-
The American Journal of Clinical... Apr 2024Predicting response to exclusive enteral nutrition (EEN) in active Crohn's disease (CD) could lead to therapy personalization and pretreatment optimization.
BACKGROUND
Predicting response to exclusive enteral nutrition (EEN) in active Crohn's disease (CD) could lead to therapy personalization and pretreatment optimization.
OBJECTIVES
This study aimed to explore the ability of pretreatment parameters to predict fecal calprotectin (FCal) levels at EEN completion in a prospective study in children with CD.
METHODS
In children with active CD, clinical parameters, dietary intake, cytokines, inflammation-related blood proteomics, and diet-related metabolites, metabolomics and microbiota in feces, were measured before initiation of 8 wk of EEN. Prediction of FCal levels at EEN completion was performed using machine learning. Data are presented with medians (IQR).
RESULTS
Of 37 patients recruited, 15 responded (FCal < 250 μg/g) to EEN (responders) and 22 did not (nonresponders). Clinical and immunological parameters were not associated with response to EEN. Responders had lesser (μmol/g) butyrate [responders: 13.2 (8.63-18.4) compared with nonresponders: 22.3 (12.0-32.0); P = 0.03], acetate [responders: 49.9 (46.4-68.4) compared with nonresponders: 70.4 (57.0-95.5); P = 0.027], phenylacetate [responders: 0.175 (0.013-0.611) compared with nonresponders: 0.943 (0.438-1.35); P = 0.021], and a higher microbiota richness [315 (269-347) compared with nonresponders: 243 (205-297); P = 0.015] in feces than nonresponders. Responders consumed (portions/1000 kcal/d) more confectionery products [responders: 0.55 (0.38-0.72) compared with nonresponders: 0.19 (0.01-0.38); P = 0.045]. A multicomponent model using fecal parameters, dietary data, and clinical and immunological parameters predicted response to EEN with 78% accuracy (sensitivity: 80%; specificity: 77%; positive predictive value: 71%; negative predictive value: 85%). Higher taxon abundance from Ruminococcaceae, Lachnospiraceae, and Bacteroides and phenylacetate, butyrate, and acetate were the most influential variables in predicting lack of response to EEN.
CONCLUSIONS
We identify microbial signals and diet-related metabolites in feces, which could comprise targets for pretreatment optimization and personalized nutritional therapy in pediatric CD.
Topics: Child; Humans; Crohn Disease; Enteral Nutrition; Prospective Studies; Remission Induction; Microbiota; Metabolome; Butyrates; Acetates; Phenylacetates
PubMed: 38569785
DOI: 10.1016/j.ajcnut.2023.12.027 -
Journal of Psychiatric Research Aug 2022Iron and zinc have been associated with attention-deficit/hyperactivity disorder (ADHD), executive functioning, and response to methylphenidate, given their link with... (Randomized Controlled Trial)
Randomized Controlled Trial
Iron and zinc have been associated with attention-deficit/hyperactivity disorder (ADHD), executive functioning, and response to methylphenidate, given their link with the dopaminergic system. This study aimed to investigate the effect of withdrawing methylphenidate after long-term treatment on serum levels of ferritin and zinc; and if baseline (pre-discontinuation) serum levels of these nutritional markers moderated the effects of withdrawing methylphenidate on ADHD and oppositional defiant disorder (ODD) symptoms, and working memory. Blood samples were collected from 63 children and adolescents who participated in a randomized, placebo-controlled methylphenidate discontinuation study. They were assigned to either seven weeks of continued treatment with methylphenidate or to gradual withdrawal to placebo. With mixed models for repeated measures we (i) compared changes in ferritin and zinc serum levels between both groups, and (ii) investigated moderating effects of ferritin and zinc on the effects of discontinuation on ADHD and ODD symptoms, and working memory. We additionally explored correlations of baseline and change serum levels with respective symptom scores. Withdrawing methylphenidate led to a decrease in ferritin levels. Higher baseline ferritin was associated with a larger increase (i.e., worsening) of teacher-rated hyperactivity-impulsivity and ODD symptoms after withdrawal; and higher baseline zinc with a larger increase in number of errors on the working memory task after withdrawal. Serum levels did not correlate with ADHD and ODD symptoms. Our preliminary results suggest that ferritin and zinc may be potential biomarkers for the effectiveness of long-term treatment with methylphenidate.
