Synthesis of deuterium-labelled methylphenidate, p-hydroxy-methylphenidate, ritalinic acid and p-hydroxyritalinic acid

International Nuclear Information System (INIS)

Patrick, K.; Kilts, C.; Breese, G.

1982-01-01

The synthesis of threo-dl-methylphenidate (Ritalin 1), threo-dl-p-hydroxy-methylphenidate (3), threo-dl-ritalinic acid (2), and threo-dl-p-hydroxyritalinic acid (4) with deuterium incorporated in the piperidine ring is described. These compounds were synthesized for use as internal standards for mass fragmentographic assays of methylphenidate and its metabolites. The synthetic scheme described resulted in less than 0.05% 2 H 0 in the piperidine ring in any of the preparations. (author)

Methylphenidate Attenuates Limbic Brain Inhibition after Cocaine-Cues Exposure in Cocaine Abusers

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Volkow, Nora D.; Wang, Gene-Jack; Tomasi, Dardo; Telang, Frank; Fowler, Joanna S.; Pradhan, Kith; Jayne, Millard; Logan, Jean; Goldstein, Rita Z.; Alia-Klein, Nelly; Wong, Christopher

2010-01-01

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and...

Resolution of methylphenidate osmotic release oral system-induced hair loss in two siblings after dose escalation.

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Ardic, Ulku Akyol; Ercan, Eyup Sabri

2017-11-01

This report describes the cases of two siblings who experienced hair loss after treatment with methylphenidate (MPH) osmotic release oral system (OROS). Hair loss was resolved after discontinuation of the drug, but the children re-initiated treatment, after which hair loss again occurred, but they continued the treatment. After dose escalation, the hair loss resolved. This is the first report to describe resolution of OROS-MPH-induced hair loss after dose escalation. © 2017 Japan Pediatric Society.

Effects of methylphenidate and MDMA on appraisal of erotic stimuli and intimate relationships.

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Schmid, Yasmin; Hysek, Cédric M; Preller, Katrin H; Bosch, Oliver G; Bilderbeck, Amy C; Rogers, Robert D; Quednow, Boris B; Liechti, Matthias E

2015-01-01

Methylphenidate mainly enhances dopamine neurotransmission whereas 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") mainly enhances serotonin neurotransmission. However, both drugs also induce a weaker increase of cerebral noradrenaline exerting sympathomimetic properties. Dopaminergic psychostimulants are reported to increase sexual drive, while serotonergic drugs typically impair sexual arousal and functions. Additionally, serotonin has also been shown to modulate cognitive perception of romantic relationships. Whether methylphenidate or MDMA alter sexual arousal or cognitive appraisal of intimate relationships is not known. Thus, we evaluated effects of methylphenidate (40 mg) and MDMA (75 mg) on subjective sexual arousal by viewing erotic pictures and on perception of romantic relationships of unknown couples in a double-blind, randomized, placebo-controlled, crossover study in 30 healthy adults. Methylphenidate, but not MDMA, increased ratings of sexual arousal for explicit sexual stimuli. The participants also sought to increase the presentation time of implicit sexual stimuli by button press after methylphenidate treatment compared with placebo. Plasma levels of testosterone, estrogen, and progesterone were not associated with sexual arousal ratings. Neither MDMA nor methylphenidate altered appraisal of romantic relationships of others. The findings indicate that pharmacological stimulation of dopaminergic but not of serotonergic neurotransmission enhances sexual drive. Whether sexual perception is altered in subjects misusing methylphenidate e.g., for cognitive enhancement or as treatment for attention deficit hyperactivity disorder is of high interest and warrants further investigation. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Methylphenidate alters selective attention by amplifying salience.

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ter Huurne, Niels; Fallon, Sean James; van Schouwenburg, Martine; van der Schaaf, Marieke; Buitelaar, Jan; Jensen, Ole; Cools, Roshan

2015-12-01

Methylphenidate, the most common treatment of attention deficit hyperactivity disorder (ADHD), is increasingly used by healthy individuals as a "smart drug" to enhance cognitive abilities like attention. A key feature of (selective) attention is the ability to ignore irrelevant but salient information in the environment (distractors). Although crucial for cognitive performance, until now, it is not known how the use of methylphenidate affects resistance to attentional capture by distractors. The present study aims to clarify how methylphenidate affects distractor suppression in healthy individuals. The effect of methylphenidate (20 mg) on distractor suppression was assessed in healthy subjects (N = 20), in a within-subject double-blind placebo-controlled crossover design. We used a visuospatial attention task with target faces flanked by strong (faces) or weak distractors (scrambled faces). Methylphenidate increased accuracy on trials that required gender identification of target face stimuli (methylphenidate 88.9 ± 1.4 [mean ± SEM], placebo 86.0 ± 1.2 %; p = .003), suggesting increased processing of the faces. At the same time, however, methylphenidate increased reaction time when the target face was flanked by a face distractor relative to a scrambled face distractor (methylphenidate 34.9 ± 3.73, placebo 26.7 ± 2.84 ms; p = .027), suggesting enhanced attentional capture by distractors with task-relevant features. We conclude that methylphenidate amplifies salience of task-relevant information at the level of the stimulus category. This leads to enhanced processing of the target (faces) but also increased attentional capture by distractors drawn from the same category as the target.

Differential therapeutic effects of 12-week treatment of atomoxetine and methylphenidate on drug-naïve children with attention deficit/hyperactivity disorder: A counting Stroop functional MRI study.

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Chou, Tai-Li; Chia, Seng; Shang, Chi-Yung; Gau, Susan Shur-Fen

2015-12-01

Methylphenidate and atomoxetine are effective in treating attention-deficit/hyperactivity disorder (ADHD) with underlying distinct pharmacological mechanisms. To relate neural mechanisms to clinical response, we conducted a comparative trial to differentiate the changes in brain activation of drug-naïve children with ADHD when performing neuropsychological tasks after 12 weeks of pharmacotherapy. We randomized 50 drug-naïve children with ADHD, aged 7-17, to treatment with methylphenidate (n=25) or atomoxetine (n=25). These children were scanned twice with functional magnetic resonance imaging (fMRI) during the counting Stroop task before and after treatment. Focused attention and impulsivity were assessed twice by using the Conner's Continuous Performance Test (CCPT). The final sample for fMRI analysis comprised 20 in the methylphenidate group and 22 in the atomoxetine group. Atomoxetine decreased activations in the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex, which correlated with improvement in focused attention assessed by the CCPT. In contrast, methylphenidate increased activations in the inferior frontal gyrus, which correlated with the decreasing severity of impulsivity assessed by the CCPT. The current findings suggest that differential therapeutic effects on neuronal changes induced by 12-week treatment atomoxetine and methylphenidate may contribute to behavioral improvement. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Changes in plasma Brain-derived neurotrophic factor (BDNF) levels induced by methylphenidate in children with Attention deficit-hyperactivity disorder (ADHD).

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Amiri, Ali; Torabi Parizi, Gholamreza; Kousha, Maryam; Saadat, Farshid; Modabbernia, Mohammad-Jafar; Najafi, Kiomars; Atrkar Roushan, Zahra

2013-12-02

It has been suggested that BDNF may play a role in the pathogenesis of ADHD. Our aim is to determine whether methylphenidate can induce changes in plasma BDNF levels of children with ADHD. We assessed levels of plasma BDNF in 28 ADHD patients (age range = 3.5-10 years) before and after 6 weeks treatment with effective dosages of methylphenidate. Then we evaluated the correlation of levels of plasma BDNF with clinical variables, especially ADHD Conner's parents rating scale. According to the paired sample T-test, the mean plasma BDNF level in the baseline was 193.06 pg/ml, whereas 271.06 pg/ml in the end point, thus showing significantly higher mean plasma BDNF levels in the post-treatment situation than in the pretreatment (t = -3.393, df = 27, p = 0.002). Pearson's correlation test revealed that there was also significant negative correlation between levels of BDNF in the plasma of ADHD patients before treatment and improvement in hyperactivity symptoms with treatment (Pearson's correlation = -0.395, p = 0.037). The mean plasma BDNF levels increased after 6 weeks of treatment with methylphenidate. Also, we found an improvement in hyperactivity symptoms with decreasing baseline plasma BDNF levels. We recommend that more studies should be conducted in order to assess the possible roles of plasma BDNF levels in treatment response prediction and prognosis. © 2013 Elsevier Inc. All rights reserved.

Acute effects of 3,4-methylenedioxymethamphetamine and methylphenidate on circulating steroid levels in healthy subjects.

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Seibert, Julia; Hysek, Cédric M; Penno, Carlos A; Schmid, Yasmin; Kratschmar, Denise V; Liechti, Matthias E; Odermatt, Alex

2014-01-01

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') and methylphenidate are widely used psychoactive substances. MDMA primarily enhances serotonergic neurotransmission, and methylphenidate increases dopamine but has no serotonergic effects. Both drugs also increase norepinephrine, resulting in sympathomimetic properties. Here we studied the effects of MDMA and methylphenidate on 24-hour plasma steroid profiles. 16 healthy subjects (8 men, 8 women) were treated with single doses of MDMA (125 mg), methylphenidate (60 mg), MDMA + methylphenidate, and placebo on 4 separate days using a cross-over study design. Cortisol, cortisone, corticosterone, 11-dehydrocorticosterone, aldosterone, 11-deoxycorticosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone were repeatedly measured up to 24 h using liquid chromatography-tandem mass spectroscopy. MDMA significantly increased the plasma concentrations of cortisol, corticosterone, 11-dehydrocorticosterone, and 11-deoxycorticosterone and also tended to moderately increase aldosterone levels compared with placebo. MDMA also increased the sum of cortisol + cortisone and the cortisol/cortisone ratio, consistent with an increase in glucocorticoid production. MDMA did not alter the levels of cortisone, DHEA, DHEAS, androstenedione, or testosterone. Methylphenidate did not affect any of the steroid concentrations, and it did not change the effects of MDMA on circulating steroids. In summary, the serotonin releaser MDMA has acute effects on circulating steroids. These effects are not observed after stimulation of the dopamine and norepinephrine systems with methylphenidate. The present findings support the view that serotonin rather than dopamine and norepinephrine mediates the acute pharmacologically induced stimulation of the hypothalamic-pituitary-adrenal axis in the absence of other stressors. © 2014 S. Karger AG, Basel.

Working Memory after Traumatic Brain Injury: The Neural Basis of Improved Performance with Methylphenidate.

