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European Child & Adolescent Psychiatry Apr 2016
Topics: Adolescent; Attention; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Evidence-Based Medicine; Humans; Methylphenidate
PubMed: 27021055
DOI: 10.1007/s00787-016-0845-2 -
Arthritis & Rheumatology (Hoboken, N.J.) Aug 2016
Topics: Acetamides; Phenylacetates
PubMed: 26990165
DOI: 10.1002/art.39687 -
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 -
Topical bioequivalence: Experimental and regulatory considerations following formulation complexity.International Journal of Pharmaceutics May 2022Documenting topical bioequivalence can be an extremely complex process, which is intrinsically dependent on the formulation technological features. According to EMA...
Documenting topical bioequivalence can be an extremely complex process, which is intrinsically dependent on the formulation technological features. According to EMA guideline, for simple formulations, BE may be demonstrated by documenting the qualitative (Q1), quantitative (Q2), microstructure (Q3) and performance (Q4) equivalence. Nevertheless, when addressing complex semisolids, equivalence regarding local availability should also be demonstrated. The purpose of this study is to pursue this strategy using two opposite scenarios: a simple dimetindene maleate 1 mg/g gel formulation and a diclofenac diethylammonium 23.2 mg/g emulgel, representing a complex formulation. For both formulations, Q1/Q2 test (TP) and reference products (RP) were used. Rheology, in vitro release (IVRT) and in vitro permeation methods (IVPT) were developed and validated for both products. For the dimetindene formulation, equivalence pertaining to Q4 was established. However, high variability was observed for some rheology endpoints, especially for the different RP batches. Therefore, equivalence could not be established for Q3 as per EMA requirements. Can some rheology endpoints be waived? Can we establish reasonable criteria that are overall feasible for generic manufacturers and at the same time safe for the patient? An attempt was made to propose a wider acceptance range based on the inter-batch variability of the RP. For that, the rationale presented in the EMA guideline on bioequivalence for highly variable products was used. For the diclofenac formulation, Q3 equivalence was likewise not established. Q4 equivalence was only found for some batch combinations and when applying a wider acceptance criterion (75-133%). Furthermore, IVPT equivalence also failed to be demonstrated. Nevertheless, since the TP displays an equivalent pharmacokinetic profile compared to the RP, the observed Q3, Q4 and local availability differences are not expected to be clinically significant. This study draws attention to an effective search to determine the most appropriate strategy for assessing topical bioequivalence on a case-by-case basis.
Topics: Diclofenac; Dimethindene; Drugs, Generic; Humans; In Vitro Techniques; Therapeutic Equivalency
PubMed: 35358644
DOI: 10.1016/j.ijpharm.2022.121705 -
The Journal of Nutrition Oct 2017Parkinson disease (PD) is a neurodegenerative disorder that has been associated with many factors, including oxidative stress, inflammation, and iron accumulation. The...
Parkinson disease (PD) is a neurodegenerative disorder that has been associated with many factors, including oxidative stress, inflammation, and iron accumulation. The antioxidant, anti-inflammatory, and iron-chelating properties of epigallocatechin gallate (EGCG), a major polyphenol in green tea, may offer protection against PD. We sought to determine the neurorescue effects of EGCG and the role of iron in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. We evaluated the neurorescue effect of EGCG (25 mg/kg, 7 d, oral administration) against MPTP-induced (20 mg/kg, 3 d, intraperitoneal injection) neurodegeneration in C57 male black mice. Thirty mice weighing ∼25 g were divided into 3 groups: control, MPTP, and MPTP + EGCG. The neurorescue effect of EGCG was assessed with the use of motor behavior tests, neurotransmitter analysis, oxidative stress indicators, and iron-related protein expression. Compared with the control group, MPTP treatment shortened the mice's latency to fall from the rotarod by 16% ( < 0.05), decreased the striatal dopamine concentration by 58% ( < 0.001) and dihydroxyphenylacetic acid by 35% ( < 0.05), and increased serum protein carbonyls by 71% ( = 0.07). However, EGCG rescued MPTP-induced neurotoxicity by increasing the rotational latency by 17% ( < 0.05) to a value similar to the control group. Striatal dopamine concentrations were 40% higher in the MPTP + EGCG group than in the MPTP group ( < 0.05), but the values were significantly lower than in the control group. Compared with the MPTP and control groups, mice in the MPTP + EGCG group had higher substantia nigra ferroportin expression (44% and 35%, respectively) ( < 0.05) but not hepcidin and divalent metal transporter 1 expression. Overall, our study demonstrated that EGCG regulated the iron-export protein ferroportin in substantia nigra, reduced oxidative stress, and exerted a neurorescue effect against MPTP-induced functional and neurochemical deficits in mice.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antioxidants; Behavior, Animal; Blood Proteins; Catechin; Cation Transport Proteins; Disease Models, Animal; Dopamine; Hepcidins; Iron; Male; Mice, Inbred C57BL; Motor Activity; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Phenylacetates; Phytotherapy; Plant Extracts; Protein Carbonylation; Substantia Nigra; Tea
PubMed: 28835392
DOI: 10.3945/jn.117.255034 -
Lancet (London, England) Feb 2016
Topics: Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; History, 20th Century; History, 21st Century; Humans; Methylphenidate
PubMed: 26913307
DOI: 10.1016/s0140-6736(16)00332-9 -
Journal of Cellular and Molecular... Nov 2023The most prominent adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DF) are hepato-renal damage. Natural antioxidants can be...
