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Journal of Child and Adolescent... Mar 2023Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and Tolerability of Serdexmethylphenidate/Dexmethylphenidate Capsules in Children with Attention-Deficit/Hyperactivity Disorder: A 12-Month, Open-Label Safety Study.
Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A pivotal double-blind (DB) study of children aged 6-12 years with ADHD demonstrated efficacy for ADHD with good tolerability. In this study, we assessed the safety and tolerability of daily oral SDX/d-MPH for up to 1 year in children with ADHD. This was a dose-optimized, open-label safety study with SDX/d-MPH in children aged 6-12 years with ADHD that included subjects who successfully completed the DB study (rollover) and new subjects. The study consisted of a 30-day screening phase, a dose optimization phase for new subjects only, a 360-day treatment phase, and follow-up. Adverse events (AEs) were assessed from the first day of SDX/d-MPH administration to the end of the study. During the treatment phase, ADHD Rating Scale-5 (ADHD-RS-5) and Clinical Global Impressions-Severity (CGI-S) scale assessments were used to evaluate ADHD severity. Of the 282 subjects enrolled (70 rollover; 212 new), 28 discontinued treatment in the dose optimization phase and 254 entered the treatment phase. By study completion, 127 had discontinued and 155 had completed the study. The treatment-phase safety population included all enrolled subjects who received ≥1 dose of study drug and had ≥1 postdose safety assessment. Of 238 subjects assessed in the treatment-phase safety population, 143 (60.1%) had ≥1 treatment-emergent adverse events (TEAEs), and 36 (15.1%), 95 (39.9%), and 12 (5.0%) had mild, moderate, or severe TEAEs, respectively. The most common TEAEs were decreased appetite (18.5%), upper respiratory tract infection (9.7%), nasopharyngitis (8.0%), decreased weight (7.6%), and irritability (6.7%). There were no clinically meaningful trends in electrocardiograms, cardiac events, or blood pressure events, and none led to discontinuation. Two subjects had eight serious AEs that were unrelated to treatment. There were overall reductions in ADHD symptoms and severity as assessed by ADHD-RS-5 and CGI-S during the treatment phase. In this 1-year study, SDX/d-MPH was found to be safe and well tolerated and comparable with other methylphenidate products, with no unexpected safety findings. SDX/d-MPH also showed sustained efficacy during the 1-year treatment period. ClinicalTrials.gov identifier: NCT03460652.
Topics: Humans; Child; Attention Deficit Disorder with Hyperactivity; Dexmethylphenidate Hydrochloride; Central Nervous System Stimulants; Treatment Outcome; Delayed-Action Preparations; Methylphenidate; Double-Blind Method; Dose-Response Relationship, Drug
PubMed: 36809150
DOI: 10.1089/cap.2022.0076 -
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 -
Journal of Veterinary Pharmacology and... Jul 2022Robenacoxib is a veterinary-approved non-steroidal anti-inflammatory drug (NSAID) of the coxib group. It possesses anti-hyperalgesic, anti-inflammatory and anti-pyretic... (Review)
Review
Robenacoxib is a veterinary-approved non-steroidal anti-inflammatory drug (NSAID) of the coxib group. It possesses anti-hyperalgesic, anti-inflammatory and anti-pyretic properties. Robenacoxib inhibits the cyclooxygenase (COX)-2 isoform of COX selectively (in vitro IC ratios COX-1:COX-2, 129:1 in dogs, 32:1 in cats). At registered dosages (2 mg/kg subcutaneously in dogs and cats, 1-4 mg/kg orally in dogs and 1-2.4 mg/kg orally in cats), robenacoxib produces significant inhibition of COX-2 whilst sparing COX-1. The pharmacokinetic (PK) profile of robenacoxib is characterized by a high degree of binding to plasma proteins (>98%) and moderate volume of distribution (at steady state, 240 ml/kg in dogs and 190 ml/kg in cats). In consequence, the terminal half-life in blood (<2 h) is short, despite moderate body clearance (0.81 L/kg/h) in dogs and low clearance (0.44 L/kg/h) in cats. Excretion is principally in the bile (65% in dogs and 72% in cats). Robenacoxib concentrates in inflamed tissues, and clinical efficacy is achieved with once-daily dosing, despite the short blood terminal half-life. In dogs, no relevant breed differences in robenacoxib PK have been detected. Robenacoxib has a wide safety margin; in healthy laboratory animals daily oral doses 20-fold (dog, 1 month), eight-fold (cat, 6 weeks) and five-fold (dog, 6 months) higher than recommended clinical doses were well tolerated. Clinical efficacy and safety have been demonstrated in orthopaedic and soft tissue surgery, and in musculoskeletal disorders in dogs and cats.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cat Diseases; Cats; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Diphenylamine; Dog Diseases; Dogs; Phenylacetates
PubMed: 35460083
DOI: 10.1111/jvp.13052 -
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 -
Atherosclerosis Nov 2023Since plasma metabolites can modulate blood pressure (BP) and vary between men and women, we examined sex differences in plasma metabolite profiles associated with BP...
