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Journal of Chromatography. A Feb 2021In order to make high-performance liquid chromatography (HPLC) more widely available at home and in small-scale settings, we have simplified two of its most costly...
In order to make high-performance liquid chromatography (HPLC) more widely available at home and in small-scale settings, we have simplified two of its most costly modules, namely the pump and the detector. This should make the setup affordable for home or small laboratory use. A manual HPLC pump was constructed so as to fit into a caulk gun from a local hardware store enabling the generation of 100-150 bar of pressure. In order to limit the pressure drop during the running of a chromatogram, a pulse dampener was developed. We further modified the electrochemical detection (ECD) system so as to use a cheap boron-doped diamond electrode with an overlay of thin filter paper, causing an eluent flow over the electrode by wicking and gravity. Both the pump and the detector are at least ten times cheaper than conventional HPLC modules. Using a home-packed Jupiter Proteo reversed phase capillary column we show how this low-cost HPLC system generates well resolving chromatograms after direct injection of fresh urine. The ECD did not lose its sensitivity during regular use over more than half a year. For homovanillic acid (HVA), which is of medical interest, we measured a linear dynamic range of two orders of magnitude, a detection limit of HVA in the injected sample of 3 μM and a coefficient of variation <10%. The contribution to peak broadening by the detector was much smaller than the contributions by the injector and by the column. After consumption of table olives containing hydroxytyrosol (HT), its metabolite HVA in the corresponding urine could be measured quantitatively. An approach to quantify HT in table olives is presented, as well. This method provides a new tool for investigating physiology of oneself or of dear ones at home.
Topics: Benzophenones; Chromatography, High Pressure Liquid; Electrochemistry; Electrodes; Homovanillic Acid; Humans; Ketones; Olea; Polyethylene Glycols; Polymers; Pressure; Signal Processing, Computer-Assisted
PubMed: 33556779
DOI: 10.1016/j.chroma.2021.461925 -
Journal of Child and Adolescent... Jun 2022The study was designed to determine (1) the pharmacokinetic (PK) profile of dexmethylphenidate (d-MPH) after oral administration of three dosage strengths of a new...
Dose Proportionality and Steady-State Pharmacokinetics of Serdexmethylphenidate/Dexmethylphenidate, a Novel Prodrug Combination to Treat Attention-Deficit/Hyperactivity Disorder.
The study was designed to determine (1) the pharmacokinetic (PK) profile of dexmethylphenidate (d-MPH) after oral administration of three dosage strengths of a new treatment containing d-MPH and a novel prodrug, serdexmethylphenidate (SDX); (2) the dose proportionality of the different SDX/d-MPH dosages; and (3) the steady-state PK profile of d-MPH and SDX after multiple dosing of SDX/d-MPH. Twenty-three healthy volunteers (aged 18-55 years) under fasted conditions received in a crossover design SDX/d-MPH 26.1/5.2 mg (Treatment A), 39.2/7.8 mg (Treatment B), and 52.3/10.4 mg (Treatment C) for a total d-MPH hydrochloride equivalent dose of 20, 30, and 40 mg, respectively. After a 96-hour washout period, all participants received four consecutive daily doses of SDX/d-MPH 52.3/10.4 mg. Blood samples were collected for measurement of plasma d-MPH and SDX and for PK analysis. Administration of all three doses of SDX/d-MPH resulted in a rapid rise and slow decline in the plasma concentration of d-MPH. For Treatments A, B, and C, mean (± standard deviation) maximum concentrations () were 7.1 ± 2.1, 9.8 ± 2.8, and 13.8 ± 3.8 ng/mL, and overall exposures (AUC) were 97.2 ± 28.8, 142.5 ± 41.2, and 199.8 ± 57.2 h*ng/mL, respectively. Dose-normalized , AUC, and AUC for d-MPH were similar when comparing the high and low doses versus the middle dose. Power model regression analysis revealed that and AUC proportionally increased with an increase in SDX/d-MPH dose. In the multiple-dose study, d-MPH reached steady state before the third dose, and SDX after the first dose. The PK profile of SDX/d-MPH is characterized by a rapid rise and a gradual decline in d-MPH concentration, with proportional and AUC across doses. The PK attributes of SDX/d-MPH may optimize symptom control from early morning to early evening, while the demonstrated dose proportionality may facilitate initial dose titration and ongoing dose adjustment.