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Ferritins; Humans; Methylphenidate; Zinc
PubMed: 35714551
DOI: 10.1016/j.jpsychires.2022.06.014 -
Journal of Child and Adolescent... May 2023Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A...
Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A 12-month, open-label safety study with SDX/d-MPH in children with ADHD showed that SDX/d-MPH was well tolerated and comparable with other methylphenidate products. In this analysis of the 12-month study, the objective was to characterize the effect of SDX/d-MPH on growth in children with ADHD over 12 months. This was a analysis of a dose-optimized, open-label, phase 3 safety study of SDX/d-MPH in children aged 6-12 years with ADHD (NCT03460652). Weight and height -score analyses were conducted. -score change from baseline was calculated based on the baseline values for the subjects remaining in the study at the observation time point. Subjects ( = 238) from the treatment-phase safety population included all enrolled subjects who received ≥1 dose of study drug and had ≥1 postdose safety assessment. During treatment, the mean weight and height -scores decreased over time from their respective baselines. At the 12-month time point, mean (standard deviation [SD]) -score changes from baseline for weight and height for the subjects remaining in the study were -0.20 (0.50) and -0.21 (0.39), respectively; however, these mean changes in Z-scores were not clinically significant (change <0.5 SD). Long-term treatment with SDX/d-MPH was associated with modest reductions in expected weight and lower-than-expected increases in height: effects that plateaued or diminished later in treatment. The overall effects of SDX/d-MPH on growth velocity (the change in weight and height from one time point to the next) were minimal, and the range of changes was not considered clinically significant. ClinicalTrials.gov identifier: NCT03460652.
Topics: Child; Humans; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Double-Blind Method; Methylphenidate; Treatment Outcome
PubMed: 37204277
DOI: 10.1089/cap.2023.0012 -
Developmental Cognitive Neuroscience Oct 2023Children with attention-deficit/hyperactivity disorder (ADHD) exhibit impairments in response inhibition. These impairments are ameliorated by modulating dopamine (DA)... (Randomized Controlled Trial)
Randomized Controlled Trial
Children with attention-deficit/hyperactivity disorder (ADHD) exhibit impairments in response inhibition. These impairments are ameliorated by modulating dopamine (DA) via the administration of rewards or stimulant medication like methylphenidate (MPH). It is currently unclear whether intrinsic DA availability impacts these effects of dopaminergic modulation on response inhibition. Thus, we estimated intrinsic DA availability using magnetic resonance-based assessments of basal ganglia and thalamic tissue iron in 36 medication-naïve children with ADHD and 29 typically developing (TD) children (8-12 y) who underwent fMRI scans and completed standard and rewarded go/no-go tasks. Children with ADHD additionally participated in a double-blind, randomized, placebo-controlled, crossover MPH challenge. Using linear regressions covarying for age and sex, we determined there were no group differences in brain tissue iron. We additionally found that higher putamen tissue iron was associated with worse response inhibition performance in all participants. Crucially, we observed that higher putamen and caudate tissue iron was associated with greater responsivity to MPH, as measured by improved task performance, in participants with ADHD. These results begin to clarify the role of subcortical brain tissue iron, a measure associated with intrinsic DA availability, in the cognitive effects of reward- and MPH-related dopaminergic modulation in children with ADHD and TD children.
Topics: Humans; Child; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Dopamine; Neurophysiology; Methylphenidate; Brain; Cognition
PubMed: 37453207
DOI: 10.1016/j.dcn.2023.101274 -
Drug Development and Industrial Pharmacy Apr 2021The possible application of a hot-melt ram extrusion printing to the preparation of diclofenac orodispersible films (ODF) made of maltodextrin was studied focusing the...