BACKGROUND AND AIMS
Since plasma metabolites can modulate blood pressure (BP) and vary between men and women, we examined sex differences in plasma metabolite profiles associated with BP and sympathicovagal balance. Our secondary aim was to investigate associations between gut microbiota composition and plasma metabolites predictive of BP and heart rate variability (HRV).
METHODS
From the HELIUS cohort, we included 196 women and 173 men. Office systolic BP and diastolic BP were recorded, and heart rate variability (HRV) and baroreceptor sensitivity (BRS) were calculated using finger photoplethysmography. Plasma metabolomics was measured using untargeted LC-MS/MS. Gut microbiota composition was determined using 16S sequencing. We used machine learning models to predict BP and HRV from metabolite profiles, and to predict metabolite levels from gut microbiota composition.
RESULTS
In women, best predicting metabolites for systolic BP included dihomo-lineoylcarnitine, 4-hydroxyphenylacetateglutamine and vanillactate. In men, top predictors included sphingomyelins, N-formylmethionine and conjugated bile acids. Best predictors for HRV in men included phenylacetate and gentisate, which were associated with lower HRV in men but not in women. Several of these metabolites were associated with gut microbiota composition, including phenylacetate, multiple sphingomyelins and gentisate.
CONCLUSIONS
Plasma metabolite profiles are associated with BP in a sex-specific manner. Catecholamine derivatives were more important predictors for BP in women, while sphingomyelins were more important in men. Several metabolites were associated with gut microbiota composition, providing potential targets for intervention.
Topics: Humans; Male; Female; Blood Pressure; Heart Rate; Sphingomyelins; Sex Characteristics; Chromatography, Liquid; Gentisates; Tandem Mass Spectrometry; Phenylacetates
PubMed: 37286456
DOI: 10.1016/j.atherosclerosis.2023.05.016 -
Proceedings of the National Academy of... Dec 2023The amplitude of low-frequency fluctuations (ALFF) and global functional connectivity density (gFCD) are fMRI (Functional MRI) metrics widely used to assess resting...
The amplitude of low-frequency fluctuations (ALFF) and global functional connectivity density (gFCD) are fMRI (Functional MRI) metrics widely used to assess resting brain function. However, their differential sensitivity to stimulant-induced dopamine (DA) increases, including the rate of DA rise and the relationship between them, have not been investigated. Here we used, simultaneous PET-fMRI to examine the association between dynamic changes in striatal DA and brain activity as assessed by ALFF and gFCD, following placebo, intravenous (IV), or oral methylphenidate (MP) administration, using a within-subject double-blind placebo-controlled design. In putamen, MP significantly reduced D receptor availability and strongly reduced ALFF and increased gFCD in the brain for IV-MP (Cohen's d > 1.6) but less so for oral-MP (Cohen's d < 0.6). Enhanced gFCD was associated with both the level and the rate of striatal DA increases, whereas decreased ALFF was only associated with the level of DA increases. These findings suggest distinct representations of neurovascular activation with ALFF and gFCD by stimulant-induced DA increases with differential sensitivity to the rate and the level of DA increases. We also observed an inverse association between gFCD and ALFF that was markedly enhanced during IV-MP, which could reflect an increased contribution from MP's vasoactive properties.
Topics: Brain; Dopamine; Magnetic Resonance Imaging; Methylphenidate; Double-Blind Method
PubMed: 38109535
DOI: 10.1073/pnas.2314596120 -
Forensic Toxicology Jul 2023Methylphenidate analogs appeared on the drug market during the last years. Its analogs contain two chiral centers and, thus, have potential varying configurations (i.e.,...
PURPOSE
Methylphenidate analogs appeared on the drug market during the last years. Its analogs contain two chiral centers and, thus, have potential varying configurations (i.e., threo and erythro forms). This study presents the analytical characterization of 4-fluoroethylphenidate (4-FEP) and its differentiation between threo- and erythro-4-FEP.
METHODS
Analysis of the samples included high-performance liquid chromatography (HPLC), gas chromatography-electron ionization-mass spectrometry (GC-EI-MS), high-resolution mass spectrometry (HRMS) analyses, nuclear magnetic resonance (NMR) spectroscopy and X-ray crystal structure analysis.
RESULTS
NMR spectroscopic investigations confirmed the differences between threo- and erythro-4-FEP, and demonstrated that both isomers could be separated using HPLC and GC methods. Two samples obtained from one vendor in 2019 consisted of threo-4-FEP, whereas the other two samples obtained from a different vendor in 2020 consisted of a mixture of threo- and erythro-4-FEP.
