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Molecules (Basel, Switzerland) Oct 2022A new series of cytotoxic platinum(IV) complexes (-) incorporating halogenated phenylacetic acid derivatives (4-chlorophenylacetic acid, 4-fluorophenylacetic acid,...
A new series of cytotoxic platinum(IV) complexes (-) incorporating halogenated phenylacetic acid derivatives (4-chlorophenylacetic acid, 4-fluorophenylacetic acid, 4-bromophenylacetic acid and 4-iodophenylacetic acid) were synthesised and characterised using spectroscopic and spectrometric techniques. Complexes - were assessed on a panel of cell lines including HT29 colon, U87 glioblastoma, MCF-7 breast, A2780 ovarian, H460 lung, A431 skin, Du145 prostate, BE2-C neuroblastoma, SJ-G2 glioblastoma, MIA pancreas, the ADDP-resistant ovarian variant, and the non-tumour-derived MCF10A breast line. The in vitro cytotoxicity results confirmed the superior biological activity of the studied complexes, especially those containing 4-fluorophenylacetic acid and 4-bromophenylacetic acid ligands, namely and , eliciting an average GI value of 20 nM over the range of cell lines tested. In the Du145 prostate cell line, exhibited the highest degree of potency amongst the derivatives, displaying a GI value of 0.7 nM, which makes it 1700-fold more potent than cisplatin (1200 nM) and nearly 7-fold more potent than our lead complex, (4.6 nM) in this cell line. Notably, in the ADDP-resistant ovarian variant cell line, (6 nM) was found to be almost 4700-fold more potent than cisplatin. Reduction reaction experiments were also undertaken, along with studies aimed at determining the complexes' solubility, stability, lipophilicity, and reactive oxygen species production.
Topics: Humans; Female; Platinum; Cisplatin; Cell Line, Tumor; Reactive Oxygen Species; Glioblastoma; Ovarian Neoplasms; Antineoplastic Agents; Phenylacetates
PubMed: 36296713
DOI: 10.3390/molecules27207120 -
Journal of Attention Disorders Dec 2022Dysregulated emotional behavior occurs often in adults with ADHD. Analysis of clinical trials may guide clinical intervention and future research.
OBJECTIVE
Dysregulated emotional behavior occurs often in adults with ADHD. Analysis of clinical trials may guide clinical intervention and future research.
METHOD
Controlled trials of adult ADHD measuring emotional behavior were included if another study offered a comparable analysis of the same treatment method. Standardized Mean Difference (SMD) of effects were calculated, and the size of effects for emotional and non-emotional ADHD behavior were compared.
RESULTS
13 out of 14 studies of methylphenidate, atomoxetine, and lisdexamfetamine demonstrated significant improvement in emotional behavior measures, with small to high SMDs. The proportional effect on emotional versus non-emotional behavior ranged from 46% to 110% for methylphenidate, 56% to 129% for atomoxetine, and 36% to 96% for lisdexamfetamine.
CONCLUSION
Psychopharmacological treatments for ADHD are likely to improve emotional behavior, and available scales are sensitive to these effects. Studies dedicated to treatment of this domain of function can further refine clinical approaches.
Topics: Adult; Humans; Atomoxetine Hydrochloride; Lisdexamfetamine Dimesylate; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Methylphenidate; Treatment Outcome
PubMed: 35822610
DOI: 10.1177/10870547221110926 -
Alcohol-medication interactions: A systematic review and meta-analysis of placebo-controlled trials.Neuroscience and Biobehavioral Reviews Jan 2022Alcohol and other xenobiotics may limit the therapeutic effects of medications. We aimed at investigating alcohol-medication interactions (AMI) after the exclusion of... (Meta-Analysis)
Meta-Analysis Review
Alcohol and other xenobiotics may limit the therapeutic effects of medications. We aimed at investigating alcohol-medication interactions (AMI) after the exclusion of confounding effects related to other xenobiotics. We performed a systematic review and meta-analysis of controlled studies comparing the effects induced by alcohol versus placebo on pharmacodynamic and/or pharmacokinetic parameters of approved medications. Certainty in the evidence of AMI was assessed when at least 3 independent studies and at least 200 participants were available. We included 107 articles (3097 participants): for diazepam, cannabis, opioids, and methylphenidate, we found significant AMI and enough data to assign the certainty of evidence. Alcohol consumption significantly increases the peak plasma concentration of diazepam (low certainty; almost 290 participants), cannabis (high certainty; almost 650 participants), opioids (low certainty; 560 participants), and methylphenidate (moderate certainty; 290 participants). For most medications, we found some AMI but not enough data to assign them the certainty grades; for some medications, we found no differences between alcohol and placebo in any outcomes evaluated. Our results add further evidence for interactions between alcohol and certain medications after the exclusion of confounding effects related to other xenobiotics. Physicians should advise patients who use these specific medications to avoid alcohol consumption. Further studies with appropriate control groups, enough female participants to investigate sex differences, and elderly population are needed to expand our knowledge in this field. Short phrases suitable for indexing terms.
