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Drug Design, Development and Therapy 2021Attention-deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate and impairing levels of inattention, hyperactivity, or impulsivity, or a... (Review)
Review
Attention-deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate and impairing levels of inattention, hyperactivity, or impulsivity, or a combination of these characteristics. It is estimated to affect around 4% of adults worldwide. In the past few decades, prescriptions for ADHD drugs (psychostimulants and non-psychostimulants) have increased significantly. However, the efficacy and safety of adult ADHD medications remains controversial. Guanfacine extended-release (GXR) is a non-psychostimulant ADHD drug that is a selective α2A-adrenergic receptor agonist, first approved for treatment of adult ADHD in Japan in June 2019. Our aim was to provide an overview of GXR pharmacology and review the studies on efficacy and safety that have been conducted in adults with ADHD. The beneficial actions of guanfacine are thought to be attributed to the strengthening of prefrontal cortical network connections, which regulate attention, emotion, and behavior via the activity at post-synaptic α2A receptors. Current evidence of GXR efficacy and safety suggests that GXR is an effective monotherapy treatment option for adults with ADHD.
Topics: Adrenergic alpha-2 Receptor Agonists; Adult; Animals; Attention Deficit Disorder with Hyperactivity; Delayed-Action Preparations; Drug Design; Drug Development; Guanfacine; Humans
PubMed: 34007156
DOI: 10.2147/DDDT.S221126 -
Current Pharmaceutical Biotechnology 2023Attention Deficit Hyperactivity Disorder (ADHD) can be comorbid with depression, often leading to the prescription of both methylphenidate (MP) and selective serotonin...
BACKGROUND
Attention Deficit Hyperactivity Disorder (ADHD) can be comorbid with depression, often leading to the prescription of both methylphenidate (MP) and selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine (FLX). Moreover, these drugs are often misused as cognitive enhancers. This study examined the effects of chronic oral co-administration of MP and FLX on depressive- and anxiety-like behaviors.
METHODS
Adolescent rats received daily either water (control), MP, FLX, or the combination of MP plus FLX in their drinking water over the course of 4 weeks.
RESULTS
Data analysis shows a decrease in food consumption and body weight for rats exposed to FLX or the combination of MP and FLX. Sucrose consumption was significantly greater in FLX or MP+FLX groups compared to controls. FLX-treated rats showed no effect in the elevated plus maze (EPM; open arm time) and forced swim test (FST; latency to immobility). However, rats treated with the combination (MP+FLX) showed significant anxiolytic-like and anti-depressive-like behaviors (as measured by EPM and FST), as well as significant increases in overall activity (distance traveled in open field test). Finally, the combined MP+FLX treatment induced a decrease in anxiety and depressive- like behaviors significantly greater than the response from either of these drugs alone.
CONCLUSION
These behavioral results characterize the long-term effects of these drugs (orally administered) that are widely co-administered and co-misused and provide important insight into the potential neurobiological and neurochemical effects. Future research will determine the potential risks of the long-term use of MP and FLX together.
Topics: Rats; Animals; Fluoxetine; Methylphenidate; Selective Serotonin Reuptake Inhibitors; Attention Deficit Disorder with Hyperactivity; Anxiety
PubMed: 36306463
DOI: 10.2174/1389201024666221028092342 -
Addiction Biology Mar 2022Evidence for acute amphetamine effects on behavioural impulsivity in healthy populations remains elusive and, at times, mixed. This review collates and reviews the...
Evidence for acute amphetamine effects on behavioural impulsivity in healthy populations remains elusive and, at times, mixed. This review collates and reviews the clinical literature on the acute effects of amphetamines on measures of behavioural impulsivity in healthy adults. Randomised and placebo-controlled clinical trials that assessed behavioural impulsivity following the administration of an acute dose of amphetamine or a related psychostimulant (including amphetamine analogues and methylphenidate) were eligible for inclusion. The EBSCOHost, SCOPUS, PsychNet, Web of Science and ProQuest databases were searched from inception to 26 April 2021. Study selection, data extraction and the Cochrane risk of bias assessments were conducted by two independent reviewers. Reporting follows PRISMA guidelines, and the review was registered a priori on the PROSPERO database (Registration No: CRD42021249861). A total of 20 studies were included, comprising a total of 737 participants. Overall, results indicate that low-moderate doses of amphetamine and related psychostimulants may improve (i.e., reduce) impulsive responding without compromising performance, reflecting enhanced inhibitory control of behaviour. These effects are mild and appear most pronounced in individuals with high baseline impulsivity. This review highlights the need for greater consistency in behavioural task selection and future high-quality and well-designed studies to address current concerns around growing prescription psychostimulant use and misuse.
Topics: Adult; Amphetamine; Central Nervous System Stimulants; Humans; Impulsive Behavior; Methylphenidate
PubMed: 35229937
DOI: 10.1111/adb.13128 -
Journal of the American Chemical Society Oct 2022With the large number of Pd(II)-catalyzed C-H activation reactions of native substrates developed in the past decade, the development of catalysts to enable the use of...