Topics: Area Under Curve; Attention Deficit Disorder with Hyperactivity; Biological Availability; Central Nervous System Stimulants; Cross-Over Studies; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Humans; Methylphenidate; Prodrugs
PubMed: 35666231
DOI: 10.1089/cap.2022.0015 -
The International Journal of Risk &... 2017Few studies have reported on long-term harms caused by ADHD drugs but they are known to impair growth. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Few studies have reported on long-term harms caused by ADHD drugs but they are known to impair growth.
OBJECTIVE
To assess whether ADHD drugs impair reproduction in mammals.
METHODS
Systematic review of reproduction in studies of animals treated with ADHD drugs.
DATA SOURCES
PubMed, Biosis and EMBASE.
RESULTS
We included 17 studies. The studies were generally of poor quality or poorly reported. Two studies reported the use of one of three advised randomisation methods. Fifteen studies used placebo which suggested blinding. On clonidine, the ability to produce offspring was reduced for male rats, which approached two females each. In one study, 10 treated rats produced no offspring while all four controls did. In another study, 10 treated rats impregnated nine females while 10 controls impregnated 16. On methylphenidate, vaginal opening was delayed in two studies (in one, the mean difference was 4.0 days, 95% CI 2.5 to 5.6, and number of estrous cycles was halved; in the other, the minimum delay was 6 days), while in two other studies no difference occurred. Generally, the impairments improved after a drug-free period and were less pronounced when treatment started later in life.
CONCLUSION
ADHD drugs impair the reproduction in animals.
Topics: Animals; Attention Deficit Disorder with Hyperactivity; Clonidine; Female; Male; Methylphenidate; Reproduction
PubMed: 28885224
DOI: 10.3233/JRS-170743 -
Neuropsychopharmacology : Official... Oct 2023Methylphenidate is a widely used and effective treatment for attention-deficit/hyperactivity disorder (ADHD), yet the underlying neural mechanisms and their relationship... (Randomized Controlled Trial)
Randomized Controlled Trial
Methylphenidate is a widely used and effective treatment for attention-deficit/hyperactivity disorder (ADHD), yet the underlying neural mechanisms and their relationship to changes in behavior are not fully understood. Specifically, it remains unclear how methylphenidate affects brain and behavioral dynamics, and the interplay between these dynamics, in individuals with ADHD. To address this gap, we used a novel Bayesian dynamical system model to investigate the effects of methylphenidate on latent brain states in 27 children with ADHD and 49 typically developing children using a double-blind, placebo-controlled crossover design. Methylphenidate remediated greater behavioral variability on a continuous performance task in children with ADHD. Children with ADHD exhibited aberrant latent brain state dynamics compared to typically developing children, with a single latent state showing particularly abnormal dynamics, which was remediated by methylphenidate. Additionally, children with ADHD showed brain state-dependent hyper-connectivity in the default mode network, which was also remediated by methylphenidate. Finally, we found that methylphenidate-induced changes in latent brain state dynamics, as well as brain state-related functional connectivity between salience and default mode networks, were correlated with improvements in behavioral variability. Taken together, our findings reveal a novel latent brain state dynamical process and circuit mechanism underlying the therapeutic effects of methylphenidate in childhood ADHD. We suggest that Bayesian dynamical system models may be particularly useful for capturing complex nonlinear changes in neural activity and behavioral variability associated with ADHD. Our approach may be of value to clinicians and researchers investigating the neural mechanisms underlying pharmacological treatment of psychiatric disorders.