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Manktelow, Anne E; Menon, David K; Sahakian, Barbara J; Stamatakis, Emmanuel A

2017-01-01

Traumatic brain injury (TBI) often results in cognitive impairments for patients. The aim of this proof of concept study was to establish the nature of abnormalities, in terms of activity and connectivity, in the working memory network of TBI patients and how these relate to compromised behavioral outcomes. Further, this study examined the neural correlates of working memory improvement following the administration of methylphenidate. We report behavioral, functional and structural MRI data from a group of 15 Healthy Controls (HC) and a group of 15 TBI patients, acquired during the execution of the N-back task. The patients were studied on two occasions after the administration of either placebo or 30 mg of methylphenidate. Between group tests revealed a significant difference in performance when HCs were compared to TBI patients on placebo [ F (1, 28) = 4.426, p performance demonstrated the most benefit from methylphenidate. Changes in the TBI patient activation levels in the Left Cerebellum significantly and positively correlated with changes in performance ( r = 0.509, df = 13, p = 0.05). Whole-brain connectivity analysis using the Left Cerebellum as a seed revealed widespread negative interactions between the Left Cerebellum and parietal and frontal cortices as well as subcortical areas. Neither the TBI group on methylphenidate nor the HC group demonstrated any significant negative interactions. Our findings indicate that (a) TBI significantly reduces the levels of activation and connectivity strength between key areas of the working memory network and (b) Methylphenidate improves the cognitive outcomes on a working memory task. Therefore, we conclude that methylphenidate may render the working memory network in a TBI group more consistent with that of an intact working memory network.

Methylphenidate (Ritalin-associated Cataract and Glaucoma

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Chao-Kung Lu

2006-12-01

Full Text Available Methylphenidate hydrochloride (Ritalin is the drug of choice for attention deficit hyperactivity disorder (ADHD. However, an association of Ritalin with glaucoma has been reported. We report a case of Ritalin-associated cataract and glaucoma. A 10-year-old boy was diagnosed with ADHD and had received methylphenidate hydrochloride, 60 mg/day for 2 years. He presented with blurred vision. Best-corrected visual acuity was 6/60 in both eyes. Ocular examinations revealed intraocular pressure (IOP of 30 mmHg under medication, dense posterior subcapsular opacity of lens, pale disc with advanced cupping, and marked constriction of visual field. Despite maximal anti-glaucomatous medication, IOP still could not be controlled. The patient then received combined cataract and glaucoma surgery. Visual acuity improved and IOP was within normal limits in both eyes postoperatively. Large dose of methylphenidate may cause cataract and glaucoma. The mechanism remains unclear. Doctors should be aware of the possible ocular side effects of methylphenidate.

Methylphenidate during early consolidation affects long-term associative memory retrieval depending on baseline catecholamines.

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Wagner, Isabella C; van Buuren, Mariët; Bovy, Leonore; Morris, Richard G; Fernández, Guillén

2017-02-01

Synaptic memory consolidation is thought to rely on catecholaminergic signaling. Eventually, it is followed by systems consolidation, which embeds memories in a neocortical network. Although this sequence was demonstrated in rodents, it is unclear how catecholamines affect memory consolidation in humans. Here, we tested the effects of catecholaminergic modulation on synaptic and subsequent systems consolidation. We expected enhanced memory performance and increased neocortical engagement during delayed retrieval. Additionally, we tested if this effect was modulated by individual differences in a cognitive proxy measure of baseline catecholamine synthesis capacity. Fifty-three healthy males underwent a between-subjects, double-blind, placebo-controlled procedure across 2 days. On day 1, subjects studied and retrieved object-location associations and received 20 mg of methylphenidate or placebo. Drug intake was timed so that methylphenidate was expected to affect early consolidation but not encoding or retrieval. Memory was tested again while subjects were scanned three days later. Methylphenidate did not facilitate memory performance, and there was no significant group difference in activation during delayed retrieval. However, memory representations differed between groups depending on baseline catecholamines. The placebo group showed increased activation in occipito-temporal regions but decreased connectivity with the hippocampus, associated with lower baseline catecholamine synthesis capacity. The methylphenidate group showed stronger activation in the postcentral gyrus, associated with higher baseline catecholamine synthesis capacity. Altogether, methylphenidate during early consolidation did not foster long-term memory performance, but it affected retrieval-related neural processes depending on individual levels of baseline catecholamines.

Acute oral administration of low doses of methylphenidate targets calretinin neurons in the rat septal area.

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Alvaro eGarcía-Aviles

2015-03-01

Full Text Available Methylphenidate (MPD is a commonly administered drug to treat children suffering from attention deficit hyperactivity disorder (ADHD. Alterations in septal driven hippocampal theta rhythm may underlie attention deficits observed in these patients. Amongst others, the septo-hippocampal connections have long been acknowledged to be important in preserving hippocampal function. Thus, we wanted to ascertain if methylphenidate administration, which improves attention in patients, could affect septal areas connecting with hippocampus. We used low and orally administered methylphenidate doses (1.3; 2.7 and 5mg/Kg to rats what mimics the dosage range in humans. In our model, we observed no effect when using 1.3mg/Kg methylphenidate; whereas 2.7 and 5 mg/Kg induced a significant increase in c-fos expression specifically in the medial septum, an area intimately connected to the hippocampus. We analyzed dopaminergic areas such as nucleus accumbens and striatum, and found that only 5mg/Kg induced c-fos levels increase. In these areas tyrosine hydroxylase correlated well with c-fos staining, whereas in the medial septum the sparse tyrosine hydroxylase fibres did not overlap with c-fos positive neurons. Double immunofluorescence of c-fos with neuronal markers in the septal area revealed that co-localization with choline acethyl transferase, parvalbumin, and calbindin with c-fos did not change with MPD treatment; whereas, calretinin and c-fos double labeled neurons increased after MPD administration. Altogether, these results suggest that low and acute doses of methylphenidate primary target specific populations of caltretinin medial septal neurons.

A Randomized, Single-Blind, Substitution Study of OROS Methylphenidate (Concerta) in ADHD Adults Receiving Immediate Release Methylphenidate

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Spencer, Thomas J.; Mick, Eric; Surman, Craig B. H.; Hammerness, Paul; Doyle, Robert; Aleardi, Megan; Kotarski, Meghan; Williams, Courtney G.; Biederman, Joseph

2011-01-01

Objective: The main aim of this study was to examine the efficacy, tolerability, and compliance of an extended-release formulation of methylphenidate (OROS-MPH) in adults with ADHD receiving immediate-release methylphenidate (IR-MPH). Method: Participants were outpatient adults with ADHD who were stable on IR-MPH-administered TID. Participants…

Effects of Methylphenidate on Resting-State Functional Connectivity of the Mesocorticolimbic Dopamine Pathways in Cocaine Addiction

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Konova, Anna B.; Moeller, Scott J.; Tomasi, Dardo; Volkow, Nora D.; Goldstein, Rita Z.

2013-08-01

Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems–level effects of methylphenidate in this population have not yet been described. To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction.

Relation between therapeutic response and side effects induced by methylphenidate as observed by parents and teachers of children with ADHD

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Bhat Venkataramana

2011-04-01

Full Text Available Abstract Background The desired (therapeutic and undesired (side effects of methylphenidate might have underlying correlations. The aim of this study was to explore the strength and the possible sources of these correlations. Methods One hundred and fifty-seven children with ADHD (6-12 years were administered placebo and methylphenidate (0.5 mg/kg in a divided b.i.d. dose, each for a one-week period, in a double-blind, crossover trial. Therapeutic response was assessed using the Conners' Global Index for parents (CGI-Parents and teachers (CGI-Teachers, while side effects were assessed using the Barkley Side Effects Rating Scale (SERS. Results The side effect profile as assessed by the SERS was similar to that of previous studies with insomnia, decreased appetite, and headaches showing significant treatment effects (p Conclusion The greater "mood/anxiety" side effects on methylphenidate and placebo, the less the parents observe improvement of their children while treated with methylphenidate. This suggests that the correlations between "mood/anxiety" side effects and poor response to treatment may be driven by observer effects rather than biological commonalities between therapeutic and side effects of methylphenidate.

Activation of D1 dopamine receptors induces emergence from isoflurane general anesthesia

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Taylor, Norman E.; Chemali, Jessica J.; Brown, Emery N.; Solt, Ken

2012-01-01

BACKGROUND A recent study showed that methylphenidate induces emergence from isoflurane anesthesia. Methylphenidate inhibits dopamine and norepinephrine reuptake transporters. The objective of this study was to test the hypothesis that selective dopamine receptor activation induces emergence from isoflurane anesthesia. METHODS In adult rats, we tested the effects of chloro-APB (D1 agonist) and quinpirole (D2 agonist) on time to emergence from isoflurane general anesthesia. We then performed a dose–response study to test for chloro-APB-induced restoration of righting during continuous isoflurane anesthesia. SCH-23390 (D1 antagonist) was used to confirm that the effects induced by chloro-APB are specifically mediated by D1 receptors. In a separate group of animals, spectral analysis was performed on surface electroencephalogram recordings to assess neurophysiological changes induced by chloro-APB and quinpirole during isoflurane general anesthesia. RESULTS Chloro-APB decreased median time to emergence from 330s to 50s. The median difference in time to emergence between the saline control group (n=6) and the chloro-APB group (n = 6) was 222s (95% CI: 77–534s, Mann-Whitney test). This difference was statistically significant (p = 0.0082). During continuous isoflurane anesthesia, chloro-APB dose-dependently restored righting (n = 6) and decreased electroencephalogram delta power (n = 4). These effects were inhibited by pretreatment with SCH-23390. Quinpirole did not restore righting (n = 6) and had no significant effect on the electroencephalogram (n = 4) during continuous isoflurane anesthesia. CONCLUSIONS Activation of D1 receptors by chloro-APB decreases time to emergence from isoflurane anesthesia, and produces behavioral and neurophysiological evidence of arousal during continuous isoflurane anesthesia. These findings suggest that selective activation of a D1 receptor-mediated arousal mechanism is sufficient to induce emergence from isoflurane general

The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities.

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Faraone, Stephen V

2018-04-01

Psychostimulants, including amphetamines and methylphenidate, are first-line pharmacotherapies for individuals with attention-deficit/hyperactivity disorder (ADHD). This review aims to educate physicians regarding differences in pharmacology and mechanisms of action between amphetamine and methylphenidate, thus enhancing physician understanding of psychostimulants and their use in managing individuals with ADHD who may have comorbid psychiatric conditions. A systematic literature review of PubMed was conducted in April 2017, focusing on cellular- and brain system-level effects of amphetamine and methylphenidate. The primary pharmacologic effect of both amphetamine and methylphenidate is to increase central dopamine and norepinephrine activity, which impacts executive and attentional function. Amphetamine actions include dopamine and norepinephrine transporter inhibition, vesicular monoamine transporter 2 (VMAT-2) inhibition, and monoamine oxidase activity inhibition. Methylphenidate actions include dopamine and norepinephrine transporter inhibition, agonist activity at the serotonin type 1A receptor, and redistribution of the VMAT-2. There is also evidence for interactions with glutamate and opioid systems. Clinical implications of these actions in individuals with ADHD with comorbid depression, anxiety, substance use disorder, and sleep disturbances are discussed. Copyright © 2018 The Author. Published by Elsevier Ltd.. All rights reserved.

Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD).