With the large number of Pd(II)-catalyzed C-H activation reactions of native substrates developed in the past decade, the development of catalysts to enable the use of green oxidants under safe and practical conditions has become an increasingly important challenge. Notably, the compatibility of Pd(II) catalysts with sustainable aqueous HO has been a long-standing challenge in catalysis including Wacker-type oxidations. We report herein a bifunctional bidentate carboxyl-pyridone (CarboxPyridone) ligand that enables room-temperature Pd-catalyzed C-H hydroxylation of a broad range of benzoic and phenylacetic acids with an industry-compatible oxidant, aqueous hydrogen peroxide (35% HO). The scalability of this methodology is demonstrated by a 1000 mmol scale reaction of ibuprofen (206 g) using only a 1 mol % Pd catalyst loading. The utility of this protocol is further illustrated through derivatization of the products and synthesis of polyfluorinated natural product coumestan and pterocarpene from phenol intermediates prepared using this methodology.
Topics: Biological Products; Catalysis; Hydrogen Peroxide; Hydroxylation; Ibuprofen; Ligands; Oxidants; Palladium; Phenols; Phenylacetates; Pyridones; Temperature; Water
PubMed: 36137252
DOI: 10.1021/jacs.2c08332 -
Molecules (Basel, Switzerland) Jul 2023Diclofenac is the most prescribed nonsteroidal anti-inflammatory drug worldwide and is used to relieve pain and inflammation in inflammatory arthritis. Diclofenac is...
Diclofenac is the most prescribed nonsteroidal anti-inflammatory drug worldwide and is used to relieve pain and inflammation in inflammatory arthritis. Diclofenac is associated with serious adverse effects, even in regular-dose regimens. Drug delivery systems can overcome this issue by reducing adverse effects and optimizing their efficacy. This study evaluated the activity of lipid-core nanocapsules loaded with diclofenac (DIC-LNCs) in an experimental model of adjuvant-induced arthritis. The diclofenac nanoformulation was obtained via self-assembly. A stereological analysis approach was applied for the morphological quantification of the volume, density, and cellular profile count of the metatarsophalangeal joints of rats. Proinflammatory cytokines and biochemical profiles were also obtained. Our results showed that the diclofenac nanocapsule DIC-LNCs were able to reduce arthritis compared with the control group and the DIC group. DIC-LNCs efficiently reduced proinflammatory cytokines, C-reactive protein, and xanthine oxidase levels. Additionally, DIC-LNCs reduced the loss of synoviocytes and chondrocytes compared with the DIC ( < 0.05) and control groups ( < 0.05). These data suggest that DIC-LNCs have anti-arthritic activity and preserve joint components, making them promising for clinical use.
Topics: Rats; Animals; Diclofenac; Nanocapsules; Arthritis, Experimental; Lipids; Cytokines
PubMed: 37446881
DOI: 10.3390/molecules28135219 -
The Lancet. Child & Adolescent Health Jun 2020
Topics: Attention Deficit Disorder with Hyperactivity; Epilepsy; Humans; Methylphenidate; Seizures
PubMed: 32450119
DOI: 10.1016/S2352-4642(20)30136-X -
Journal of Hazardous Materials Mar 2022Single and multilayered TiCT MXene (referred to as SLM and MLM in this study, respectively) was applied as catalysts in the ultrasonic (US) process to treat selected...
Single and multilayered TiCT MXene (referred to as SLM and MLM in this study, respectively) was applied as catalysts in the ultrasonic (US) process to treat selected pharmaceutical compounds including diclofenac and verapamil (VRP). Due to solid surface, elemental composition, and functional groups of TiCT MXene, the free OH• production was increased by 48.8% for the US treatment with SLM and 59.8% for the US treatment with MLM compared with the US-only treatment. Additionally, adsorption affected the performance during the US treatment in the presence of the catalyst. Thus, the US treatment in the presence of TiCT MXene had an enhanced performance not only because of increased oxidation but also because of adsorption, particularly between positively charged VRP and negatively charged TiCT MXene. Moreover, although the degradation of the performance was higher for SLM (85.1%) than for MLM (81.8%), by improving the dispersion and reducing the size via sonication, the US treatment in the presence of MLM showed the highest synergy effect. In other words, the US treatment in the presence of MLM showed higher performance than the simple sum of oxidation and adsorption. These findings confirm that the US treatment in the presence of MLM may be a promising technology to treat various pharmaceuticals as a more degradable, strongly reusable, and less toxic process.
Topics: Adsorption; Diclofenac; Oxidation-Reduction; Titanium; Verapamil
PubMed: 34953257
DOI: 10.1016/j.jhazmat.2021.128120 -
Journal of the American Academy of... Jan 2023The combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with attention-deficit/hyperactivity disorder (ADHD). This study investigated the neural mechanisms underlying medication effects using cortical source analysis of electroencephalography (EEG) data.
METHOD
A total of 172 children with ADHD (aged 7-14; 118 boys) completed an 8-week randomized, double-blind, comparative study with 3 treatment arms: d-methylphenidate, guanfacine, or their combination. EEG modulations of brain oscillations at baseline and end point were measured during a spatial working memory task from cortical sources localized within the anterior cingulate (midfrontal) and primary visual cortex (midoccipital), based on previously reported ADHD and control differences. Linear mixed models examined treatment effects on EEG and performance measures.