OBJECTIVE
The possible application of a hot-melt ram extrusion printing to the preparation of diclofenac orodispersible films (ODF) made of maltodextrin was studied focusing the attention on the effects of taste-masking agents (i.e. namely mint, licorice-mint, and sucralose) and an opacifier (titanium dioxide [TiO]).
SIGNIFICANCE
This is a proof-of-concept of the feasibility to print ODF loaded with a thermosensitive drug substance by hot-melt technologies.
METHODS
Diclofenac sodium (DNa) ODF made of maltodextrin (dextrose equivalent (DE) = 6 ) plasticized with glycerol were prepared by hot-melt extrusion printing. ODF were characterized for disintegration time, drug content, and solid state, dissolution in deionized water and simulated salivary fluid at pH 5.7, tensile, and adhesive properties. Moreover, the stability of ODF was assessed in accelerated conditions over six months.
RESULTS
After the preparation, no variation in drug solid state was evident and the formation of impurity A of DNa was detected, even if it remained below the Pharmacopoeia (Ph. Eur.) limits (< 0.2%). Only the addition of DNa significantly improved the ODF tensile properties: the tensile strength increased from 0.17 ± 0.03 MPa (placebo ODF) to 2.21 ± 0.54 MPa ( ≤ 0.03). All ODF disintegrated in about 1 min, and the t was lower than 3 min. TiO reduced the static and dynamic peel forces ( ≤ 0.006) favoring the ODF detachment from the primary packaging material. During the accelerated stability study, ODF were easy to handle without fracture; the drug content, impurity A, and dissolution profiles remained superimposable.
CONCLUSION
Hot-melt printing can be suitable to prepare palatable ODF loaded with bitter thermosensitive drugs.
Topics: Child; Diclofenac; Drug Compounding; Humans; Pediatrics; Printing, Three-Dimensional; Solubility; Tensile Strength
PubMed: 33826438
DOI: 10.1080/03639045.2021.1908335 -
PeerJ 2022T-37 can infect grapes and other fruit trees and cause root cancer. Given the pollution and damage of chemical agents to the environment, the use of biological control...
BACKGROUND
T-37 can infect grapes and other fruit trees and cause root cancer. Given the pollution and damage of chemical agents to the environment, the use of biological control has become an important area of focus. L2 is a beneficial biocontrol strain isolated and identified in the laboratory, which has a good antibacterial effect on a variety of plant pathogens. The antibacterial metabolites of L2 were separated and purified to obtain a bioactive compound phenylacetic acid (PAA).
METHODS
The potential antibacterial mechanism of PAA against T-37 strain was determined by relative conductivity, leakage of nucleic acids, proteins, and soluble total sugars, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and reactive oxygen species (ROS).
RESULTS
PAA showed good antibacterial activity against strain T-37 with IC of 0.8038 mg/mL. Our data suggested that after treatment with PAA, the relative conductivity, nucleic acid, protein, and total soluble sugar of T-37 were increased significantly compared with the chloramphenicol treatment group and the negative treatment group. The total protein synthesis of T-37 cells was inhibited, the consumption of phosphorus decreased with the increase of incubation time, and the content of ROS was significantly higher than that in the negative treatment group. Meanwhile, the activity of two key enzymes (MDH and SDH) involved in the tricarboxylic acid cycle (TCA cycle) decreased. In addition, T-37 cells were found to be damaged by scanning electron microscopy observation. Our results showed that PAA can destroy cell membrane integrity, damage cell structures, affect cell metabolism, and inhibit protein synthesis to exert an antibacterial effect.
CONCLUSIONS
We concluded that the mechanism of action of the PAA against strain T-37 might be described as PAA exerting antibacterial activity by affecting cell metabolism, inhibiting protein synthesis, and destroying cell membrane integrity and cell ultrastructure. Therefore, PAA has a promising application prospect in the prevention and treatment of root cancer disease caused by .