Topics: Aged; Female; Humans; Methylphenidate; Randomized Controlled Trials as Topic
PubMed: 34826511
DOI: 10.1016/j.neubiorev.2021.11.019 -
International Journal of Environmental... Oct 2022Attention Deficit Hyperactivity Disorder is a neurodevelopmental disorder with three presentations: inattentive, hyperactive/impulsive and combined. These may represent... (Review)
Review
Attention Deficit Hyperactivity Disorder is a neurodevelopmental disorder with three presentations: inattentive, hyperactive/impulsive and combined. These may represent an independent disease entity. Therefore, the therapeutic approach must be focused on their neurobiological, psychological and social characteristics. To date, there is no comprehensive analysis of the efficacy of different treatments for each presentation of ADHD and each stage of development. This is as narrative overview of scientific papers that summarize the most recent findings and identify the most effective pharmacological and psychosocial treatments by ADHD presentation and age range. Evidence suggests that methylphenidate is the safest and most effective drug for the clinical management of children, adolescents and adults. Atomoxetine is effective in preschoolers and maintains similar efficacy to methylphenidate in adults, whereas guanfacine has proven to be an effective monotherapy for adults and is a worthy adjuvant for the management of cognitive symptoms. The psychosocial treatments with the best results in preschoolers are behavioral interventions that include training of primary caregivers. In adolescents, the combination of cognitive and cognitive-behavioral therapies has shown the best results, whereas cognitive-behavioral interventions are the most effective in adults. Pharmacological and psychosocial treatments must be adjusted to the ADHD presentation and its neurocognitive characteristics through the patient's development.
Topics: Adolescent; Adult; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Guanfacine; Humans; Methylphenidate
PubMed: 36232180
DOI: 10.3390/ijerph191912880 -
Annual Review of Microbiology Sep 2019is an opportunistic pathogen that causes a variety of acute and chronic infections. Usually a commensal on the host body, is capable of transforming into a virulent... (Review)
Review
is an opportunistic pathogen that causes a variety of acute and chronic infections. Usually a commensal on the host body, is capable of transforming into a virulent pathogen upon sensing favorable changes in the host immune system or stress cues. infections are hard to eradicate, because this pathogen has developed strong resistance to most conventional antibiotics; in addition, in chronic infections it commonly forms a biofilm matrix, which provides bacterial cells a protected environment to withstand various stresses including antibiotics. Given its importance as a human pathogen and its notorious antimicrobial tolerance, has been the subject of intensive investigations internationally. Research progress over the last two decades has unveiled a range of chemical communication systems in this pathogen. These diversified chemical communication systems endow a superb ability and remarkable flexibility to coordinate and modulate accordingly the transcriptional expression of various sets of genes associated with virulence and other physiologic activities in response to environmental changes. A fair understanding of the chemical signaling mechanisms with which governs virulence gene expression may hold the key to developing alternative therapeutic interventions that control and prevent bacterial infections.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Biofilms; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Genes, Bacterial; Host Microbial Interactions; Humans; Phenylacetates; Pseudomonas Infections; Pseudomonas aeruginosa; Quorum Sensing; Signal Transduction; Type III Secretion Systems; Virulence; Virulence Factors
PubMed: 31226024
DOI: 10.1146/annurev-micro-020518-120044 -
Indian Pediatrics Dec 2023
Topics: Humans; Cyclopentolate
PubMed: 38087795
DOI: No ID Found -
Journal of the American Academy of... Apr 2023The combination of d-methylphenidate and guanfacine (an α-2A agonist) has emerged as a potential alternative to either monotherapy in children with... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The combination of d-methylphenidate and guanfacine (an α-2A agonist) has emerged as a potential alternative to either monotherapy in children with attention-deficit/hyperactivity disorder (ADHD), but it is unclear what predicts response to these treatments. This study is the first to investigate pretreatment clinical and electroencephalography (EEG) profiles as predictors of treatment outcome in children randomized to these different medications.