CONCLUSIONS
Several analytical approaches including HPLC, GC-EI-MS, HRMS analyses, NMR spectroscopy and X-ray crystal structure analysis enabled the unambiguous identification of threo- and erythro-4-FEP. The analytical data presented in this article will be useful for identifying threo- and erythro-4-FEP included in illicit products.
Topics: Gas Chromatography-Mass Spectrometry; Methylphenidate; Mass Spectrometry; Chromatography, High Pressure Liquid; Isomerism
PubMed: 37097346
DOI: 10.1007/s11419-023-00664-y -
Journal of the American Academy of... Nov 2021Although instrumental learning deficits are, among other deficits, assumed to contribute to attention-deficit/hyperactivity disorder (ADHD), no comprehensive systematic...
OBJECTIVE
Although instrumental learning deficits are, among other deficits, assumed to contribute to attention-deficit/hyperactivity disorder (ADHD), no comprehensive systematic review of instrumental learning deficits in ADHD exists. This review examines differences between ADHD and typically developing (TD) children in basic instrumental learning and the effects of reinforcement form, magnitude, schedule, and complexity, as well as effects of medication, on instrumental learning in children with ADHD.
METHOD
A systematic search of PubMed, PsyINFO, CINAHL, EMBASE+EMBASE CLASSIC, ERIC, and Web of Science was conducted for articles up to March 16, 2020. Experimental studies comparing instrumental learning between groups (ADHD versus TD) or a manipulation of reinforcement/medication within an ADHD sample were included. Quality of studies was assessed with an adapted version of the Hombrados and Waddington criteria to assess risk of bias in (quasi-) experimental studies.
RESULTS
A total of 19 studies from among 3,384 non-duplicate screened articles were included. No difference in basic instrumental learning was found between children with ADHD and TD children, nor effects of form or magnitude of reinforcement. Results regarding reinforcement schedule and reversal learning were mixed, but children with ADHD seemed to show deficits in conditional discrimination learning compared to TD children. Methylphenidate improved instrumental learning in children with ADHD. Quality assessment showed poor quality of studies with respect to sample sizes and outcome and missing data reporting.
CONCLUSION
The review identified very few and highly heterogenous studies, with inconsistent findings. No clear deficit was found in instrumental learning under laboratory conditions. Children with ADHD do show deficits in complex forms of learning, that is, conditional discrimination learning. Clearly more research is needed, using more similar task designs and manipulations.
Topics: Attention Deficit Disorder with Hyperactivity; Child; Conditioning, Operant; Humans; Learning; Methylphenidate
PubMed: 33862167
DOI: 10.1016/j.jaac.2021.03.009 -
Human Resources For Health Jan 2023Methylphenidate (MPH) and other stimulants may be misused, mainly as cognitive enhancers and recreational drugs. Data regarding misuse among medical residents are...
BACKGROUND
Methylphenidate (MPH) and other stimulants may be misused, mainly as cognitive enhancers and recreational drugs. Data regarding misuse among medical residents are scarce. This study aimed to evaluate the prevalence of and main reasons for methylphenidate (MPH) use and misuse among Israeli medical residents.
METHODS
In this cross-sectional study, we sent an online questionnaire to medical residents who had completed their first residency exam and specialists with up to 2 years of experience. We asked about the use of MPH before and during residency and attitudes toward the use of MPH as a cognitive enhancer. We also added the Adult ADHD Self-Report Scale (ASRS) questionnaire, a validated tool used to screen for the presence of attention deficit hyperactivity disorder (ADHD). Users and misusers were classified based on self-report of use and formal ADHD diagnosis. Logistic regression analysis was used to evaluate factors associated with MPH misuse.
RESULTS
From March 2021 to August 2021, 370 physicians responded to our questionnaire (response rate 26.4%). Twenty-eight met the exclusion criteria and were not included. The respondents' average age was 36.5 years. Women comprised 63.5% of the respondents. Of the participants, 16.4% were classified as users and 35.1% as misusers. The prevalence of misusers was 45.6% among surgery and OB/GYN physicians, 39.4% among pediatricians and internists, and 24% among family physicians (P < 0.001). Misusers had a more liberal approach than others to MPH use as a cognitive enhancer. Factors associated with misuse of MPH included not being a native-born Israeli (OR-1.99, 95% CI 1.08, 3.67) and type of residency (OR-2.33, 95% CI 1.22, 4.44 and OR-4.08, 95% CI 2.06, 8.07 for pediatrics and internal medicine and surgery, respectively).
CONCLUSION
Very high levels of MPH misuse during residency may be related to stress, long working hours, night shifts, and the academic burden of the residency period. We believe that our findings should be considered by healthcare policymakers as they make decisions regarding the conditions of medical residencies. The use of MPH as a cognitive enhancer should be further studied and discussed.
Topics: Adult; Female; Humans; Child; Male; Methylphenidate; Cross-Sectional Studies; Israel; Internship and Residency; Nootropic Agents; Physicians, Family
PubMed: 36721145
DOI: 10.1186/s12960-023-00792-x