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Scientific Reports Sep 2023The formation of protein aggregates is a hallmark of many neurodegenerative diseases and systemic amyloidoses. These disorders are associated with the fibrillation of a...
The formation of protein aggregates is a hallmark of many neurodegenerative diseases and systemic amyloidoses. These disorders are associated with the fibrillation of a variety of proteins/peptides, which ultimately leads to cell toxicity and tissue damage. Understanding how amyloid aggregation occurs and developing compounds that impair this process is a major challenge in the health science community. Here, we demonstrate that pathogenic proteins associated with Alzheimer's disease, diabetes, AL/AA amyloidosis, and amyotrophic lateral sclerosis can aggregate within stress-inducible physiological amyloid-based structures, termed amyloid bodies (A-bodies). Using a limited collection of small molecule inhibitors, we found that diclofenac could repress amyloid aggregation of the β-amyloid (1-42) in a cellular setting, despite having no effect in the classic Thioflavin T (ThT) in vitro fibrillation assay. Mapping the mechanism of the diclofenac-mediated repression indicated that dysregulation of cyclooxygenases and the prostaglandin synthesis pathway was potentially responsible for this effect. Together, this work suggests that the A-body machinery may be linked to a subset of pathological amyloidosis, and highlights the utility of this model system in the identification of new small molecules that could treat these debilitating diseases.
Topics: Humans; Diclofenac; Amyloidogenic Proteins; Amyloidosis; Prostaglandin-Endoperoxide Synthases; Immunoglobulin Light-chain Amyloidosis
PubMed: 37660155
DOI: 10.1038/s41598-023-41712-2 -
Acta Ophthalmologica Dec 2018Current cataract surgery guidelines recommend routine use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) in preventing pseudophakic cystoid macular oedema...
PURPOSE
Current cataract surgery guidelines recommend routine use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) in preventing pseudophakic cystoid macular oedema (PCME). Here, we compare the clinical efficacy and tolerability of two potent NSAIDs, nepafenac and preservative-free diclofenac following cataract surgery.
METHODS
Randomized, double-blind, prospective single-centre study. Ninety-six eyes of 95 patients undergoing routine cataract surgery were randomized 1:1 either to nepafenac (Nevanac, 1 mg/ml) or diclofenac (Dicloabak, 1 mg/ml) for 3 weeks. Seventy-three patients accounting for 73 eyes completed the entire follow-up. Aqueous flare and central retinal thickness (CRT) analysis were conducted preoperatively and at control visits 28 days and 3 months after surgery. A structured home questionnaire and interview were used to record any adverse effects of the topical medications, subjective visual recovery and the dispenser's ease of use.
RESULTS
No differences were observed between the groups for aqueous flare, CRT, speed of recovery or visual acuity gain. Seven patients (16%) on nepafenac and 20 patients (48%) on preservative-free diclofenac reported symptoms related to topical use of NSAID medications (p = 0.001).
CONCLUSION
No differences in clinical efficacy were found between potent NSAIDs, while tolerability might be an issue.
Topics: Administration, Topical; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Benzeneacetamides; Cataract Extraction; Diclofenac; Double-Blind Method; Drug Tolerance; Female; Follow-Up Studies; Humans; Macular Edema; Male; Middle Aged; Ophthalmic Solutions; Phenylacetates; Postoperative Care; Preservatives, Pharmaceutical; Prospective Studies; Tomography, Optical Coherence; Treatment Outcome
PubMed: 30284393
DOI: 10.1111/aos.13843 -
Journal of Oleo Science 2022Disorganization and breakdown of extracellular matrix proteins like fibronectin, collagen, and elastin are key characteristics of skin aging due to the increased...
Disorganization and breakdown of extracellular matrix proteins like fibronectin, collagen, and elastin are key characteristics of skin aging due to the increased activation of important proteolytic enzymes like elastases and collagenase enzymes. Also, inhibition of their enzymatic activities by natural molecules might be a promising factor to prevent extrinsic skin aging. All chemicals were obtained from Sigma-Aldrich unless otherwise stated. The assay employed was based on spectrophotometric methods reported in the literature. The collagenase and elastase inhibition assays of some phenolic compounds were performed according to the previous studies. These compounds showed excellent to good inhibitory activities of vulpinic acid against studied these enzymes with IC50 values of 195.36 µM for collagenase and 25.24 µM for elastase. The molecular docking calculations were conducted to investigate the chemical and biological activity of vulpinic acid and usnic acid against collagenase and elastase. The results indicated that these two compounds can interact with the essential residues of the enzymes and affect their activities. The calculations of binding free energies were also performed to obtain more details about the characteristics and free energies of the ligand-enzyme complexes. Additionally, both compounds exhibited the most potent inhibition in the three lung cancer cells, with an IC50 value of 21-68 µM, indicating that vulpinic acid is more potent than Doxorubicin, which exhibited an IC50 value of 21-29 µM.
Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Collagenases; Dose-Response Relationship, Drug; Extracellular Matrix Proteins; Furans; Geroscience; Humans; Lung Neoplasms; Models, Molecular; Pancreatic Elastase; Phenylacetates; Skin Aging
PubMed: 35110467
DOI: 10.5650/jos.ess21276 -
Molecules (Basel, Switzerland) May 2022Self-assembly of organic ions in aqueous solutions is a hot topic at the present time, and substances that are well-soluble in water are usually studied. In this work,...
Self-assembly of organic ions in aqueous solutions is a hot topic at the present time, and substances that are well-soluble in water are usually studied. In this work, aqueous solutions of sodium diclofenac are investigated, which, like most medicinal compounds, is poorly soluble in water. Classical MD modeling of an aqueous solution of diclofenac sodium showed equilibrium between the hydrated anion and the hydrated dimer of the diclofenac anion. The assignment and interpretation of the bands in the UV, NIR, and IR spectra are based on DFT calculations in the discrete-continuum approximation. It has been shown that the combined use of spectroscopic methods in various frequency ranges with classical MD simulations and DFT calculations provides valuable information on the association processes of medical compounds in aqueous solutions. Additionally, such a combined application of experimental and calculation methods allowed us to put forward a hypothesis about the mechanism of the effect of diclofenac sodium in high dilutions on a solution of diclofenac sodium.
Topics: Anions; Diclofenac; Ions; Solutions; Water
PubMed: 35630826
DOI: 10.3390/molecules27103350 -
Pharmacology, Biochemistry, and Behavior Sep 2018Chronic oral methylphenidate (MP) exposure in rats is associated with numerous developmental and behavioral consequences. The present study investigated the persistence...
Chronic oral methylphenidate (MP) exposure in rats is associated with numerous developmental and behavioral consequences. The present study investigated the persistence of the effects of chronic oral MP exposure after abstinence from MP use. Male and female rats were exposed to daily orally self-administered water, low dose MP (LD), or high dose (HD) MP for 13 weeks, followed by a 4-week abstinence period. Fluid, food consumption and bodyweights were monitored and animals were tested for locomotor activity, anxiety- and depressive-like symptoms, learning and memory, and social behavior during both the treatment and abstinence phases of the experiment. During treatment, MP attenuated bodyweight regardless of sex, but increased food and fluid consumption in females and males by 20.7% and 30.1%, respectively. MP also increased locomotor activity in both males and females observed as increased distance travelled in an open field. (59.1% and 95.9%, respectively) and increased locomotor activity in the home cage over a 24-hour circadian cycle (45.5% and 63.0%). Additionally, MP exerted an anxiolytic effect observed as increased time spent in the open arms of an elevated plus maze (31.1% in HD males, 59.2% in HD females), and an increased latency to immobility in a forced swim test (330% in HD males, 418% in HD females). The effects of MP (bodyweight, consumption, locomotion, anxiolytic, and anti-depressive) were, almost without exception, eliminated during the abstinence period. MP had no impact on learning and memory performance as measured by a T-maze, or social behavior during treatment. These findings suggest that the behavioral consequences of chronic oral MP treatment in our preclinical model are reversible in rats following an abstinence period from use of the drug.
Topics: Administration, Oral; Animals; Central Nervous System Stimulants; Female; Male; Methylphenidate; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome
PubMed: 30030127
DOI: 10.1016/j.pbb.2018.07.001 -
BMJ Open Mar 2019To assess the methodological advantages and disadvantages of parallel and crossover designs in randomised clinical trials on methylphenidate for children and adolescents... (Meta-Analysis)
Meta-Analysis
Methodological advantages and disadvantages of parallel and crossover randomised clinical trials on methylphenidate for attention deficit hyperactivity disorder: a systematic review and meta-analyses.
OBJECTIVE
To assess the methodological advantages and disadvantages of parallel and crossover designs in randomised clinical trials on methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).
DESIGN
Secondary analyses of a Cochrane systematic review.
SETTING AND PARTICIPANTS
We searched relevant databases up to March 2015 and included data from parallel and crossover randomised trials assessing children and adolescents up to 18 years with ADHD.
INTERVENTIONS
Methylphenidate compared with placebo or no-treatment interventions.
PRIMARY AND SECONDARY OUTCOMES
The primary outcomes were teacher-rated ADHD symptoms and serious adverse events. The secondary outcomes were non-serious adverse events.