Topics: Agrobacterium tumefaciens; Bacillus megaterium; Reactive Oxygen Species; Solanum lycopersicum; Anti-Bacterial Agents; Phenylacetates
PubMed: 36389424
DOI: 10.7717/peerj.14304 -
Physiological Research Dec 2023Methylphenidate is a psychostimulant that increases dopamine and noradrenaline levels. Recent studies have shown that methylphenidate potentiates the effect of morphine...
Methylphenidate is a psychostimulant that increases dopamine and noradrenaline levels. Recent studies have shown that methylphenidate potentiates the effect of morphine and together suppress acute and chronic pain. In clinical practice, methylphenidate has been used as a treatment for ADHD and changes of pain threshold have been noted in these patients. The aim of this study was to determine the effect of methylphenidate in an animal model of peripheral neuropathic pain. Neuropathic pain was modeled by the chronic constriction of the sciatic nerve (CCI) in Wistar rats. We evaluated the effect of methylphenidate (1 mg/kg, s.c.) on evoked pain (reflex tests - plantar test, vonFrey test and operant test - thermal place preference) and on spontaneous pain (conditioned place preference). CCI induced thermal, mechanical and cold hyperalgesia/allodynia. Methyphenidate suppressed mechanical and cold hyperalgesia/allodynia, while had no effect on thermal one. Therefore, methylphenidate seems to be a new potential pharmacotherapy for the treatment of neuropathic pain.
Topics: Humans; Rats; Animals; Hyperalgesia; Methylphenidate; Rats, Wistar; Disease Models, Animal; Neuralgia
PubMed: 38165759
DOI: 10.33549/physiolres.935215 -
Molecular Psychiatry Feb 2022Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized....
Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized. Here we assessed whether there are sex differences in the brain dopamine system in humans that could contribute to these effects. We analyzed data from two independent [C]raclopride PET brain imaging studies that measured methylphenidate-induced dopamine increases in the striatum using different routes of administration (Cohort A = oral 60 mg; Cohort B = intravenous 0.5 mg/kg; total n = 95; 65 male, 30 female), in blinded placebo-controlled designs. Females when compared to males reported stronger feeling of "drug effects" and showed significantly greater dopamine release in the ventral striatum (where nucleus accumbens is located) to both oral and intravenous methylphenidate. In contrast, there were no significant differences in methylphenidate-induced increases in dorsal striatum for either oral or intravenous administration nor were there differences in levels of methylphenidate in plasma. The greater dopamine increases with methylphenidate in ventral but not dorsal striatum in females compared to males suggests an enhanced sensitivity specific to the dopamine reward system that might underlie sex differences in the vulnerability to substance use disorders and to attention-deficit/hyperactivity disorder (ADHD).
Topics: Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Corpus Striatum; Dopamine; Female; Humans; Male; Methylphenidate; Raclopride; Sex Characteristics; Ventral Striatum
PubMed: 34707237
DOI: 10.1038/s41380-021-01294-9 -
Journal of Veterinary Pharmacology and... Nov 2022The aim of this study was to evaluate the pharmacokinetics (PK) of robenacoxib (RX), a COX-2 selective non-steroidal anti-inflammatory drug, in sheep after single...
The aim of this study was to evaluate the pharmacokinetics (PK) of robenacoxib (RX), a COX-2 selective non-steroidal anti-inflammatory drug, in sheep after single subcutaneous (SC), oral (PO), and intravenous (IV) administration. Five healthy female sheep underwent a three-phase parallel study design with a washout period of 4 weeks, in which sheep received a 4 mg/kg SC dose in phase 1, a 4 mg/kg PO administration in phase 2, and a 2 mg/kg IV administration in phase 3. Plasma RX concentrations were measured over a 48 h period for each treatment using HPLC coupled to a UV multiple wavelength detector, and the PK parameters were estimated using a non-compartmental method. Following IV administration, terminal elimination half-life, volume of distribution at steady state, and total clearance were 2.64 h, 0.077 L/kg, and 0.056 L/h kg, respectively. The mean peak plasma concentrations following SC and PO administrations were 7.04 and 3.01 μg/mL, respectively. The mean bioavailability following SC and PO administrations were 45.98% and 16.58%, respectively. The SC route may be proposed for use in sheep. However, the multi-dose and pharmacodynamic studies are necessary to establish more accurately its safety and efficacy in sheep.