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dela Peña, Ike; Kim, Hee Jin; Sohn, Aeree; Kim, Bung-Nyun; Han, Doug Hyun; Ryu, Jong Hoon; Shin, Chan Young; Noh, Minsoo; Cheong, Jae Hoon

2014-05-06

Methylphenidate is the most commonly used stimulant drug for the treatment of attention-deficit/hyperactivity disorder (ADHD). Research has found that methylphenidate is a "reinforcer" and that individuals with ADHD also abuse this medication. Nevertheless, the molecular consequences of long-term recreational methylphenidate use or abuse in individuals with ADHD are not yet fully known. Spontaneously hypertensive rats (SHR), the most validated and widely used ADHD animal model, were pretreated with methylphenidate (5 mg/kg, i.p.) during their adolescence (post-natal day [PND] 42-48) and tested for subsequent methylphenidate-induced conditioned place preference (CPP) and self-administration. Thereafter, the differentially expressed genes in the prefrontal cortex (PFC) and striatum of representative methylphenidate-treated SHRs, which showed CPP to and self-administration of methylphenidate, were analyzed. Genome-wide transcriptome profiling analyses revealed 30 differentially expressed genes in the PFC, which include transcripts involved in apoptosis (e.g. S100a9, Angptl4, Nfkbia), transcription (Cebpb, Per3), and neuronal plasticity (Homer1, Jam2, Asap1). In contrast, 306 genes were differentially expressed in the striatum and among them, 252 were downregulated. The main functional categories overrepresented among the downregulated genes include those involved in cell adhesion (e.g. Pcdh10, Ctbbd1, Itgb6), positive regulation of apoptosis (Perp, Taf1, Api5), (Notch3, Nsbp1, Sik1), mitochondrion organization (Prps18c, Letm1, Uqcrc2), and ubiquitin-mediated proteolysis (Nedd4, Usp27x, Ube2d2). Together, these changes indicate methylphenidate-induced neurotoxicity, altered synaptic and neuronal plasticity, energy metabolism and ubiquitin-dependent protein degradation in the brains of methylphenidate-treated SHRs, which showed methylphenidate CPP and self-administration. In addition, these findings may also reflect cognitive impairment associated with chronic

Methylphenidate use and school performance among primary school children: a descriptive study.

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van der Schans, Jurjen; Çiçek, Rukiye; Vardar, Sefike; Bos, Jens Hj; de Vries, Tjalling W; Hoekstra, Pieter J; Hak, Eelko

2017-03-29

There is no conclusive evidence that stimulants have beneficial effects on major associated outcome parameters, particularly school performance. We assessed the differences in school performance among children using methylphenidate at the end of primary school in relation to various parameters of methylphenidate use. We linked children from a pharmacy prescription database with standardized achievement test results at the end of primary school. We explored differences in test scores between current methylphenidate users versus never users and methylphenidate users who stopped treatment at least 6 months before the test, early versus late starters, different dosage of methylphenidate, and concurrent antipsychotic or asthma treatment. Out of the 7736 children, 377 (4.9%) children were treated with methylphenidate at the time of the test. After adjusting for confounders the methylphenidate users (532.58 ± .48) performed significantly lower on the test than never users (534.72 ± .11). Compared with late starters of methylphenidate treatment (536.94 ± 1.51) we found significantly lower test scores for the early starters (532.33 ± .50). Our study indicates that children using methylphenidate still perform less at school compared to their peers. Our study also suggests that earlier start of methylphenidate treatment is associated with a lower school performance compared to children starting later with the treatment. This result could either indicate a limited effect of long term treatment or a more strongly affected group of early starters.

Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal and Subcortical Limbic Mechanisms in Rats

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Achterberg, E.J. Marijke; van Kerkhof, Linda W.M.; Damsteegt, Ruth; Trezza, Viviana

2015-01-01

Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD. PMID:25568111

Pharmacogenetics of Methylphenidate Response in Preschoolers with ADHD

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McGough, James; McCracken, James; Swanson, James; Riddle, Mark; Kollins, Scott; Greenhill, Laurence; Abikoff, Howard; Davies, Mark; Chuang, Shirley; Wigal, Tim; Wigal, Sharon; Posner, Kelly; Skrobala, Anne; Kastelic, Elizabeth; Ghuman, Jaswinder; Cunningham, Charles; Shigawa, Sharon; Moyzis, Robert; Vitiello, Benedetto

2006-01-01

Objective: The authors explored genetic moderators of symptom reduction and side effects in methylphenidate-treated preschool-age children diagnosed with attention-deficit/hyperactivity disorder (ADHD). Method: DNA was isolated from 81 subjects in a double-blind, placebo-controlled, crossover methylphenidate titration. Parents and teachers…

Prevalence of methylphenidate use by university students in Campos dos Goytacazes, RJ

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Fernanda Fraga Pessanha

2014-08-01

Full Text Available Methylphenidate is a central nervous system stimulant commonly prescribed for children with Attention Deficit Hyperactivity Disorder. The aim of this study was to identify the prevalence of methylphenidate users among college students, as well as the main reasons for it, ways of acquisition, and possible side effects. The study demonstrated a 60% prevalence of the use of methylphenidate by university students in Campos dos Goytacazes. We conclude that there is a high rate of use of methylphenidate among students in this city. The authors suggest an awareness campaign on the risks of inappropriate use of methylphenidate.

Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder

International Nuclear Information System (INIS)

Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Tomasi, D.; Kollins, S.H.; Wigal, T.L.; Newcorn, J.H.; Telang, F.W.; Fowler, J.S.; Logan, J.; Wong, C.T.; Swanson, J.M.

2012-01-01

Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and ( 11 C)raclopride (D 2 /D 3 receptor radioligand sensitive to competition with endogenous dopamine). Clinical responses were assessed using the Conners Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D 2 /D 3 receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response.

Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder

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Volkow N. D.; Wang G.; Volkow, N.D.; Wang, G.-J.; Tomasi, D.; Kollins, S.H.; Wigal, T.L.; Newcorn, J.H.; Telang, F.W.; Fowler, J.S.; Logan, J.; Wong, C.T.; Swanson, J.M.

2012-01-18

Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [{sup 11}C]raclopride (D{sub 2}/D{sub 3} receptor radioligand sensitive to competition with endogenous dopamine). Clinical responses were assessed using the Conners Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D{sub 2}/D{sub 3} receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response.

Perioperative Outcome of Dyssomnia Patients on Chronic Methylphenidate Use

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Nicoleta Stoicea MD, PhD

2014-01-01

Full Text Available Methylphenidate is frequently prescribed for attention deficit hyperactivity disorder, narcolepsy, and other sleep disorders requiring psychostimulants. Our report is based on 2 different clinical experiences of patients with chronic methylphenidate use, undergoing general anesthesia. These cases contrast different strategies of taking versus withholding the drug treatment on the day of surgery. From the standpoint of anesthetic management and patient safety, the concerns for perioperative methylphenidate use are mainly related to cardiovascular stability and possible counteraction of sedatives and anesthetics.

Chronic methylphenidate-effects over circadian cycle of young and adult rats submitted to open-field and object recognition tests.

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Gomes, Karin M; Souza, Renan P; Valvassori, Samira S; Réus, Gislaine Z; Inácio, Cecília G; Martins, Márcio R; Comim, Clarissa M; Quevedo, João

2009-11-01

In this study age-, circadian rhythm- and methylphenidate administration- effect on open field habituation and object recognition were analyzed. Young and adult male Wistar rats were treated with saline or methylphenidate 2.0 mg/kg for 28 days. Experiments were performed during the light and the dark cycle. Locomotor activity was significantly altered by circadian cycle and methylphenidate treatment during the training session and by drug treatment during the testing session. Exploratory activity was significantly modulated by age during the training session and by age and drug treatment during the testing session. Object recognition memory was altered by cycle at the training session; by age 1.5 h later and by cycle and age 24 h after the training session. These results show that methylphenidate treatment was the major modulator factor on open-field test while cycle and age had an important effect on object recognition experiment.

Methylphenidate for Apathy in Community-Dwelling Older Veterans With Mild Alzheimer's Disease: A Double-Blind, Randomized, Placebo-Controlled Trial.

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Padala, Prasad R; Padala, Kalpana P; Lensing, Shelly Y; Ramirez, Daniel; Monga, Varun; Bopp, Melinda M; Roberson, Paula K; Dennis, Richard A; Petty, Frederick; Sullivan, Dennis H; Burke, William J

2018-02-01

Apathy is a common behavioral problem in Alzheimer's disease. Apathy has profound consequences, such as functional impairment, higher service utilization, higher caregiver burden, and increased mortality. The authors' objective was to study the effects of methylphenidate on apathy in Alzheimer's disease. A 12-week, prospective, double-blind, randomized, placebo-controlled trial (methylphenidate versus placebo) was conducted in community-dwelling veterans (N=60) with mild Alzheimer's disease. The primary outcome for apathy (Apathy Evaluation Scale-Clinician) and secondary outcomes for cognition (Mini-Mental State Examination, Modified Mini-Mental State Examination), functional status (activities of daily living, instrumental activities of daily living), improvement and severity (Clinical Global Impressions Scale [CGI]), caregiver burden (Zarit Burden Scale), and depression (Cornell Scale for Depression in Dementia) were measured at baseline and at 4, 8, and 12 weeks. Participants were all men (77 years old, SD=8). After adjusting for baseline, the methylphenidate group had significantly greater improvement in apathy than the placebo group at 4 weeks, 8 weeks, and 12 weeks. At 12 weeks, there was also greater improvement in cognition, functional status, caregiver burden, CGI scores, and depression in the methylphenidate group compared with the placebo group. Methylphenidate improved apathy in a group of community-dwelling veterans with mild Alzheimer's disease. Methylphenidate also improved cognition, functional status, caregiver burden, CGI scores, and depression.

Developmental rates of immatures of three Chrysomya species (Diptera: Calliphoridae) under the effect of methylphenidate hydrochloride, phenobarbital, and methylphenidate hydrochloride associated with phenobarbital.

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Rezende, Fábio; Alonso, Marcela A; Souza, Carina M; Thyssen, Patrícia J; Linhares, Arício X

2014-05-01

Entomotoxicology is focused on obtaining data on necrophagous entomofauna, for criminal investigations purposes. This study aimed to evaluate the effect of different concentrations of methylphenidate hydrochloride, phenobarbital, and their association on the developmental rate, larval and pupal survivorship, and the interval of emergence of adults of Chrysomya albiceps (Wiedemann), Chrysomya megacephala (Fabricius), and Chrysomya putoria (Wiedemann) (Diptera: Calliphoridae). Considering the therapeutic dose (TD) of methylphenidate hydrochloride (0.29 mg/Kg), the concentrations tested were 10× TD, 50× TD, and 100× TD. For phenobarbital, the concentrations used were 1× TD (=150 mg/Kg), 3.3× TD, and 6.7× TD. For the association of the drugs, the combinations used were 10× TD-methylphenidate hydrochloride plus 1× TD-phenobarbital, 50× TD-methylphenidate hydrochloride plus 3.3× TD-phenobarbital, and 100× TD-methylphenidate hydrochloride plus 6.7× TD-phenobarbital. The control group, without addition of drug, was maintained under the same conditions of temperature (25 ± 1 °C), humidity (70 ± 10%), and photoperiod (12 h). Specimens of each group were weighed every 12 h until pupariation. The developmental rate of the three Chrysomya species immatures was monitored. For C. albiceps the developmental time was delayed in 24 h for methylphenidate hydrochloride group and in 12 h for the phenobarbital and the drugs association groups. The effect was observed only at specific ages for C. megacephala, without altering the developmental time. For C. putoria, the developmental time was delayed in 12 h for methylphenidate hydrochloride group and in 24 h for the phenobarbital and the drugs association groups. The emergence interval was similar among all experimental groups, but larval and pupal viabilities were affected in different ways.