RESULTS
Combined treatment decreased midoccipital EEG power across most frequency bands and task phases. Several midoccipital EEG measures also showed significantly greater changes with combined treatment than with monotherapies. D-methylphenidate significantly increased midoccipital theta during retrieval, while guanfacine produced only trend-level reductions in midoccipital alpha during maintenance and retrieval. Task accuracy improved with combined treatment, was unchanged with d-methylphenidate, and worsened with guanfacine. Treatment-related changes in midoccipital power correlated with improvement in ADHD severity.
CONCLUSION
These findings show that combined treatment ameliorates midoccipital neural activity associated with treatment-related behavioral improvements and previously implicated in visuo-attentional deficits in ADHD. Both monotherapies had limited effects on EEG measures, with guanfacine further showing detrimental effects on performance. The identified midoccipital EEG profile may aid future treatment monitoring for children with ADHD.
CLINICAL TRIAL REGISTRATION INFORMATION
Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); https://clinicaltrials.gov/; NCT00429273.
DIVERSITY & INCLUSION STATEMENT
We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. We actively worked to promote sex and gender balance in our author group.
Topics: Male; Child; Female; Humans; Attention Deficit Disorder with Hyperactivity; Guanfacine; Methylphenidate; Memory, Short-Term; Electroencephalography; Central Nervous System Stimulants
PubMed: 35963558
DOI: 10.1016/j.jaac.2022.06.017 -
Scientific Reports Sep 2023Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the homogentisate 1,2-dioxygenase (HGD) gene. This leads to a...
Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder caused by pathogenic variants in the homogentisate 1,2-dioxygenase (HGD) gene. This leads to a deficient HGD enzyme with the consequent accumulation of homogentisic acid (HGA) in different tissues causing complications in various organs, particularly in joints, heart valves and kidneys. The genetic basis of AKU in Egypt is completely unknown. We evaluated the clinical and genetic spectrum of six pediatric and adolescents AKU patients from four unrelated Egyptian families. All probands had a high level of HGA in urine by qualitative GC/MS before genetic confirmation by Sanger sequencing. Recruited AKU patients were four females and two males (median age 13 years). We identified four different pathogenic missense variants within HGD gene. Detected variants included a novel variant c.1079G > T;p.(Gly360Val) and three recurrent variants; c.1078G > C;p.(Gly360Arg), c.808G > A;p.(Gly270Arg) and c.473C > T;p.(Pro158Leu). All identified variants were properly segregating in the four families consistent with autosomal recessive inheritance. In this study, we reported the phenotypic and genotypic spectrum of alkaptonuria for the first time in Egypt. We further enriched the HGD-variant database with another novel pathogenic variant. The recent availability of nitisinone may promote the need for genetic confirmation at younger ages to start therapy earlier and prevent serious complications.
Topics: Adolescent; Female; Male; Humans; Child; Alkaptonuria; Egypt; Homogentisate 1,2-Dioxygenase; Phenylacetates; Homogentisic Acid; Dioxygenases
PubMed: 37658095
DOI: 10.1038/s41598-023-41200-7 -
Translational Psychiatry Dec 2022Methylphenidate (MPH) is the recommended first-line treatment for attention-deficit/hyperactivity disorder (ADHD). While MPH's mechanism of action as a dopamine and... (Randomized Controlled Trial)
Randomized Controlled Trial
Methylphenidate (MPH) is the recommended first-line treatment for attention-deficit/hyperactivity disorder (ADHD). While MPH's mechanism of action as a dopamine and noradrenaline transporter blocker is well known, how this translates to ADHD-related symptom mitigation is still unclear. As functional connectivity is reliably altered in ADHD, with recent literature indicating dysfunctional connectivity dynamics as well, one possible mechanism is through altering brain network dynamics. In a double-blind, placebo-controlled MPH crossover trial, 19 medication-naïve children with ADHD underwent two functional MRI scanning sessions (one on MPH and one on placebo) that included a resting state scan and two inhibitory control tasks; 27 typically developing (TD) children completed the same protocol without medication. Network control theory, which quantifies how brain activity reacts to system inputs based on underlying connectivity, was used to assess differences in average and modal functional controllability during rest and both tasks between TD children and children with ADHD (on and off MPH) and between children with ADHD on and off MPH. Children with ADHD on placebo exhibited higher average controllability and lower modal controllability of attention, reward, and somatomotor networks than TD children. Children with ADHD on MPH were statistically indistinguishable from TD children on almost all controllability metrics. These findings suggest that MPH may stabilize functional network dynamics in children with ADHD, both reducing reactivity of brain organization and making it easier to achieve brain states necessary for cognitively demanding tasks.
Topics: Child; Humans; Attention Deficit Disorder with Hyperactivity; Brain; Central Nervous System Stimulants; Double-Blind Method; Magnetic Resonance Imaging; Methylphenidate; Treatment Outcome; Cross-Over Studies
PubMed: 36528602
DOI: 10.1038/s41398-022-02283-4