METHOD
A total of 181 children with ADHD (aged 7-14 years; 123 boys) completed an 8-week randomized, double-blind, comparative study with d-methylphenidate, guanfacine, or combined treatments. Pretreatment assessments included ratings on ADHD, anxiety, and oppositional behavior. EEG activity from cortical sources localized within midfrontal and midoccipital regions was measured during a spatial working memory task with encoding, maintenance, and retrieval phases. Analyses tested whether pretreatment clinical and EEG measures predicted treatment-related change in ADHD severity.
RESULTS
Higher pretreatment hyperactivity-impulsivity and oppositional symptoms and lower anxiety predicted greater ADHD improvements across all medication groups. Pretreatment event-related midfrontal beta power predicted treatment outcome with combined and monotherapy treatments, albeit in different directions. Weaker beta modulations predicted improvements with combined treatment, whereas stronger modulation during encoding and retrieval predicted improvements with d-methylphenidate and guanfacine, respectively. A multivariate model including EEG and clinical measures explained twice as much variance in ADHD improvement with guanfacine and combined treatment (R= 0.34-0.41) as clinical measures alone (R = 0.14-.21).
CONCLUSION
We identified treatment-specific and shared predictors of response to different pharmacotherapies in children with ADHD. If replicated, these findings would suggest that aggregating information from clinical and brain measures may aid personalized treatment decisions in ADHD.
CLINICAL TRIAL REGISTRATION INFORMATION
Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; https://clinicaltrials.gov; NCT00429273.
Topics: Male; Child; Humans; Attention Deficit Disorder with Hyperactivity; Guanfacine; Methylphenidate; Adrenergic alpha-2 Receptor Agonists; Treatment Outcome; Central Nervous System Stimulants; Double-Blind Method
PubMed: 35963559
DOI: 10.1016/j.jaac.2022.08.001 -
Journal of Psychiatric Research Jul 2023Roughly 20-30% of patients with Attention-deficit/hyperactivity disorder (ADHD) fail to respond to central stimulant (CS) medication. Genetic, neuroimaging, biochemical...
BACKGROUND
Roughly 20-30% of patients with Attention-deficit/hyperactivity disorder (ADHD) fail to respond to central stimulant (CS) medication. Genetic, neuroimaging, biochemical and behavioral biomarkers for CS response have been investigated, but currently there are no biomarkers available for clinical use that help identify CS responders and non-responders.
METHODS
In the present paper, we studied if incentive salience and hedonic experience evaluated after a single-dose CS medication could predict response and non-response to CS medication. We used a bipolar visual analogue 'wanting' and 'liking' scale to gauge incentive salience and hedonic experience in 25 healthy controls (HC) and 29 ADHD patients. HC received 30 mg methylphenidate (MPH) and ADHD patients received either MPH or lisdexamphetamine (LDX) as selected by their clinician, with dosage individually determined for optimal effect. Clinician-evaluated global impression - severity (CGI-S) and improvement (CGI-I) and patient-evaluated improvement (PGI-I) were used to assess response to CS medication. Resting state functional magnetic resonance imaging (fMRI) was conducted before and after single-dose CS to correlate wanting and liking scores to changes in functional connectivity.
RESULTS
Roughly 20% of the ADHD patients were CS non-responders (5 of 29). CS responders had significantly higher incentive salience and hedonic experience scores compared to healthy controls and CS non-responders. Resting state fMRI showed that wanting scores were significantly associated to changes in functional connectivity in ventral striatum including nucleus accumbens.
CONCLUSION
Incentive salience and hedonic experience evaluated after a single-dose CS medication segregate CS responders and non-responders, with corresponding neuroimaging biomarkers in the brain reward system.
Topics: Humans; Central Nervous System Stimulants; Attention Deficit Disorder with Hyperactivity; Magnetic Resonance Imaging; Brain; Motivation; Methylphenidate
PubMed: 37269772
DOI: 10.1016/j.jpsychires.2023.05.073 -
BMC Microbiology Sep 2022Environmental contamination from synthetic plastics and their additives is a widespread problem. Phthalate esters are a class of refractory synthetic organic compounds...
BACKGROUND
Environmental contamination from synthetic plastics and their additives is a widespread problem. Phthalate esters are a class of refractory synthetic organic compounds which are widely used in plastics, coatings, and for several industrial applications such as packaging, pharmaceuticals, and/or paints. They are released into the environment during production, use and disposal, and some of them are potential mutagens and carcinogens. Isophthalate (1,3-benzenedicarboxylic acid) is a synthetic chemical that is globally produced at a million-ton scale for industrial applications and is considered a priority pollutant. Here we describe the biochemical characterization of an enzyme involved in anaerobic degradation of isophthalate by the syntrophically fermenting bacterium Syntrophorhabdus aromaticivorans strain UI that activate isophthalate to isophthalyl-CoA followed by its decarboxylation to benzoyl-CoA.