The most prominent adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DF) are hepato-renal damage. Natural antioxidants can be preferred as an alternative and/or combination to improve this damage. This present study was conducted to evaluate the protective effect of Tubuloside A (TA) against diclofenac (DF)-induced hepato-renal damage. TA (1 mg/kg, ip) was administered to male Sprague-Dawley rats for 5 days, and DF (50 mg/kg, ip) was administered on Days 4 and 5. Plasma aspartate amino transferase, alanine amino transferase, alkaline phosphatase, blood urea nitrogen and creatinine were measured to evaluate liver and kidney functions. Additionally, oxidative stress parameters (malondialdehyde, glutathione, superoxide dismutase, catalase, and 8-oxo-7,8-dihydro-2'-deoxyguanosine) in blood, liver, and kidney tissues, changes in mRNA expression of genes involved in the Nrf2/HO-1 signalling pathway (Nrf2, HO-1, NQO-1, IL-6, iNOS, Cox-2, TNF-α, IL1-β and NFκB) and apoptotic process (Bcl-2, Cas-3 and Bax) in liver and kidney tissues were determined. Additionally, tissue sections were evaluated histopathologically. Biochemical, histopathological, and molecular results demonstrated the hepato-renal toxic effects of DF, and TA treatment protected the liver and kidney from DF-induced damage. This provides an explanation for the hepato-nephro damage caused by DF and offers new ideas and drug targets together with TA for the prevention and treatment of DF injury.
Topics: Rats; Animals; Male; Diclofenac; NF-E2-Related Factor 2; Glycosides; Rats, Sprague-Dawley; Oxidative Stress; Antioxidants; Kidney; Apoptosis
PubMed: 37772986
DOI: 10.1111/jcmm.17968 -
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 -
BMC Research Notes Nov 2020We previously reported the pharmaceutical quality of eight brands of 50 mg enteric-coated diclofenac sodium tablet available on the Saudi market. Here, we assess the...
OBJECTIVE
We previously reported the pharmaceutical quality of eight brands of 50 mg enteric-coated diclofenac sodium tablet available on the Saudi market. Here, we assess the quality of reference (R1) and four generic (G1-G4) brands of 50 mg immediate-release diclofenac potassium tablet and of reference (R2) and generic (G5) brands of 100 mg sustained-release diclofenac sodium tablet.
RESULTS
Weight variation (range as % difference from mean), active substance content (mean (SD) as % difference from label), breaking force [mean (SD)], and friability (as % weight loss) were 95-104% and 99-102%, 100.9% (3.4%) and 105.6 (4.2%), 12.2 (1.3) and 12.9 (1.8) kg, and 0.0014% and 0.0012%, for R1 and R2, respectively. For G1-G5, they were ≤ ± 2%, 98.8% (2.7%) to 109.2% (3.8%), 6.4 (0.6) to 13.3 (1.0) kg, and 0.0007% to 0.0261%, respectively. R1 and G1-G4 disintegrated within 04:50-17:20 min: seconds and released a mean of 89-100% of label active substance content by 60 min in buffer (pH 6.8). R2 and G5 did not disintegrate or dissolve in 0.1 N HCl for 2 h, disintegrated in buffer (pH 6.8) in 01:58-02:15 h: minutes, and fulfilled dissolution criteria (pH 7.5) for both United States Pharmacopoeia test-1 and test-2. Thus all seven brands met pre-specified quality criteria.
Topics: Chemistry, Pharmaceutical; Diclofenac; Pharmacy; Saudi Arabia; Solubility; Tablets; Tablets, Enteric-Coated
PubMed: 33243292
DOI: 10.1186/s13104-020-05385-8 -
International Journal of Molecular... Sep 2022Attention deficit hyperactivity disorder (ADHD) is one of the most common worldwide mental disorders in children, young and adults. If left untreated, the disorder can...
Attention deficit hyperactivity disorder (ADHD) is one of the most common worldwide mental disorders in children, young and adults. If left untreated, the disorder can continue into adulthood. The abuse of ADHD-related drugs to improve mental performance for studying, working and everyday life is also rising. The potentially high number of subjects with controlled or uncontrolled use of such substances increases the impact of possible side effects. It has been shown before that the early ADHD drug methylphenidate influences bone metabolism negatively. This study focused on the influence of three more recent cognitive enhancers, modafinil, atomoxetine and guanfacine, on the differentiation of mesenchymal stem cells to osteoblasts and on their cell functions, including migration. Human mesenchymal stem cells (hMSCs) were incubated with a therapeutic plasma dosage of modafinil, atomoxetine and guanfacine. Gene expression analyses revealed a high beta-2 adrenoreceptor expression in hMSC, suggesting it as a possible pathway to stimulate action. In bone formation assays, all three cognitive enhancers caused a significant decrease in the mineralized matrix and an early slight reduction of cell viability without triggering apoptosis or necrosis. While there was no effect of the three substances on early differentiation, they showed differing effects on the expression of (), () and () in the later stages of osteoblast development, suggesting alternative modes of action. All three substances significantly inhibited hMSC migration. This effect could be rescued by a selective beta-blocker (Imperial Chemical Industries ICI-118,551) in modafinil and atomoxetine, suggesting mediation via beta-2 receptor stimulation. In conclusion, modafinil, atomoxetine and guanfacine negatively influence hMSC differentiation to bone-forming osteoblasts and cell migration through different intracellular pathways.
Topics: Adult; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Cell Differentiation; Central Nervous System Stimulants; Child; Guanfacine; Humans; Ligands; Methylphenidate; Modafinil; Nootropic Agents; Osteoprotegerin; Receptor Activator of Nuclear Factor-kappa B
PubMed: 36142172
DOI: 10.3390/ijms231810257