Topics: Humans; Child; Methylphenidate; Attention Deficit Disorder with Hyperactivity; Bayes Theorem; Brain; Nerve Net; Central Nervous System Stimulants
PubMed: 37491674
DOI: 10.1038/s41386-023-01668-3 -
Molecules (Basel, Switzerland) Dec 20224-Arylhydrazinylidene-5-(polyfluoroalkyl)pyrazol-3-ones (4-AHPs) were found to be obtained by the regiospecific cyclization of...
4-Arylhydrazinylidene-5-(polyfluoroalkyl)pyrazol-3-ones (4-AHPs) were found to be obtained by the regiospecific cyclization of 2-arylhydrazinylidene-3-(polyfluoroalkyl)-3-oxoesters with hydrazines, by the azo coupling of 4-nonsubstituted pyrazol-5-oles with aryldiazonium chlorides or by the firstly discovered acid-promoted self-condensation of 2-arylhydrazinylidene-3-oxoesters. All the 4-AHPs had an acceptable ADME profile. Varying the substituents in 4-AHPs promoted the switching or combining of their biological activity. The polyfluoroalkyl residue in 4-AHPs led to the appearance of an anticarboxylesterase action in the micromolar range. An NH-fragment and/or methyl group instead of the polyfluoroalkyl one in the 4-AHPs promoted antioxidant properties in the ABTS, FRAP and ORAC tests, as well as anti-cancer activity against HeLa that was at the Doxorubicin level coupled with lower cytotoxicity against normal human fibroblasts. Some Ph-N-substituted 4-AHPs could inhibit the growth of bacteria at MIC 0.9 μg/mL. The possibility of using 4-AHPs for cell visualization was shown. Most of the 4-AHPs exhibited a pronounced analgesic effect in a hot plate test in vivo at and above the diclofenac and metamizole levels except for the ones with two chlorine atoms in the aryl group. The methylsulfonyl residue was proved to raise the anti-inflammatory effect also. A mechanism of the antinociceptive action of the 4-AHPs through blocking the TRPV1 receptor was proposed and confirmed using in vitro experiment and molecular docking.
Topics: Humans; Molecular Docking Simulation; Diclofenac; Antioxidants; Pharmaceutical Preparations
PubMed: 36615256
DOI: 10.3390/molecules28010059 -
Clinical & Experimental Optometry Mar 2021In clinical practice, 1% atropine and 1% cyclopentolate are used as cycloplegia agents to diagnose refractive error. The influence of 1% atropine on ocular biometry is... (Randomized Controlled Trial)
Randomized Controlled Trial
CLINICAL RELEVANCE
In clinical practice, 1% atropine and 1% cyclopentolate are used as cycloplegia agents to diagnose refractive error. The influence of 1% atropine on ocular biometry is obscure, and the impact of 1% cyclopentolate remains controversial.
BACKGROUND
This study aims to compare the effects of atropine versus cyclopentolate cycloplegia on ocular biometry in myopic children and to determine the sites of action for atropine.
METHODS
A total of 207 myopic children aged 6-12-years were included in the analysis. All participants underwent comprehensive eye examinations before and after cyclopentolate cycloplegia, after which they were randomly assigned into two groups, A and B, in a ratio of 1:1, to receive 1% or 0.01% atropine, respectively. The treatment was administered once every night for a week. Participants were re-examined one week later.
RESULTS
Cyclopentolate cycloplegia caused a decrease in choroidal thickness (-3 ± 9 μm, p = 0.001), elongation of axial length (9 ± 16 μm, p < 0.001), loss of lens power (-0.14 ± 0.37 dioptre, p < 0.001), and a hyperopic shift (0.14 ± 0.22 dioptre, p < 0.001) in both groups. However, ocular biometry showed different changes after one-week use of 1% or 0.01% atropine (all p < 0.001). In Group A, choroid thickening (24 ± 13 μm, p < 0.001) and reduced axial length (-30 ± 27 μm, p < 0.001) were observed after atropine cycloplegia, with greater changes in lens power (0.50 ± 0.37 dioptre, p < 0.001) and spherical equivalent (0.52 ± 0.23 dioptre, p < 0.001). Group B showed a slight increase in choroidal thickness following one-week use of 0.01% atropine (6 ± 9 μm, p < 0.001), but other biometric measures showed no significant changes.