RESULTS
Isophthalate:Coenzyme A ligase (IPCL, AMP-forming) that activates isophthalate to isophthalyl-CoA was heterologously expressed in E. coli (49.6 kDa) for biochemical characterization. IPCL is homologous to phenylacetate-CoA ligase that belongs to the family of ligases that form carbon-sulfur bonds. In the presence of coenzyme A, Mg and ATP, IPCL converts isophthalate to isophthalyl-CoA, AMP and pyrophosphate (PPi). The enzyme was specifically induced after anaerobic growth of S. aromaticivorans in a medium containing isophthalate as the sole carbon source. Therefore, IPCL exhibited high substrate specificity and affinity towards isophthalate. Only substrates that are structurally related to isophthalate, such as glutarate and 3-hydroxybenzoate, could be partially converted to the respective coenzyme A esters. Notably, no activity could be measured with substrates such as phthalate, terephthalate and benzoate. Acetyl-CoA or succinyl-CoA did not serve as CoA donors. The enzyme has a theoretical pI of 6.8 and exhibited optimal activity between pH 7.0 to 7.5. The optimal temperature was between 25 °C and 37 °C. Denaturation temperature (Tm) of IPCL was found to be at about 63 °C. The apparent K values for isophthalate, CoA, and ATP were 409 μM, 642 μM, and 3580 μM, respectively. Although S. aromaticivorans is a strictly anaerobic bacterium, the enzyme was found to be oxygen-insensitive and catalysed isophthalyl-CoA formation under both anoxic and oxic conditions.
CONCLUSION
We have successfully cloned the ipcl gene, expressed and characterized the corresponding IPCL enzyme, which plays a key role in isophthalate activation that initiates its activation and further degradation by S. aromaticivorans. Its biochemical characterization represents an important step in the elucidation of the complete degradation pathway of isophthalate.
Topics: Acetyl Coenzyme A; Adenosine Monophosphate; Adenosine Triphosphate; Anaerobiosis; Base Composition; Benzoates; Carbon; Carcinogens; Coenzyme A; Coenzyme A Ligases; Diphosphates; Environmental Pollutants; Escherichia coli; Glutarates; Hydroxybenzoates; Mutagens; Oxygen; Phenylacetates; Phthalic Acids; Phylogeny; Plastics; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Sulfur; Xenobiotics
PubMed: 36171563
DOI: 10.1186/s12866-022-02630-x -
Biosensors Nov 2021A novel, integrated experimental and modeling framework was applied to an inhibition-based bi-enzyme (IBE) electrochemical biosensor to detect acetylcholinesterase...
A novel, integrated experimental and modeling framework was applied to an inhibition-based bi-enzyme (IBE) electrochemical biosensor to detect acetylcholinesterase (AChE) inhibitors that may trigger neurological diseases. The biosensor was fabricated by co-immobilizing AChE and tyrosinase (Tyr) on the gold working electrode of a screen-printed electrode (SPE) array. The reaction chemistry included a redox-recycle amplification mechanism to improve the biosensor's current output and sensitivity. A mechanistic mathematical model of the biosensor was used to simulate key diffusion and reaction steps, including diffusion of AChE's reactant (phenylacetate) and inhibitor, the reaction kinetics of the two enzymes, and electrochemical reaction kinetics at the SPE's working electrode. The model was validated by showing that it could reproduce a steady-state biosensor current as a function of the inhibitor (PMSF) concentration and unsteady-state dynamics of the biosensor current following the addition of a reactant (phenylacetate) and inhibitor phenylmethylsulfonylfluoride). The model's utility for characterizing and optimizing biosensor performance was then demonstrated. It was used to calculate the sensitivity of the biosensor's current output and the redox-recycle amplification factor as a function of experimental variables. It was used to calculate dimensionless Damkohler numbers and current-control coefficients that indicated the degree to which individual diffusion and reaction steps limited the biosensor's output current. Finally, the model's utility in designing IBE biosensors and operating conditions that achieve specific performance criteria was discussed.
Topics: Acetylcholinesterase; Biosensing Techniques; Cholinesterase Inhibitors; Electrochemical Techniques; Electrodes; Enzymes, Immobilized; Monophenol Monooxygenase; Phenylacetates
PubMed: 34821676
DOI: 10.3390/bios11110459