolismus MeSH
- receptory spřažené s G-proteiny * metabolismus MeSH
- sexuální faktory MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- adrenalin MeSH
- Gper1 protein, rat MeSH Prohlížeč
- protoonkogenní proteiny c-akt * MeSH
- receptory pro estrogeny MeSH
- receptory spřažené s G-proteiny * MeSH
Dietary polyphenols have been associated with many beneficial cardiovascular effects. However, these effects are rather attributed to small phenolic metabolites formed by the gut microbiota, which reach sufficient concentrations in systemic circulation. 4-Methylcatechol (4-MC) is one such metabolite. As it is shown to possess considerable vasorelaxant effects, this study aimed to unravel its mechanism of action. To this end, experimental in vitro and in silico approaches were employed. In the first step, isometric tension recordings were performed on rat aortic rings. 4-MC potentiated the effect of cyclic nucleotides, but the effect was not mediated by either soluble guanylyl cyclase (sGC), modification of cyclic adenosine monophosphate levels, or protein kinase G. Hence, downstream targets such as calcium or potassium channels were considered. Inhibition of voltage-gated K+ channels (KV) markedly decreased the effect of 4-MC, and vasodilation was partly decreased by inhibition of the KV7 isoform. Contrarily, other types of K+ channels or L-type Ca2+ channels were not involved. In silico reverse docking confirmed that 4-MC binds to KV7.4 through hydrogen bonding and hydrophobic interactions. In particular, it interacts with two crucial residues for KV7.4 activation: Trp242 and Phe246. In summary, our findings suggested that 4-MC exerts vasorelaxation by opening KV channels with the involvement of KV7.4.
- MeSH
- aorta účinky léků metabolismus MeSH
- draslíkové kanály řízené napětím * metabolismus MeSH
- katecholy * farmakologie MeSH
- krysa rodu Rattus MeSH
- potkani Wistar MeSH
- quercetin * farmakologie MeSH
- simulace molekulového dockingu MeSH
- vazodilatace * účinky léků MeSH
- vazodilatancia farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 4-methylcatechol MeSH Prohlížeč
- draslíkové kanály řízené napětím * MeSH
- katecholy * MeSH
- quercetin * MeSH
- vazodilatancia MeSH
Renal nerves play a critical role in cardiorenal interactions. Renal denervation (RDN) improved survival in some experimental heart failure (HF) models. It is not known whether these favorable effects are indirect, explainable by a decrease in vascular afterload, or diminished neurohumoral response in the kidneys, or whether RDN procedure per se has direct myocardial effects in the failing heart. To elucidate mechanisms how RDN affects failing heart, we studied load-independent indexes of ventricular function, gene markers of myocardial remodeling, and cardiac sympathetic signaling in HF, induced by chronic volume overload (aorto-caval fistula, ACF) of Ren2 transgenic rats. Volume overload by ACF led to left ventricular (LV) hypertrophy and dysfunction, myocardial remodeling (upregulated Nppa, MYH 7/6 genes), increased renal and circulating norepinephrine (NE), reduced myocardial NE content, increased monoaminoxidase A (MAO-A), ROS production and decreased tyrosine hydroxylase (+) nerve staining. RDN in HF animals decreased congestion in the lungs and the liver, improved load-independent cardiac function (Ees, PRSW, Ees/Ea ratio), without affecting arterial elastance or LV pressure, reduced adverse myocardial remodeling (Myh 7/6, collagen I/III ratio), decreased myocardial MAO-A and inhibited renal neprilysin activity. RDN increased myocardial expression of acetylcholinesterase (Ache) and muscarinic receptors (Chrm2), decreased circulating and renal NE, but increased myocardial NE content, restoring so autonomic control of the heart. These changes likely explain improvements in survival after RDN in this model. The results suggest that RDN has remote, load-independent and favorable intrinsic myocardial effects in the failing heart. RDN therefore could be a useful therapeutic strategy in HF.
- Klíčová slova
- Heart failure, Norepinephrine, Renal denervation, Sympathetic nervous system, Volume overload,
- MeSH
- krysa rodu Rattus MeSH
- ledviny * inervace metabolismus MeSH
- modely nemocí na zvířatech * MeSH
- myokard * metabolismus MeSH
- noradrenalin * krev metabolismus MeSH
- potkani transgenní * MeSH
- remodelace komor fyziologie MeSH
- srdce inervace patofyziologie MeSH
- srdeční selhání * patofyziologie metabolismus MeSH
- sympatektomie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- noradrenalin * MeSH
Substituted catechols include both natural and synthetic compounds found in the environment and foods. Some of them are flavonoid metabolites formed by the gut microbiota which are absorbed afterwards. Our previous findings showed that one of these metabolites, 4-methylcatechol, exerts potent vasorelaxant effects in rats. In the current study, we aimed at testing of its 22 structural congeners in order to find the most potent structure and to investigate the mechanism of action. 3-methoxycatechol (3-MOC), 4-ethylcatechol, 3,5-dichlorocatechol, 4-tert-butylcatechol, 4,5-dichlorocatechol, 3-fluorocatechol, 3-isopropylcatechol, 3-methylcatechol and the parent 4-methylcatechol exhibited high vasodilatory activities on isolated rat aortic rings with EC50s ranging from ∼10 to 24 μM. Some significant sex-differences were found. The most potent compound, 3-MOC, relaxed also resistant mesenteric artery but not porcine coronary artery, and decreased arterial blood pressure in both male and female spontaneously hypertensive rats in vivo without affecting heart rate. It potentiated the vasodilation mediated by cAMP and cGMP, but did not impact L-type Ca2+-channels. By using two inhibitors, activation of voltage-gated potassium channels (KV) was found to be involved in the mechanism of action. This was corroborated by docking analysis of 3-MOC with the KV7.4 channel. None of the most active catechols decreased the viability of the A-10 rat embryonic thoracic aorta smooth muscle cell line. Our findings showed that various catechols can relax vascular smooth muscles and hence could provide templates for developing new antihypertensive vasodilator agents without affecting coronary circulation.
- Klíčová slova
- Blood vessel, Catechol, K(V) channel, Phenolic, Vasorelaxant,
- MeSH
- aorta thoracica účinky léků metabolismus MeSH
- arteriae mesentericae * účinky léků metabolismus MeSH
- arteriální tlak účinky léků MeSH
- draslíkové kanály řízené napětím metabolismus antagonisté a inhibitory účinky léků MeSH
- guanosinmonofosfát cyklický metabolismus MeSH
- hypertenze farmakoterapie patofyziologie metabolismus MeSH
- katecholy * farmakologie chemie MeSH
- koronární cévy účinky léků metabolismus MeSH
- krysa rodu Rattus MeSH
- modely nemocí na zvířatech MeSH
- myocyty hladké svaloviny účinky léků metabolismus MeSH
- potkani inbrední SHR * MeSH
- prasata MeSH
- sexuální faktory MeSH
- simulace molekulového dockingu * MeSH
- svaly hladké cévní účinky léků metabolismus MeSH
- vazodilatace * účinky léků MeSH
- vazodilatancia * farmakologie chemie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- draslíkové kanály řízené napětím MeSH
- guanosinmonofosfát cyklický MeSH
- katecholy * MeSH
- vazodilatancia * MeSH