CONCLUSION
Cyclopentolate and atropine cycloplegia have different effects on ocular biometry. Both 1% cyclopentolate cycloplegia and 0.01% atropine resulted in choroidal thickening, indicating that the choroid may be a site of action for atropine.
Topics: Atropine; Child; Choroid; Cyclopentolate; Humans; Mydriatics; Refraction, Ocular
PubMed: 32844483
DOI: 10.1111/cxo.13128 -
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 -
Acta Ophthalmologica Jun 2022To compare the refractive outcome and residual accommodation with respect to various degrees of iris and skin pigmentation in hypermetropic children using 2 drops of... (Randomized Controlled Trial)
Randomized Controlled Trial
Eye colour and skin pigmentation as significant factors for refractive outcome and residual accommodation in hypermetropic children: a randomized clinical trial using cyclopentolate 1% and tropicamide 1.
PURPOSE
To compare the refractive outcome and residual accommodation with respect to various degrees of iris and skin pigmentation in hypermetropic children using 2 drops of cyclopentolate 1% (C + C) or 1 drop of cyclopentolate 1% and 1 drop of tropicamide 1% (C + T).
METHODS
Two hundred fifty-one hypermetropic children were classified according to iris and skin pigmentation (light, medium, dark) and received randomized and double-blind C + C or C + T. Refractive error (spherical equivalent, SEQ) was determined using the Retinomax-K + 3. In 204 subjects, residual accommodation (RA) was determined using the PlusoptiX PowerRefractor.
RESULTS
A linear mixed model with a light-irided and light skin-pigmented reference group receiving C + T (mean SEQ +3.10 ± 1.87D) indicated significant less hypermetropia in subjects with a dark iris having a medium- and dark-pigmented skin in C + T, -1.02 ± 0.29 (-1.59/-0.45) and -1.53 ± 0.30 (-2.10/-0.95); and in subjects having a light-, medium- and dark-pigmented skin in C + C, -0.74 ± 0.34 (-1.41/-0.06), -1.26 ± 0.30 (-1.85/-0.66) and -1.84 ± 0.30 (-2.42/-1.26). Similar findings were present for RA. Our model with a light-irided and light skin-pigmented reference group receiving C + T (mean RA +0.84 ± 0.61D) indicated significantly higher RA in dark-irided subjects with medium- and dark-pigmented skin in C + T, +1.05 ± 0.19 (+0.67/+1.43) and +1.35 ± 0.20 (+0.9/+1.74), and in C + C, +1.13 ± 0.21 (+0.71/+1.55) and +1.90 ± 0.19 (+1.51/+2.28).
CONCLUSIONS
We found solid evidence that skin pigmentation rather than iris pigmentation is the decisive factor for effectiveness of cycloplegics. Awareness of the limitations of cycloplegic regimens in dark-irided/pigmented children is needed. Our study showed that cyclopentolate 1% combined with tropicamide 1% provides more accurate refractive outcomes both statistically and clinically integrating the factor skin pigmentation for dark-irided subjects.