Topics: Female; Sheep; Animals; Area Under Curve; Phenylacetates; Diphenylamine; Administration, Intravenous; Administration, Oral; Biological Availability; Half-Life
PubMed: 35899473
DOI: 10.1111/jvp.13089 -
Sichuan Da Xue Xue Bao. Yi Xue Ban =... Nov 2023To investigate the effect of sleep deprivation on the metabolism of the hippocampal region in mice.
OBJECTIVE
To investigate the effect of sleep deprivation on the metabolism of the hippocampal region in mice.
METHODS
The mice were randomly assigned to three groups, a control group, a 24-h sleep deprivation (SD) group, and a 48-h SD group. Each group had 10 mice. The sleep deprivation model was induced by the modified multiple platform method. The mice's anxiety-like behaviors were assessed with the open field test (OFT) and their depression-like behaviors were assessed with the sucrose preference test (SPT), the forced swimming test (FST), and tail suspension test (TST). High performance liquid chromatography (HPLC) was performed to determine the levels of 6 monoamine neurotransmitters, including 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), gamma-aminobutyric acid (GABA), 5-dihydroxyphenylacetic acid (5-DOPAC), and homovanillic acid (HVA), and 4 amino acids, including glutamic acid (Glu), aspartic acid (Asp), serine (Ser), and taurine (Tau), in the hippocampal region. Immunofluorescence staining was performed to examine the expression of glial cells in the hippocampal region of the mice. The main indicators measured were the levels of monoamine neurotransmitters and amino acids.
RESULTS
According to the results of the behavioral analysis, in comparison with the findings for the control group, the 24-h SD mice exhibited increased consumption of sucrose in SFT, significantly decreased total immobility time in FST and TST, and increased total distance covered in OFT, while the 48-h SD mice showed decreased consumption of sucrose in SFT, prolonged total immobility time in FST and TST, and decreased total distance covered in OFT. The results of the HPLC analysis of the monoamine neurotransmitter showed that 24-h SD mice had in their hippocampal region increased levels of DA (<0.001) and NE (<0.01) and decreased levels of GABA (<0.05) in comparison with those of the control mice, while their 5-HT, 5-DOPAC, and HVA levels were not significantly different from those of the control mice. In comparison with those of the control mice, the 48-h SD mice had, in their hippocampal region, decreased levels of 5-HT and NE (all <0.05), decreased DA (<0.01), and increased level of GABA (<0.01), while the levels of 5-DOPAC and HAV were not significantly different. The 48-h SD group showed a significant decrease in the levels of Tau and Glu in comparison with those of the 24-h SD group (all <0.05). According to the results of immunofluorescence assay, there was no significant difference between the control group and the 24-h SD group in the cell count of glial fibrillary acidic protein (GFAP)-positive cells, while a decline in GFAP-positive cells in comparison with that of the control group was observed in the 48-h SD group.
CONCLUSION
SD of 24 hours may induce anxiety-like behavioral changes in mice by activating their hippocampal glial cells, upregulating the levels of 5-HT, DA, and NE, and increasing the levels of Glu and Tau in the hippocampal region. SD of 48 hours may induce depression-like behavioral changes in mice by inhibiting the activation of glial cells in the hippocampal region and regulating in the opposite direction the levels of the above-mentioned monoamine neurotransmitters and amino acids in the hippocampal region.
Topics: Mice; Animals; Sleep Deprivation; Serotonin; Amino Acids; 3,4-Dihydroxyphenylacetic Acid; Hippocampus; Dopamine; Norepinephrine; Homovanillic Acid; Neurotransmitter Agents; gamma-Aminobutyric Acid; Sucrose
PubMed: 38162057
DOI: 10.12182/20231160203