Methylphenidate Modulates Functional Network Connectivity to Enhance Attention

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Zhang, Sheng; Hsu, Wei-Ting; Scheinost, Dustin; Finn, Emily S.; Shen, Xilin; Constable, R. Todd; Li, Chiang-Shan R.; Chun, Marvin M.

2016-01-01

Recent work has demonstrated that human whole-brain functional connectivity patterns measured with fMRI contain information about cognitive abilities, including sustained attention. To derive behavioral predictions from connectivity patterns, our group developed a connectome-based predictive modeling (CPM) approach (Finn et al., 2015; Rosenberg et al., 2016). Previously using CPM, we defined a high-attention network, comprising connections positively correlated with performance on a sustained attention task, and a low-attention network, comprising connections negatively correlated with performance. Validating the networks as generalizable biomarkers of attention, models based on network strength at rest predicted attention-deficit/hyperactivity disorder (ADHD) symptoms in an independent group of individuals (Rosenberg et al., 2016). To investigate whether these networks play a causal role in attention, here we examined their strength in healthy adults given methylphenidate (Ritalin), a common ADHD treatment, compared with unmedicated controls. As predicted, individuals given methylphenidate showed patterns of connectivity associated with better sustained attention: higher high-attention and lower low-attention network strength than controls. There was significant overlap between the high-attention network and a network with greater strength in the methylphenidate group, and between the low-attention network and a network with greater strength in the control group. Network strength also predicted behavior on a stop-signal task, such that participants with higher go response rates showed higher high-attention and lower low-attention network strength. These results suggest that methylphenidate acts by modulating functional brain networks related to sustained attention, and that changing whole-brain connectivity patterns may help improve attention. SIGNIFICANCE STATEMENT Recent work identified a promising neuromarker of sustained attention based on whole

Early life stress induces attention-deficit hyperactivity disorder (ADHD)-like behavioral and brain metabolic dysfunctions: functional imaging of methylphenidate treatment in a novel rodent model.

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Bock, J; Breuer, S; Poeggel, G; Braun, K

2017-03-01

In a novel animal model Octodon degus we tested the hypothesis that, in addition to genetic predisposition, early life stress (ELS) contributes to the etiology of attention-deficit hyperactivity disorder-like behavioral symptoms and the associated brain functional deficits. Since previous neurochemical observations revealed that early life stress impairs dopaminergic functions, we predicted that these symptoms can be normalized by treatment with methylphenidate. In line with our hypothesis, the behavioral analysis revealed that repeated ELS induced locomotor hyperactivity and reduced attention towards an emotionally relevant acoustic stimulus. Functional imaging using ( 14 C)-2-fluoro-deoxyglucose-autoradiography revealed that the behavioral symptoms are paralleled by metabolic hypoactivity of prefrontal, mesolimbic and subcortical brain areas. Finally, the pharmacological intervention provided further evidence that the behavioral and metabolic dysfunctions are due to impaired dopaminergic neurotransmission. Elevating dopamine in ELS animals by methylphenidate normalized locomotor hyperactivity and attention-deficit and ameliorated brain metabolic hypoactivity in a dose-dependent manner.

Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents

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Storebø, Ole Jakob; Krogh, Helle B; Ramstad, Erica

2015-01-01

STUDY QUESTION: Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents? METHODS: Electronic databases were searched up to February 2015 for parallel and crossover randomised clinical trials comparing methylphenidate...

Working memory capacity predicts effects of methylphenidate on reversal learning

NARCIS (Netherlands)

Schaaf, M.E. van der; Fallon, S.J.; Huurne, N.P. ter; Buitelaar, J.K.; Cools, R.

2013-01-01

Increased use of stimulant medication, such as methylphenidate, by healthy college students has raised questions about its cognitive-enhancing effects. Methylphenidate acts by increasing extracellular catecholamine levels and is generally accepted to remediate cognitive and reward deficits in

Possible effect of norepinephrine transporter polymorphisms on methylphenidate-induced changes in neuropsychological function in attention-deficit hyperactivity disorder.

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Park, Subin; Kim, Jae-Won; Yang, Young-Hui; Hong, Soon-Beom; Park, Min-Hyeon; Kim, Boong-Nyun; Shin, Min-Sup; Yoo, Hee-Jeong; Cho, Soo-Churl

2012-05-16

Dysregulation of noradrenergic system may play important roles in pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We examined the relationship between polymorphisms in the norepinephrine transporter SLC6A2 gene and attentional performance before and after medication in children with ADHD. Fifty-three medication-naïve children with ADHD were genotyped and evaluated using the continuous performance test (CPT). After 8-weeks of methylphenidate treatment, these children were evaluated by CPT again. We compared the baseline CPT measures and the post-treatment changes in the CPT measures based on the G1287A and the A-3081T polymorphisms of SLC6A2. There was no significant difference in the baseline CPT measures associated with the G1287A or A-3081T polymorphisms. After medication, however, ADHD subjects with the G/G genotype at the G1287A polymorphism showed a greater decrease in the mean omission error scores (p = 0.006) than subjects with the G/A or A/A genotypes, and subjects with the T allele at the A-3081T polymorphism (T/T or A/T) showed a greater decrease in the mean commission error scores (p = 0.003) than those with the A/A genotypes. Our results provide evidence for the possible role of the G1287A and A-3081T genotypes of SLC6A2 in methylphenidate-induced improvement in attentional performance and support the noradrenergic hypothesis for the pathophysiology of ADHD.

Methylphenidate for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents

DEFF Research Database (Denmark)

Storebø, Ole J; Simonsen, Erik; Gluud, Christian

2016-01-01

CLINICAL QUESTION: Is treatment with methylphenidate associated with benefits or harms for children and adolescents with attention-deficit/hyperactivity disorder (ADHD)? BOTTOM LINE: Methylphenidate is associated with improvement in ADHD symptoms, general behavior, and quality of life; however, due...

Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments*

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Jordan, Chloe J.; Harvey, Roxann C.; Baskin, Britahny B.; Dwoskin, Linda P.; Kantak, Kathleen M.

2014-01-01

Background Attention-deficit/hyperactivity disorder (ADHD) is often comorbid with cocaine abuse. Controversy exists regarding long-term consequences of ADHD medications on cocaine abuse liability. Whereas childhood methylphenidate treatment may be preventative, methylphenidate in teens appears to further increase later cocaine abuse risk. In rodents, adolescent methylphenidate treatment further increases adult cocaine self-administration in the Spontaneously Hypertensive Rat (SHR) model of ADHD, whereas adolescent atomoxetine treatment does not. Effects of ADHD medications on cocaine cue reactivity, a critical component of addiction, are unknown. Methods To investigate this, SHR, Wistar-Kyoto (inbred control) and Wistar (outbred control) rats received therapeutically relevant doses of methylphenidate (1.5 mg/kg, oral) and atomoxetine (0.3 mg/kg, intraperitoneal), or respective vehicles from post-natal day 28–55. Cocaine seeking, reflecting cue reactivity, was measured in adulthood during self-administration maintenance and cue-induced reinstatement tests conducted under a second-order schedule. Results Compared to control strains, SHR earned more cocaine infusions, emitted more cocaine-seeking responses during maintenance and reinstatement testing, and required more sessions to reach the extinction criterion. Compared to vehicle, adolescent methylphenidate, but not atomoxetine, further increased cocaine intake during maintenance testing in SHR. Adolescent atomoxetine, but not methylphenidate, decreased cocaine seeking during reinstatement testing in SHR. Neither medication had effects on cocaine intake or cue reactivity in control strains. Conclusions The SHR successfully model ADHD and cocaine abuse comorbidity and show differential effects of adolescent ADHD medications on cocaine intake and cue reactivity during adulthood. Thus, SHR have heuristic value for assessing neurobiology underlying the ADHD phenotype and for evaluating pharmacotherapeutics for ADHD

Reversible Dopamine Transporter Modifications in Response to Methylphenidate Treatment of ADHD

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J Gordon Millichap

2005-09-01

Full Text Available Single-photon emission computed tomography (SPECT was used to monitor the dopamine transporter activity in 5 males, ages 8 to 10, with ADHD, after cessation of methylphenidate (MPH treatment, in a study at the University Hospital Maastricht, The Netherlands.

Methylphenidate significantly improves declarative memory functioning of adults with ADHD.

NARCIS (Netherlands)

Verster, J.C.; Bekker, E.M.; Kooij, J.J.; Buitelaar, J.K.; Verbaten, M.N.; Volkerts, E.R.; Olivier, B.

2010-01-01

BACKGROUND: Declarative memory deficits are common in untreated adults with attention-deficit hyperactivity disorder (ADHD), but limited evidence exists to support improvement after treatment with methylphenidate. The objective of this study was to examine the effects of methylphenidate on memory

Methylphenidate administration determines enduring changes in neuroglial network in rats.

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Cavaliere, Carlo; Cirillo, Giovanni; Bianco, Maria Rosaria; Adriani, Walter; De Simone, Antonietta; Leo, Damiana; Perrone-Capano, Carla; Papa, Michele

2012-01-01

Repeated exposure to psychostimulant drugs induces complex molecular and structural modifications in discrete brain regions of the meso-cortico-limbic system. This structural remodeling is thought to underlie neurobehavioral adaptive responses. Administration to adolescent rats of methylphenidate (MPH), commonly used in attention deficit and hyperactivity disorder (ADHD), triggers alterations of reward-based behavior paralleled by persistent and plastic synaptic changes of neuronal and glial markers within key areas of the reward circuits. By immunohistochemistry, we observe a marked increase of glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) expression and a down-regulation of glial glutamate transporter GLAST in dorso-lateral and ventro-medial striatum. Using electron microscopy, we find in the prefrontal cortex a significant reduction of the synaptic active zone length, paralleled by an increase of dendritic spines. We demonstrate that in limbic areas the MPH-induced reactive astrocytosis affects the glial glutamatergic uptake system that in turn could determine glutamate receptor sensitization. These processes could be sustained by NO production and synaptic rearrangement and contribute to MPH neuroglial induced rewiring. Copyright © 2011. Published by Elsevier B.V.

Effect of repeated oral therapeutic doses of methylphenidate on food intake and growth rate in rats.