RESULTS
We included 38 parallel trials (n=5111) and 147 crossover trials (n=7134). When comparing methylphenidate with placebo or no-treatment on ADHD symptoms, we found no differences between the end of parallel trials and the first-period from crossover trials (Χ²=1.06, df=1, p=0.30, I²=5.5%). We also found no differences when combining the end of first-period crossover trials with the end of parallel trials and comparing them to the end of last-period crossover trials (Χ²=3.25, df=1, p=0.07, I²=69.2%). We found no differences in serious and non-serious adverse events, and no risk of period and carryover effects. However, only two trials contributed data to the latter analyses.
CONCLUSIONS
Both parallel and crossover trials seem suitable for investigating methylphenidate in children and adolescents with ADHD, with comparable estimates on ADHD symptom severity and adverse events. However, parallel trials might still offer ethical and statistical advantages over crossover trials.
Topics: Adolescent; Child; Female; Humans; Male; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Cross-Over Studies; Methylphenidate; Randomized Controlled Trials as Topic
PubMed: 30928951
DOI: 10.1136/bmjopen-2018-026478 -
Nutrients Jan 2022Regular intake of polyphenol-rich food has been associated with a wide variety of beneficial health effects, including the prevention of cardiovascular diseases....
Regular intake of polyphenol-rich food has been associated with a wide variety of beneficial health effects, including the prevention of cardiovascular diseases. However, the parent flavonoids have mostly low bioavailability and, hence, their metabolites have been hypothesized to be bioactive. One of these metabolites, 3-hydroxyphenylacetic acid (3-HPAA), formed by the gut microbiota, was previously reported to exert vasorelaxant effects ex vivo. The aim of this study was to shed more light on this effect in vivo, and to elucidate the mechanism of action. 3-HPAA gave rise to a dose-dependent decrease in arterial blood pressure when administered i.v. both as a bolus and infusion to spontaneously hypertensive rats. In contrast, no significant changes in heart rate were observed. In ex vivo experiments, where porcine hearts from a slaughterhouse were used to decrease the need for laboratory animals, 3-HPAA relaxed precontracted porcine coronary artery segments via a mechanism partially dependent on endothelium integrity. This relaxation was significantly impaired after endothelial nitric oxide synthase inhibition. In contrast, the blockade of SKCa or IKCa channels, or muscarinic receptors, did not affect 3-HPAA relaxation. Similarly, no effects of 3-HPAA on cyclooxygenase nor L-type calcium channels were observed. Thus, 3-HPAA decreases blood pressure in vivo via vessel relaxation, and this mechanism might be based on the release of nitric oxide by the endothelial layer.
Topics: Animals; Blood Pressure; Disease Models, Animal; Flavonoids; Phenylacetates; Rats; Rats, Inbred SHR
PubMed: 35057508
DOI: 10.3390/nu14020328 -
Free Radical Biology & Medicine Jan 2016During inflammation, leukocyte-derived eosinophil peroxidase catalyses the formation of hypobromous acid, which can brominate tyrosine residues in proteins to form...
During inflammation, leukocyte-derived eosinophil peroxidase catalyses the formation of hypobromous acid, which can brominate tyrosine residues in proteins to form bromotyrosine. Since eosinophils are involved in the pathogenesis of allergic reactions, such as asthma, urinary bromotyrosine level has been used for the assessment of children with asthma. However, little is known about the metabolism and disposition of bromotyrosine in vivo. The aim of this study was to identify the major urinary metabolites formed during bromotyrosine metabolism and to develop mass spectrometric methods for their quantitation. Deuterium-labeled bromotyrosine was synthesized by deuterium exchange. [D3]bromotyrosine (500 nmole) was injected intraperitoneally into Sprague-Dawley rats and urine was collected for 24h in a metabolic cage. (13)C-labeled derivatives of bromotyrosine and its major urinary metabolite were synthesized and used as internal standards for quantitation. Following solid phase extraction, urine samples were derivatized to the pentafluorobenzyl ester, and analyzed using isotope dilution gas chromatography and negative-ion chemical ionization mass spectrometry. A novel brominated metabolite, 3-bromo-4-hydroxyphenylacetic acid (bromo-HPA), was identified as the major brominated metabolite of bromotyrosine. Bromo-HPA only accounted for 0.43 ± 0.04% of infused [D3]bromotyrosine and 0.12 ± 0.02% of infused [D3]bromotyrosine was excreted in the urine unchanged. However, ~1.3% (6.66 ± 1.33 nmole) of infused [D3]bromotyrosine was excreted in the urine as the de-brominated metabolite, [D3]4-hydroxyphenylacetic acid, which is also a urinary metabolite of tyrosine in mammals. We also tested whether or not iodotyrosine dehalogenase can catalyse de-bromination of bromotyrosine and showed that iodotyrosine dehalogenase is able to de-brominate free bromotyrosine in vitro. We identified bromo-HPA as the main brominated urinary metabolite of bromotyrosine in rats. However, de-halogenation of bromotyrosine is the major metabolic pathway to eliminate free brominated tyrosine in vivo.