Topics: Child; Cyclopentolate; Eye Color; Humans; Mydriatics; Ophthalmic Solutions; Skin Pigmentation; Tropicamide
PubMed: 34672100
DOI: 10.1111/aos.15016 -
Journal of Pharmaceutical Sciences Dec 2014We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery, drug interactions, biomarker for dl-methylphenidate (MPH)-ethanol... (Review)
Review
We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery, drug interactions, biomarker for dl-methylphenidate (MPH)-ethanol exposure, potentiation of dl-MPH abuse liability, contemporary "designer drug," pertinence to the newer transdermal and chiral switch MPH formulations, as well as problematic internal standard. d-EPH selectively targets the dopamine transporter, whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. This selectivity carries implications for the advancement of tailored attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in the era of genome-based diagnostics. Abuse of dl-MPH often involves ethanol coabuse. Carboxylesterase 1 enantioselectively transesterifies l-MPH with ethanol to yield l-EPH accompanied by significantly increased early exposure to d-MPH and rapid potentiation of euphoria. The pharmacokinetic component of this drug interaction can largely be avoided using dexmethylphenidate (dexMPH). This notwithstanding, maximal potentiated euphoria occurs following dexMPH-ethanol. C57BL/6 mice model dl-MPH-ethanol interactions: an otherwise depressive dose of ethanol synergistically increases dl-MPH stimulation; a substimulatory dose of dl-MPH potentiates a low, stimulatory dose of ethanol; ethanol elevates blood, brain, and urinary d-MPH concentrations while forming l-EPH. Integration of EPH preclinical neuropharmacology with clinical studies of MPH-ethanol interactions provides a translational approach toward advancement of ADHD personalized medicine and management of comorbid alcohol use disorder.
Topics: Animals; Biomarkers; Dopamine; Dopamine Agonists; Esterification; Ethanol; Humans; Methylphenidate
PubMed: 25303048
DOI: 10.1002/jps.24202 -
Toxicology Feb 2018Polychlorinated biphenyls (PCB) exposure at low chronic levels is a significant public health concern. Animal and epidemiological studies indicate that low PCB body...
Polychlorinated biphenyls (PCB) exposure at low chronic levels is a significant public health concern. Animal and epidemiological studies indicate that low PCB body burden may cause neurotoxicity and be a risk factor for neurodegenerative diseases. In the current study, we measured the ability of two non-dioxin like PCBs, 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and 2,2'3,5',6-pentachlorobiphenyl (PCB95), to alter dopamine (DA) levels and metabolism using the dopaminergic PC12 cell line. Our hypothesis is that treatment of PC12 cells with non-toxic concentrations of PCB153 or PCB95 for 12 and 24 h will have different effects due to different congener structures. Levels of DA and of 3,4-dihydroxyphenylacetaldehyde (DOPAL), 3, 4-dihyroxylphenylethanol (DOPET), and 3,4-dihyroxylphenylacetic acid (DOPAC) metabolite, gene expression of the dopamine synthesis enzyme tyrosine hydroxylase (TH) and the vesicular monoamine transporter (VMAT2), and gene expression of the anti-oxidant enzymes Cu/Zn and Mn superoxide oxidase (Cu/ZnSOD, MnSOD), glutathione peroxidase (GPx) and catalase were determined. PCB153 decreased intracellular and extracellular levels of DA after 12 h exposure and this was consistent with an increase in DA metabolites. After 24 h, the level of DA in medium increased compared to the control. In contrast, PCB95 exposure increased the intracellular DA level and decreased DA in medium consistent with a down-regulation of VMAT2 expression at 12 h. After 24 h exposure, PCB95 increased DA levels in media. Expression of TH mRNA increased slightly following 12 h but not at 24 h exposure. MnSOD mRNA increased up to 6-7 fold and Cu/ZnSOD increased less than two-fold after treatment with both congeners. Catalase expression was up-regulated following 24 h exposure to PCB153 and PCB95, but GPx expression was down-regulated after 12 h exposure to PCB95 only. These results suggest that PCB153 and PCB95 are neurotoxic and affect DA turnover with structure-dependent differences between these two congeners.
Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Dopamine; Male; Neurotoxicity Syndromes; PC12 Cells; Polychlorinated Biphenyls; Rats
PubMed: 29233657
DOI: 10.1016/j.tox.2017.12.003