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Alam, Nausheen; Najam, Rahila

2015-01-01

Central nervous system stimulants are known to produce anorexia. Previous data suggest that methylphenidate can have variable effects on caloric intake and growth rate. A dose-response study was performed to monitor caloric intake, liquid intake and growth rate in rats following repeated administration of human oral therapeutic doses 2 mg/kg/day, 5mg/kg/day and 8mg/kg/day of methylphenidate. We found that food intake and water intake, increased in all weeks and at all doses used in the study. Growth rate increased more at higher dose (8mg/kg/day) and at low dose (2mg/kg/day) of methylphenidate in 1(st) and 2(nd) week whereas more decreased by the above doses in 3(rd) week, suggesting that food stimulation leads to initial increase in growth rate but long term administration of methylphenidate attenuate growth rate that is not due to modulation of appetite but may be due to anxiety and increased activity produce by stimulants. A possible role of DA, 5HT receptors in modulation of appetite and anxiety is discussed.

Prevalence of methylphenidate use among Canadian children following parental divorce.

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Strohschein, Lisa A

2007-06-05

Evidence suggests that children living in single-parent or step-parent households are more likely than children in households with 2 biological parents to be prescribed methylphenidate. I conducted a study of prospective data to investigate parental divorce as a predictor of methylphenidate use. I used data for children who participated in the National Longitudinal Survey of Children and Youth from 1994 to 2000. The sample was restricted to children who remained in the survey in 2000 and who, at initial interview, lived in a household with 2 biological parents (n = 4784). A generalized estimating equation model was used to compare the odds ratios of methylphenidate use among children whose parents obtained a divorce between 1994 and 2000 relative to children whose parents remained married during this period. Between 1994 and 2000, 633 children (13.2%) experienced the divorce of their parents. The proportion of children who received methylphenidate at any time between 1994 and 2000 was 3.3% among those whose parents remained married and 6.1% among those whose parents divorced during this period. After adjustment for age of the mother and sex and age of the child, I found that methylphenidate use was significantly higher among children whose parents subsequently divorced than among those whose parents remained married (odds ratio 1.82, 95% confidence interval 1.01-3.33). The increased risk of children receiving a prescription for methylphenidate in the period following parental divorce raises questions about the causal links in this association. Future research is needed to replicate these findings and to investigate possible explanations.

Methylphenidate: increased abuse or appropriate use?

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Llana, M E; Crismon, M L

1999-01-01

To address the question of the significant increase in methylphenidate (MPD) prescriptions being written and to make recommendations for health care providers involved in providing care for patients with attention deficit hyperactivity disorder (ADHD) and their families. Medline search 1966-1998 for professional articles using the following search terms--methylphenidate, children, adolescents, abuse; Internet search using MPD, Ritalin, and ADHD; and Paper Chase search using methylphenidate. The available literature regarding potential abuse or diversion of MPD consists of case reports, review articles, newspaper articles, and a Drug Enforcement Administration (DEA) publication. All available literature sources were used. Although the media and DEA report significant abuse and diversion of prescribed MPD, a review of the available literature did not reveal data to substantiate these claims. Nonetheless, there are reasons to suspect that abuse and diversion occur. A potential contributing factor to abuse is the reported similarities in pharmacodynamics and pharmacokinetics between MPD and cocaine. Recommendations are made to decrease the possibility of abuse and diversion of prescribed MPD. A balanced middle ground must be found regarding the benefits of MPD and its abuse potential. Education of clinicians, patients, and family members is key in ensuring that MPD is used appropriately.

Laboratory measures of methylphenidate effects in cocaine-dependent patients receiving treatment.

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Roache, J D; Grabowski, J; Schmitz, J M; Creson, D L; Rhoades, H M

2000-02-01

Two experiments examined the effects of methylphenidate in male and female patients enrolled in an outpatient treatment program for primary cocaine dependence. The first study was a component of a double-blind efficacy trial wherein 57 patients were first tested in a human laboratory for their initial responsiveness to medication. Patients were randomly assigned to receive either placebo or methylphenidate treatment and received their first dose in the human laboratory environment before continuing in outpatient treatment. Methylphenidate was given as a 20-mg sustained-release dose (twice daily) plus an additional 5-mg immediate-release dose combined with the morning dose. Methylphenidate increased heart rate and subjective ratings; however, the subjective effects were primarily of a "dysphoric" nature, and significant effects were limited to increases in anxiety, depression, and anger on the Profile of Mood States; shaky/jittery ratings on a visual analog scale; and dysphoria on the lysergic acid diethylamide (LSD) scale of the Addiction Research Center Inventory. Methylphenidate did not increase cocaine craving nor ratings suggesting abuse potential (i.e., Morphine-Benzedrine Group or drug-liking scores, etc.). None of the drug effects observed in the human laboratory was of clinical concern, and no subject was precluded from continuing in the outpatient study. After outpatient treatment completion, 12 patients were brought back into a second double-blind human laboratory study in which three doses (15, 30, and 60 mg) of immediate-release methylphenidate were administered in an ascending series preceded and followed by placebo. Methylphenidate produced dose-related increases in heart rate, subjective ratings of shaky/jittery, and LSD/dysphoria without significantly altering cocaine craving or stimulant euphoria ratings. These results suggest that stimulant substitution-type approaches to the treatment of cocaine dependence are not necessarily contraindicated

Effects of methylphenidate on attention in Wistar rats treated with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4).

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Hauser, Joachim; Reissmann, Andreas; Sontag, Thomas-A; Tucha, Oliver; Lange, Klaus W

2017-05-01

The aim of this study was to assess the effects of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) on attention in rats as measured using the 5-choice-serial-reaction-time task (5CSRTT) and to investigate whether methylphenidate has effects on DSP4-treated rats. Methylphenidate is a noradrenaline and dopamine reuptake inhibitor and commonly used in the pharmacological treatment of individuals with attention deficit/hyperactivity disorder (ADHD). Wistar rats were trained in the 5CSRTT and treated with one of three doses of DSP4 or saline. Following the DSP4 treatment rats were injected with three doses of methylphenidate or saline and again tested in the 5CSRTT. The treatment with DSP4 caused a significant decline of performance in the number of correct responses and a decrease in response accuracy. A reduction in activity could also be observed. Whether or not the cognitive impairments are due to attention deficits or changes in explorative behaviour or activity remains to be investigated. The treatment with methylphenidate had no beneficial effect on the rats' performance regardless of the DSP4 treatment. In the group without DSP4 treatment, methylphenidate led to a reduction in response accuracy and bidirectional effects in regard to parameters related to attention. These findings support the role of noradrenaline in modulating attention and call for further investigations concerning the effects of methylphenidate on attentional processes in rats.

The adolescent outcome of children with attention deficit hyperactivity disorder treated with methylphenidate or methylphenidate combined with multimodal behaviour therapy: Results of a naturalistic follow-up study

NARCIS (Netherlands)

van der Oord, S.; Prins, P.J.M.; Oosterlaan, J.; Emmelkamp, P.M.G

2012-01-01

Objective: Children with attention deficit hyperactivity disorder (ADHD) who participated in a randomized clinical trial, which compared a brief intensive multimodal behaviour therapy combined with optimally titrated methylphenidate to optimally titrated methylphenidate alone (n=45), were

Cardiac Arrest following a Myocardial Infarction in a Child Treated with Methylphenidate

DEFF Research Database (Denmark)

Munk, Kim; Gormsen, Lise Kirstine; Kim, Won Yong

2015-01-01

-years, did not report any cases of myocardial infarction in current users of methylphenidate, and the risk of serious adverse cardiac events was not found to be increased. We present a case with an 11-year-old child, treated with methylphenidate, who suffered cardiac arrest and was diagnosed with a remote...... myocardial infarction. This demonstrates that myocardial infarction can happen due to methylphenidate exposure in a cardiac healthy child, without cardiovascular risk factors....

Possible effect of norepinephrine transporter polymorphisms on methylphenidate-induced changes in neuropsychological function in attention-deficit hyperactivity disorder

Directory of Open Access Journals (Sweden)

Park Subin

2012-05-01

Full Text Available Abstract Background Dysregulation of noradrenergic system may play important roles in pathophysiology of attention-deficit/hyperactivity disorder (ADHD. We examined the relationship between polymorphisms in the norepinephrine transporter SLC6A2 gene and attentional performance before and after medication in children with ADHD. Methods Fifty-three medication-naïve children with ADHD were genotyped and evaluated using the continuous performance test (CPT. After 8-weeks of methylphenidate treatment, these children were evaluated by CPT again. We compared the baseline CPT measures and the post-treatment changes in the CPT measures based on the G1287A and the A-3081T polymorphisms of SLC6A2. Results There was no significant difference in the baseline CPT measures associated with the G1287A or A-3081T polymorphisms. After medication, however, ADHD subjects with the G/G genotype at the G1287A polymorphism showed a greater decrease in the mean omission error scores (p = 0.006 than subjects with the G/A or A/A genotypes, and subjects with the T allele at the A-3081T polymorphism (T/T or A/T showed a greater decrease in the mean commission error scores (p = 0.003 than those with the A/A genotypes. Conclusions Our results provide evidence for the possible role of the G1287A and A-3081T genotypes of SLC6A2 in methylphenidate-induced improvement in attentional performance and support the noradrenergic hypothesis for the pathophysiology of ADHD.

Methylphenidate as a cognitive enhancer in healthy young people

Science.gov (United States)

Batistela, Silmara; Bueno, Orlando Francisco Amodeo; Vaz, Leonardo José; Galduróz, José Carlos Fernandes

2016-01-01

ABSTRACT The so-called cognitive enhancers have been widely and increasingly used by healthy individuals who seek improvements in cognitive performance despite having no pathologies. One drug used for this purpose is methylphenidate, a first-line drug for the treatment of attention deficit hyperactivity disorder (ADHD). Objective: The aim of the present study was to test the effect of acute administration of varying doses of methylphenidate (10 mg, 20 mg, 40 mg and placebo) on a wide range of cognitive functions in healthy young people. Methods: A total of 36 young university students and graduates participated in the study. The participants underwent tests of attention and of episodic, and working memory. Results: No differences in performance were observed on any of the tests. There was a dose-dependent (40 mg > placebo) effect on self-reported wellbeing. Conclusions: According to the recent literature, psychostimulant medications, such as methylphenidate, improve performance when cognitive processes are below an optimal level, which was not the case for the subjects of the present study. We suggest the impression that methylphenidate enhances cognitive performance in healthy young people, justifying its use, may be due to improvements in subjective wellbeing promoted by the drug. PMID:29213444

[Methylphenidate use in dogs with attention deficit hyperactivity disorder (ADHD). A case report of a Weimaraner bitch].