Topics: Animals; Bromine; Deuterium; Gas Chromatography-Mass Spectrometry; Male; Phenylacetates; Rats; Rats, Sprague-Dawley; Tyrosine
PubMed: 26638695
DOI: 10.1016/j.freeradbiomed.2015.11.030 -
AAPS PharmSciTech Jul 2021An emulsion is a biphasic dosage form comprising of dispersed phase containing droplets that are uniformly distributed into a surrounding liquid which forms the... (Review)
Review
An emulsion is a biphasic dosage form comprising of dispersed phase containing droplets that are uniformly distributed into a surrounding liquid which forms the continuous phase. An emulsifier is added at the interface of two immiscible liquids to stabilize the thermodynamically unstable emulsion. Various types of emulsions such as water-in-oil (w-o), oil-in-water (o-w), microemulsions, and multiple emulsions are used for delivering certain drugs in the body. Water (aqueous) phase is commonly used for encapsulating proteins and several other drugs in water-in-oil-in-water (w-o-w) emulsion technique. But this method has posed certain problems such as decreased stability, burst release, and low entrapment efficiency. Thus, a novel "solid-in-oil-in-water" (s-o-w) emulsion system was developed for formulating certain drugs, probiotics, proteins, antibodies, and tannins to overcome these issues. In this method, the active ingredient is encapsulated as a solid and added to an oil phase, which formed a solid-oil dispersion. This dispersion was then mixed with water to form a continuous phase for enhancing the drug absorption. This article focuses on the various studies done to investigate the effectiveness of formulations prepared as solid-oil-water emulsions in comparison to conventional water-oil-water emulsions. A summary of the results obtained in each study is presented in this article. The s-o-w emulsion technique may become beneficial in near future as it has shown to improve the stability and efficacy of the entrapped active ingredient.
Topics: Diclofenac; Drug Carriers; Drug Stability; Emulsions; Microspheres; Nanostructures; Oils; Polylactic Acid-Polyglycolic Acid Copolymer; Proteins; Water
PubMed: 34212274
DOI: 10.1208/s12249-021-02074-y -
Clinical Pharmacokinetics Dec 2021Elevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders,...
BACKGROUND
Elevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders, but limited clinical data are available for hepatic encephalopathy. Phenylacetic acid (PAA) plasma exposure has been reported to correlate with neurologic adverse events in patients with cancer but not in patients with urea cycle disorders or hepatic encephalopathy. Ornithine phenylacetate, an intravenous dosage form of the L-ornithine salt of phenylacetate, is under development for hepatic encephalopathy.
OBJECTIVE
This analysis summarized the pharmacokinetics and safety of ornithine phenylacetate to support the dosing strategy and to assist with the monitoring and management of neurologic adverse events in a global clinical development program.
METHODS
Phenylacetic acid and phenylacetylglutamine (PAGN) pharmacokinetic data and adverse events from five clinical studies were included in the analysis. Hepatic and renal dysfunction were assessed by baseline Child-Pugh score and creatinine clearance, respectively. Predicted plasma exposures of PAA at the occurrence of neurologic adverse events were used for exposures and neurologic adverse event analysis.
RESULTS
Phenylacetic acid exhibited nonlinear pharmacokinetics. Phenylacetic acid exposure was 35% higher in Child-Pugh C than in Child-Pugh B. No significant pharmacokinetic difference was identified between Caucasian and Asian subjects after body weight adjustment. Phenylacetylglutamine renal clearance decreased by five-fold in severe renal impairment compared with subjects with normal renal function. Renal dysfunction significantly elevated PAGN plasma concentrations; however, elevated PAGN due to reduced excretion of PAGN did not change PAA exposure and plasma ammonia levels. No correlation was observed between PAA plasma exposure and neurologic adverse events in patients with stable cirrhosis or acute hepatic encephalopathy.
CONCLUSIONS
Dose adjustment should be considered for patients with low body weight and severely impaired hepatic function. Phenylacetic acid plasma exposure was not correlated with neurologic adverse events in the ornithine phenylacetate target patient population.
Topics: Ammonia; Glutamine; Humans; Phenylacetates
PubMed: 34125423
DOI: 10.1007/s40262-021-01047-5