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Piturru, P

2014-04-16

A 10-month-old Weimaraner bitch was presented at the practice exhibiting agitation, hyperactivity, inability to learn and attention deficit. The diagnostic findings were excessive, long-lasting acoustic and locomotory activity with unexpected inappropriate reactions. Hematological and biochemical blood analyses did not demonstrate abnormal findings. The first attempts at behavioral therapy and fluoxetine application were unsatisfactory. Therefore, a test was conducted with medication for central nervous system stimulation to confirm a diagnosis of hyperkinesis. Following the diagnosis of attention deficit hyperactivity disorder, the therapy was continued with behavioral modifications, with special consideration of rehabituation and resocialization as well as the use of methylphenidate. During the course of the therapy the bitch developed hyperactivity again when on heat. After changing the dosage of methylphenidate and additionally using dog appeasing pheromone, the behavior of the bitch became normal after 8 days. Two months later endoscopic ovarioectomy was performed. Twelve months after the initial use of methylphenidate the medication could be discontinued completely and the dog's behavior was normal. The methylphenidate dosage used during this therapy was much higher than recommended in the literature.

The Safety and Efficacy of Methylphenidate and Dexmethylphenidate in Adults with Attention Deficit/Hyperactivity Disorder

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Michael A. Sopko

2010-01-01

Full Text Available Objective To review the literature on the safety and efficacy of methylphenidate, OROS-methylphenidate, methylphenidate ER, and dexmethylphenidate in adults with Attention-Deficit/Hyperactivity Disorder (ADHD. To analyze the effects of different doses of methylphenidate, it's various formulations, and methylphenidate on efficacy and safety in this population. Data Sources Literature retrieval was performed through Pubmed/MEDLINE (Up to May 2010 using the terms methylphenidate, dexmethylphenidate, and attention-deficit hyperactivity disorder. In addition, reference citations from publications identified were reviewed. Study Selection and Data Extraction Double-blinded, placebo-controlled clinical trials, as well as crossover and open-label trials found using the search criteria listed above were included for review. Case reports were not included in this review. Data Synthesis Attention-deficit/hyperactivity disorder (ADHD is a psychiatric condition that is commonly seen in children and adolescents, that persists into adulthood for about 50% of patients. Methylphenidate and dexmethylphenidate are often prescribed to treat the symptoms associated with ADHD. The literature validating the safety and efficacy of methylphenidate and dexmethylphenidate in children and adolescents with ADHD is substantial. However, the literature specifically addressing the safety and efficacy of these medications in the adult population is less extensive and prescribing is often anecdotal based on child and adolescent data. Understanding the literature regarding methylphenidate and dexmethylphenidate and its effects in adults can enhance evidence-based medicine (EBM and improve treatment outcomes Conclusion Methylphenidate and dexmethylphenidate are safe and effective medications to treat the symptoms of ADHD in adults. Based on the literature, increased doses are associated with better treatment response with moderate safety concerns. The different dosage forms

Prescription, dispensation and marketing patterns of methylphenidate

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Edson Perini

2014-12-01

Full Text Available OBJECTIVE To analyze the patterns and legal requirements of methylphenidate consumption. METHODS We conducted a cross-sectional study of the data from prescription notification forms and balance lists of drugs sales – psychoactive and others – subject to special control in the fifth largest city of Brazil, in 2006. We determined the defined and prescribed daily doses, the average prescription and dispensation periods, and the regional sales distribution in the municipality. In addition, we estimated the costs of drug acquisition and analyzed the individual drug consumption profile using the Lorenz curve. RESULTS The balance lists data covered all notified sales of the drug while data from prescription notification forms covered 50.6% of the pharmacies that sold it, including those with the highest sales volumes. Total methylphenidate consumption was 0.37 DDD/1,000 inhabitants/day. Sales were concentrated in more developed areas, and regular-release tablets were the most commonly prescribed pharmaceutical formulation. In some regions of the city, approximately 20.0% of the prescriptions and dispensation exceeded 30 mg/day and 30 days of treatment. CONCLUSIONS Methylphenidate was widely consumed in the municipality and mainly in the most developed areas. Of note, the consumption of formulations with the higher abuse risk was the most predominant. Both its prescription and dispensation contrasted with current pharmacotherapeutic recommendations and legal requirements. Therefore, the commercialization of methylphenidate should be monitored more closely, and its use in the treatment of behavioral changes of psychological disorders needs to be discussed in detail, in line with the concepts of the quality use of medicines.

Methylphenidate alleviates manganese-induced impulsivity but not distractibility

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Beaudin, Stephane A.; Strupp, Barbara J.; Uribe, Walter; Ysais, Lauren; Strawderman, Myla; Smith, Donald R.

2017-01-01

Recent studies from our lab have demonstrated that postnatal manganese (Mn) exposure in a rodent model can cause lasting impairments in fine motor control and attention, and that oral methylphenidate (MPH) treatment can effectively treat the dysfunction in fine motor control. However, it is unknown whether MPH treatment can alleviate the impairments in attention produced by Mn exposure. Here we used a rodent model of postnatal Mn exposure to determine whether (1) oral MPH alleviates attention and impulse control deficits caused by postnatal Mn exposure, using attention tasks that are variants of the 5-choice serial reaction time task, and (2) whether these treatments affected neuronal dendritic spine density in the medial prefrontal cortex (mPFC) and dorsal striatum. Male Long-Evans rats were exposed orally to 0 or 50 mg Mn/kg/d throughout life starting on PND 1, and tested as young adults (PND 107 – 115) on an attention task that specifically tapped selective attention and impulse control. Animals were treated with oral MPH (2.5 mg/kg/d) throughout testing on the attention task. Our findings show that lifelong postnatal Mn exposure impaired impulse control and selective attention in young adulthood, and that a therapeutically relevant oral MPH regimen alleviated the Mn-induced dysfunction in impulse control, but not selective attention, and actually impaired focused attention in the Mn group. In addition, the effect of MPH was qualitatively different for the Mn-exposed versus control animals across a range of behavioral measures of inhibitory control and attention, as well as dendritic spine density in the mPFC, suggesting that postnatal Mn exposure alters catecholaminergic systems modulating these behaviors. Collectively these findings suggest that MPH may hold promise for treating the behavioral dysfunction caused by developmental Mn exposure, although further research is needed with multiple MPH doses to determine whether a dose can be identified that

Methylphenidate alleviates manganese-induced impulsivity but not distractibility.

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Beaudin, Stephane A; Strupp, Barbara J; Uribe, Walter; Ysais, Lauren; Strawderman, Myla; Smith, Donald R

2017-05-01

Recent studies from our lab have demonstrated that postnatal manganese (Mn) exposure in a rodent model can cause lasting impairments in fine motor control and attention, and that oral methylphenidate (MPH) treatment can effectively treat the dysfunction in fine motor control. However, it is unknown whether MPH treatment can alleviate the impairments in attention produced by Mn exposure. Here we used a rodent model of postnatal Mn exposure to determine whether (1) oral MPH alleviates attention and impulse control deficits caused by postnatal Mn exposure, using attention tasks that are variants of the 5-choice serial reaction time task, and (2) whether these treatments affected neuronal dendritic spine density in the medial prefrontal cortex (mPFC) and dorsal striatum. Male Long-Evans rats were exposed orally to 0 or 50Mn/kg/d throughout life starting on PND 1, and tested as young adults (PND 107-115) on an attention task that specifically tapped selective attention and impulse control. Animals were treated with oral MPH (2.5mg/kg/d) throughout testing on the attention task. Our findings show that lifelong postnatal Mn exposure impaired impulse control and selective attention in young adulthood, and that a therapeutically relevant oral MPH regimen alleviated the Mn-induced dysfunction in impulse control, but not selective attention, and actually impaired focused attention in the Mn group. In addition, the effect of MPH was qualitatively different for the Mn-exposed versus control animals across a range of behavioral measures of inhibitory control and attention, as well as dendritic spine density in the mPFC, suggesting that postnatal Mn exposure alters catecholaminergic systems modulating these behaviors. Collectively these findings suggest that MPH may hold promise for treating the behavioral dysfunction caused by developmental Mn exposure, although further research is needed with multiple MPH doses to determine whether a dose can be identified that ameliorates the

Clinical effect of venlafaxine combined with methylphenidate hydrochloride on narcolepsy

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YAN Bin

2013-11-01

Full Text Available This study aims to explore the clinical effect of venlafaxine sustained-release capsules combined with methylphenidate hydrochloride tablets on narcolepsy. Thirty-eight cases of narcoleptic patients were randomly divided into venlafaxine combined with methylphenidate hydrochloride treatment group (observation group, N = 19 and methylphenidate hydrochloride and clomipramine treatment group (control group, N = 19. After a total of 12-week treatment, clinical curative effect and adverse drug reactions were observed in 2 groups of patients. The results showed that effective rate of the treatment for excessive daytime sleepiness (EDS in observation group was higher than that of the control group (15/19 vs 8/19, P = 0.044, and effective rate of the treatment for cataplexy in observation group was higher than that of the control group (13/19 vs 6/19, P = 0.048. The rate of adverse drug reactions in observation group was lower than that in the control group (χ2 = 8.889, P = 0.003. It was indicated that venlafaxine combined with methylphenidate had good curative effect on narcolepsy with EDS and cataplexy symptoms.

Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.

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Chun-Lei Zhang

Full Text Available Methylphenidate (MPH, commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD. Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC. To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca(2+ increase, but does not require PKA and extracellular Ca(2+ influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.

Methylphenidate as a cognitive enhancer in healthy young people

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Silmara Batistela

Full Text Available ABSTRACT The so-called cognitive enhancers have been widely and increasingly used by healthy individuals who seek improvements in cognitive performance despite having no pathologies. One drug used for this purpose is methylphenidate, a first-line drug for the treatment of attention deficit hyperactivity disorder (ADHD. Objective: The aim of the present study was to test the effect of acute administration of varying doses of methylphenidate (10 mg, 20 mg, 40 mg and placebo on a wide range of cognitive functions in healthy young people. Methods: A total of 36 young university students and graduates participated in the study. The participants underwent tests of attention and of episodic, and working memory. Results: No differences in performance were observed on any of the tests. There was a dose-dependent (40 mg > placebo effect on self-reported wellbeing. Conclusions: According to the recent literature, psychostimulant medications, such as methylphenidate, improve performance when cognitive processes are below an optimal level, which was not the case for the subjects of the present study. We suggest the impression that methylphenidate enhances cognitive performance in healthy young people, justifying its use, may be due to improvements in subjective wellbeing promoted by the drug.

The Risk of Treatment-Emergent Mania With Methylphenidate in Bipolar Disorder.

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Viktorin, Alexander; Rydén, Eleonore; Thase, Michael E; Chang, Zheng; Lundholm, Cecilia; D'Onofrio, Brian M; Almqvist, Catarina; Magnusson, Patrik K E; Lichtenstein, Paul; Larsson, Henrik; Landén, Mikael

2017-04-01

The authors sought to determine the risk of treatment-emergent mania associated with methylphenidate, used in monotherapy or with a concomitant mood-stabilizing medication, in patients with bipolar disorder. Using linked Swedish national registries, the authors identified 2,307 adults with bipolar disorder who initiated therapy with methylphenidate between 2006 and 2014. The cohort was divided into two groups: those with and those without concomitant mood-stabilizing treatment. To adjust for individual-specific confounders, including disorder severity, genetic makeup, and early environmental factors, Cox regression analyses were used, conditioning on individual to compare the rate of mania (defined as hospitalization for mania or a new dispensation of stabilizing medication) 0-3 months and 3-6 months after medication start following nontreated periods. Patients on methylphenidate monotherapy displayed an increased rate of manic episodes within 3 months of medication initiation (hazard ratio=6.7, 95% CI=2.0-22.4), with similar results for the subsequent 3 months. By contrast, for patients taking mood stabilizers, the risk of mania was lower after starting methylphenidate (hazard ratio=0.6, 95% CI=0.4-0.9). Comparable results were observed when only hospitalizations for mania were counted. No evidence was found for a positive association between methylphenidate and treatment-emergent mania among patients with bipolar disorder who were concomitantly receiving a mood-stabilizing medication. This is clinically important given that up to 20% of people with bipolar disorder suffer from comorbid ADHD. Given the markedly increased hazard ratio of mania following methylphenidate initiation in bipolar patients not taking mood stabilizers, careful assessment to rule out bipolar disorder is indicated before initiating monotherapy with psychostimulants.

Non-medical use of methylphenidate among medical students of the University of the Free State

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Roshini Jain

2017-01-01

Full Text Available Background: Faced with demanding training programmes, medical students may be more prone to use methylphenidate for non-medical purposes in order to improve concentration, alertness and academic performance. Aim: The study aimed to investigate the prevalence of the non-medical use of methylphenidate and knowledge of this drug among undergraduate medical students of the University of the Free State. Methods: This was a cross-sectional study. A self-administered, anonymous questionnaire was distributed during lectures to all students in the five year groups of the undergraduate medical programme. Results: Of the 643 undergraduate medical students, 541 completed the questionnaire (response rate: 84.1%. Approximately 11.0% of surveyed students were using methylphenidate at the time of the study, of which the majority (67.9% used it for academic purposes and 70.6% received it from a medical health professional. Less than a third of users had been diagnosed with Attention-Deficit/Hyperactivity Disorder. Methylphenidate users’ median knowledge was greater than non-users, and methylphenidate knowledge increased from first-year and second-year students to third-year to fifth-year students. Median knowledge scores per year group ranged from 52.0% to 60.0%. Conclusion: Methylphenidate is mainly used for non-medical purposes by medical students. Students generally have a low level of knowledge on methylphenidate. Specific information on methylphenidate should be included in lectures on stress management and study methods during the course of the medical curriculum.

Differences in methylphenidate abuse rates among methadone maintenance treatment patients in two clinics.

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Peles, Einat; Schreiber, Shaul; Linzy, Shirley; Domani, Yoav; Adelson, Miriam

2015-07-01

Methylphenidate, an amphetamine-like prescription medication for attention deficit hyperactivity disorder (ADHD) was suspected as being abused among methadone maintenance treatment (MMT) patients. We tested its presence in the routine urine monitoring of all patients in both Tel Aviv and Las Vegas MMT clinics. Data on demographic and addiction history, ADHD (Wender Utah Rating Scale), cognitive impairment (Mini Mental State Exam), and lifetime DSM-IV-TR psychiatric diagnosis from admission were retrieved, and retention following 6 months. None of the 190 patients in Las Vegas tested positive for methylphenidate, while 14.7% (45/306) did in Tel Aviv. Abusers were less educated (p = 0.01), had higher ADHD scores (p = 0.02), lower cognitive scores (p = 0.05), and a higher benzodiazepine (BDZ) abuse rate (p cannabis, opiates, and cocaine abuse and infectious disease. Of the methylphenidate abuse 42.2% have take-home methadone dose privileges. Not like opiate use, being methylphenidate positive did not relate to 6-months retention. Compared to Tel Aviv, Las Vegas patients were more educated, with lower BDZ, and cocaine abuse. The greater abuse of methylphenidate among ADHD subjects might indicate their using it as self-medication, raising a possible indication for its prescription for that subgroup of MMT patients. The high rate of methylphenidate abuse in Israel needs future study. Copyright © 2015 Elsevier Inc. All rights reserved.

Methylphenidate and stimulus control of avoidance behavior1

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Stretch, Roger; Skinner, Nicholas

1967-01-01

The introduction of a warning signal that preceded a scheduled shock modified the temporal distribution of free-operant avoidance responses. With response-shock and shock-shock intervals held constant, response rates increased only slightly when the response-signal interval was reduced. The result is consistent with Sidman's (1955) findings under different conditions, but at variance with Ulrich, Holz, and Azrin's (1964) findings under similar conditions. Methylphenidate in graded doses increased response rates, modifying frequency distributions of interresponse times. Drug treatment may have disrupted a “temporal discrimination” formed within the signal-shock interval. More simply, methylphenidate influenced response rates by increasing short response latencies after signal onset; this effect was more prominent than the drug's tendency to increase the frequency of pre-signal responses. When signal-onset preceded shock by 2 sec, individual differences in performance were marked; methylphenidate suppressed responding in one rat as a function of increasing dose levels to a greater degree than in a second animal, but both subjects received more shocks than under control conditions. PMID:6050059

Effect of Methylphenidate on Retention and Retrieval of Passive Avoidance Memory in Young and Aged Mice

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Arzi

2014-10-01

Full Text Available Background Several studies showed that dopamine and norepinephrine improve retention and retrieval of memory. Methylphenidate is an enhancer of dopamine and norepinephrine in brain. Objectives In the present study, the effect of methylphenidate was evaluated on retention and retrieval of memory in young and aged mice using passive avoidance apparatus. Materials and Methods Animals were divided into groups (n = 8 as follows: test groups received electric shock plus methylphenidate (2.5, 5 and 10mg kg-1, i. P., control group received electric shock plus normal saline and blank group received only electric shock. In all groups, step-down latency for both retention and retrieval test of memory was measured. Methylphenidate was administered immediately after receiving electric shock in the retention test, but methylphenidate was administered 23.5 hours after receiving electric shock in the retrieval test. Results The mean of step-down latency on day 4 was significantly higher compared to day 2 (P < 0.05 in all young and aged groups of mice. The best response was attained with 5 mg/kg of methylphenidate. In memory retention test, the mean of step-down latency in young groups that received 2.5 and 5 mg/kg methylphenidate was significantly longer(P < 0.05 than aged groups. However, this difference was not significant in memory retrieval test. Conclusions Methylphenidate may improve memory retention and retrieval.

Differential effects of MDMA and methylphenidate on social cognition.

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Schmid, Yasmin; Hysek, Cédric M; Simmler, Linda D; Crockett, Molly J; Quednow, Boris B; Liechti, Matthias E

2014-09-01

Social cognition is important in everyday-life social interactions. The social cognitive effects of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and methylphenidate (both used for neuroenhancement and as party drugs) are largely unknown. We investigated the acute effects of MDMA (75 mg), methylphenidate (40 mg) and placebo using the Facial Emotion Recognition Task, Multifaceted Empathy Test, Movie for the Assessment of Social Cognition, Social Value Orientation Test and the Moral Judgment Task in a cross-over study in 30 healthy subjects. Additionally, subjective, autonomic, pharmacokinetic, endocrine and adverse drug effects were measured. MDMA enhanced emotional empathy for positive emotionally charged situations in the MET and tended to reduce the recognition of sad faces in the Facial Emotion Recognition Task. MDMA had no effects on cognitive empathy in the Multifaceted Empathy Test or social cognitive inferences in the Movie for the Assessment of Social Cognition. MDMA produced subjective 'empathogenic' effects, such as drug liking, closeness to others, openness and trust. In contrast, methylphenidate lacked such subjective effects and did not alter emotional processing, empathy or mental perspective-taking. MDMA but not methylphenidate increased the plasma levels of oxytocin and prolactin. None of the drugs influenced moral judgment. Effects on emotion recognition and emotional empathy were evident at a low dose of MDMA and likely contribute to the popularity of the drug. © The Author(s) 2014.

Adverse reactions of Methylphenidate in children with attention deficit-hyperactivity disorder: Report from a referral center

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Khajehpiri, Zahra; Mahmoudi-Gharaei, Javad; Faghihi, Toktam; Karimzadeh, Iman; Khalili, Hossein; Mohammadi, Mostafa

2014-01-01

Objective: The aim of the current study was to determine various aspects of methylphenidate adverse reactions in children with attention deficit-hyperactivity disorder (ADHD) in Iran. Methods: During the 6 months period, all children under methylphenidate treatment alone or along with other agents attending a university-affiliated psychology clinic were screened regarding all subjective and objective adverse drug reactions (ADRs) of methylphenidate. Causality and seriousness of detected ADRs were assessed by relevant World Health Organization definitions. The Schumock and Thornton questionnaire was used to determine preventability of ADRs. Findings: Seventy-one patients including 25 girls and 46 boys with ADHD under methylphenidate treatment were enrolled within the study period. All (100%) ADHD children under methylphenidate treatment developed at least one ADR. Anorexia (74.3%), irritability (57.1%), and insomnia (47.2%) were the most frequent methylphenidate-related adverse reactions. Except for one, all other detected ADRs were determined to be mild. In addition, no ADR was considered to be preventable and serious. Conclusion: Our data suggested that although methylphenidate related adverse reactions were common in children with ADHD, but they were mainly mild and nonserious. PMID:25535621

Early long-term exposure with caffeine induces cross-sensitization to methylphenidate with involvement of DARPP-32 in adulthood of rats.

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Boeck, Carina R; Marques, Virgínia B; Valvassori, Samira S; Constantino, Leandra C; Rosa, Daniela V F; Lima, Fabrício F; Romano-Silva, Marco A; Quevedo, João

2009-09-01

Chronic ingestion of caffeine causes dependence and sleep disturbance in children and adolescents. In rodents, the administration of caffeine may produce behavioral cross-sensitization to some psychostimulants, such as dopaminergic psychoactive drugs. Methylphenidate (MPH; Ritalin) is a psychostimulant used in pediatric- and adult human populations to manage the symptoms associated with attention-deficit hyperactivity disorder (ADHD). Previous studies have suggested that dopamine- and cAMP-regulated phosphoproteins of 32 kDa (DARPP-32) participate in the manifestation of behavioral activity following ingestion of caffeine or MPH. The aim of the present study was to evaluate whether long-term administration of low doses of caffeine in rodents during their adolescence induces cross-sensitization to MPH challenge in their adulthood and investigate the involvement of DARPP-32 in this model. Young rats (P25) consumed water or caffeine (0.3 g/L; mean consumption was 7.5 mg/day/kg) for 28 days. The caffeine consumption was then suspended for 14 days (washout period) when the animals received saline solution or MPH (1, 2, or 10 mg/kg) (P67) intraperitoneally. The locomotor activity of these rats was assessed using the open-field test, following which the immunocontent of DARPP-32 was evaluated in samples of their prefrontal cortex, striatum, or hippocampus. Rats chronically exposed to caffeine in their adolescent period and to inactive doses of MPH (1mg/kg) in adulthood showed augmented locomotor activity. The behavioral effect observed was accompanied by increased levels of DARPP-32 in the striatum and prefrontal cortex compared to control groups (saline or caffeine). However, no alteration caused by these treatments was noted in the hippocampus. In conclusion, chronic caffeine exposure induces likely long-term cross-sensitization to MPH in a DARPP-32-dependent pathway.

Methylphenidate use in children with attention deficit hyperactivity disorder

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Felipe Salles Neves Machado

2015-01-01

Full Text Available A Brazilian Health Technology Assessment Bulletin (BRATS article regarding scientific evidence of the efficacy and safety of methylphenidate for treating attention deficit hyperactivity disorder (ADHD has caused much controversy about its methods. Considering the relevance of BRATS for public health in Brazil, we critically reviewed this article by remaking the BRATS search and discussing its methods and results. Two questions were answered: did BRATS include all references available in the literature? Do the conclusions reflect the reviewed articles? The results indicate that BRATS did not include all the references from the literature on this subject and also that the proposed conclusions are different from the results of the articles chosen by the BRATS authors themselves. The articles selected by the BRATS authors showed that using methylphenidate is safe and effective. However, the BRATS final conclusion does not reflect the aforementioned and should not be used to support decisions on the use of methylphenidate.

Methylphenidate treatment beyond adolescence maintains increased cocaine self-administration in the spontaneously hypertensive rat model of attention deficit/hyperactivity disorder.

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Baskin, Britahny M; Dwoskin, Linda P; Kantak, Kathleen M

2015-04-01

Past research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder showed that adolescent methylphenidate treatment enhanced cocaine abuse risk in SHR during adulthood. The acquisition of cocaine self-administration was faster, and cocaine dose-response functions were shifted upward under fixed-ratio and progressive ratio schedules compared to adult SHR that received adolescent vehicle treatment or to control strains that received adolescent methylphenidate treatment. The current study determined if extending treatment beyond adolescence would ameliorate long-term consequences of adolescent methylphenidate treatment on cocaine abuse risk in adult SHR. Treatments (vehicle or 1.5mg/kg/day oral methylphenidate) began on postnatal day 28. Groups of male SHR were treated with vehicle during adolescence and adulthood, with methylphenidate during adolescence and vehicle during adulthood, or with methylphenidate during adolescence and adulthood. The group receiving adolescent-only methylphenidate was switched to vehicle on P56. Cocaine self-administration began on postnatal day 77, and groups receiving methylphenidate during adolescence and adulthood were treated either 1-h before or 1-h after daily sessions. At baseline under a fixed-ratio 1 schedule, cocaine self-administration (2h sessions; 0.3mg/kg unit dose) did not differ among the four treatment groups. Under a progressive ratio schedule (4.5h maximum session length; 0.01-1.0mg/kg unit doses), breakpoints for self-administered cocaine in SHR receiving the adult methylphenidate treatment 1-h pre-session were not different from the vehicle control group. However, compared to the vehicle control group, breakpoints for self-administered cocaine at the 0.3 and 1.0mg/kg unit doses were greater in adult SHR that received adolescent-only methylphenidate or received methylphenidate that was continued into adulthood and administered 1-h post-session. These findings suggest that

Methylphenidate modulates activity within cognitive neural networks of patients with post-stroke major depression: A placebo-controlled fMRI study

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Rajamannar Ramasubbu

2008-10-01

Full Text Available Rajamannar Ramasubbu1, Bradley G Goodyear21Departments of Psychiatry and Clinical Neurosciences; 2Department of Radiology and Clinical Neurosciences, University of Calgary, Hotchkiss Brain Institute, Calgary, AB, CanadaBackground: Methylphenidate (MP is a dopamine- and noradrenaline-enhancing agent beneficial for post-stroke depression (PSD and stroke recovery due to its therapeutic effects on cognition, motivation, and mood; however, the neural mechanisms underlying its clinical effects remain unknown. This study used functional magnetic resonance imaging (fMRI to investigate the effect of MP on brain activity in response to cognitive tasks in patients with PSD.Methods: Nine stroke outpatients with DSM IV defined major depression underwent fMRI during two cognitive tasks (2-back and serial subtraction on four occasions, on the first and third day of a three-day treatment of MP and placebo. Nine healthy control (HC subjects matched for age and sex scanned during a single session served as normative data for comparison. The main outcome measure was cognitive task-dependent brain activity.Results: For the 2-back task, left prefrontal, right parietal, posterior cingulate, and temporal and bilateral cerebellar regions exhibited significantly greater activity during the MP condition relative to placebo. Less activity was detected in rostral prefrontal and left parietal regions. For serial subtraction, greater activity was detected in medial prefrontal, biparietal, bitemporal, posterior cingulate, and bilateral cerebellar regions, as well as thalamus, putamen, and insula. Further, underactivation observed during the placebo condition relative to HC improved or reversed during MP treatment. No significant differences in behavioral measures were found between MP and placebo conditions or between patients and HC.Conclusions: Short-term MP treatment may improve and normalize activity in cognitive neuronal networks in patients with PSD

Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents

DEFF Research Database (Denmark)

Simonsen, Erik; Storebø, Ole Jakob; Rosendal, Susanne

2012-01-01

This is the protocol for a review and there is no abstract. The objectives are as follows:To assess beneficial and harmful effects of methylphenidate for children and adolescents with ADHD.......This is the protocol for a review and there is no abstract. The objectives are as follows:To assess beneficial and harmful effects of methylphenidate for children and adolescents with ADHD....

Acute effects of 3,4-methylenedioxymethamphetamine and methylphenidate on circulating steroid levels in healthy subjects.

OpenAIRE

Seibert Julia; Hysek Cédric M; Penno Carlos A; Schmid Yasmin; Kratschmar Denise V; Liechti Matthias E; Odermatt Alex

2014-01-01

3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') and methylphenidate are widely used psychoactive substances. MDMA primarily enhances serotonergic neurotransmission, and methylphenidate increases dopamine but has no serotonergic effects. Both drugs also increase norepinephrine, resulting in sympathomimetic properties. Here we studied the effects of MDMA and methylphenidate on 24-h plasma steroid profiles. Sixteen healthy subjects (eight men, eight women) were treated with single doses of M...

LETTER TO THE EDITOR - COMMENTS ON CYTOGENETIC EFFECTS IN CHILDREN TREATED WITH METHYLPHENIDATE

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The recent report by El-Zein et al. suggests that chromosome alterations may be a consequence of short-term methylphenidate use for the treatment of children with Attention Deficit Hyperactivity Disorder (ADHD). The report concludes that 3 months of treatment with methylphenidate...

Core ADHD Symptom Improvement with Atomoxetine versus Methylphenidate: A Direct Comparison Meta-Analysis

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Hazell, Philip L.; Kohn, Michael R.; Dickson, Ruth; Walton, Richard J.; Granger, Renee E.; van Wyk, Gregory W.

2011-01-01

Objective: Previous studies comparing atomoxetine and methylphenidate to treat ADHD symptoms have been equivocal. This noninferiority meta-analysis compared core ADHD symptom response between atomoxetine and methylphenidate in children and adolescents. Method: Selection criteria included randomized, controlled design; duration 6 weeks; and…

Predictors of treatment outcome in adults with ADHD treated with OROS(R) methylphenidate

NARCIS (Netherlands)

Buitelaar, J.K.; Kooij, J.J.; Ramos-Quiroga, J.A.; Dejonckheere, J.; Casas, M.; Oene, J.C. van; Schauble, B.; Trott, G.E.

2011-01-01

BACKGROUND: We conducted a post-hoc analysis of the Long-Acting MethylpheniDate in Adult attention-deficit hyperactivity disorder (LAMDA) study to investigate predictors of response in adults with ADHD randomly assigned to Osmotic Release Oral System (OROS)((R))-methylphenidate hydrochloride (MPH)

A randomized, double-blind, cross-over, phase IV trial of oros-methylphenidate (CONCERTA(®)) and generic novo-methylphenidate ER-C (NOVO-generic).

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Fallu, Angelo; Dabouz, Farida; Furtado, Melissa; Anand, Leena; Katzman, Martin A

2016-08-01

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder with onset during childhood. Multiple aspects of a child's development are hindered, in both home and school settings, with negative impacts on social, emotional, and cognitive functioning. If left untreated, ADHD is commonly associated with poor academic achievement and low occupational status, as well as increased risk of substance abuse and delinquency. The objective of this study was to evaluate adult ADHD subject reported outcomes when switched from a stable dose of CONCERTA(®) to the same dose of generic Novo-methylphenidate ER-C(®). Randomized, double-blind, cross-over, phase IV trial consisted of two phases in which participants with a primary diagnosis of ADHD were randomized in a 1:1 ratio to 3 weeks of treatment with CONCERTA or generic Novo-Methylphenidate ER-C. Following 3 weeks of treatment, participants were crossed-over to receive the other treatment for an additional 3 weeks. Primary efficacy was assessed through the use of the Treatment Satisfaction Questionnaire for Medication, Version II (TSQM-II). Participants with ADHD treated with CONCERTA were more satisfied in terms of efficacy and side effects compared to those receiving an equivalent dose of generic Novo-Methylphenidate ER-C. All participants chose to continue with CONCERTA treatment at the conclusion of the study. Although CONCERTA and generic Novo-Methylphenidate ER-C have been deemed bioequivalent, however the present findings demonstrate clinically and statistically significant differences between generic and branded CONCERTA. Further investigation of these differences is warranted.

Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).

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Storebø, Ole Jakob; Ramstad, Erica; Krogh, Helle B; Nilausen, Trine Danvad; Skoog, Maria; Holmskov, Mathilde; Rosendal, Susanne; Groth, Camilla; Magnusson, Frederik L; Moreira-Maia, Carlos R; Gillies, Donna; Buch Rasmussen, Kirsten; Gauci, Dorothy; Zwi, Morris; Kirubakaran, Richard; Forsbøl, Bente; Simonsen, Erik; Gluud, Christian

2015-11-25

Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive.Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD but, despite its widespread use, this is the first comprehensive systematic review of its benefits and harms. To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. In February 2015 we searched six databases (CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, Conference Proceedings Citations Index), and two trials registers. We checked for additional trials in the reference lists of relevant reviews and included trials. We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data. We included all randomised controlled trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. At least 75% of participants needed to have an intellectual quotient of at least 70 (i.e. normal intellectual functioning). Outcomes assessed included ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour and quality of life. Seventeen review authors participated in data extraction and risk of bias assessment, and two review authors independently performed all tasks. We used standard methodological procedures expected within Cochrane. Data from parallel-group trials and first period data from cross-over trials formed the basis of our primary analyses; separate analyses were undertaken using post-cross-over data from cross-over trials. We used Trial Sequential Analyses to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE

Treatment effect of methylphenidate on intrinsic functional brain network in medication-naïve ADHD children: A multivariate analysis.

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Yoo, Jae Hyun; Kim, Dohyun; Choi, Jeewook; Jeong, Bumseok

2018-04-01

Methylphenidate is a first-line therapeutic option for treating attention-deficit/hyperactivity disorder (ADHD); however, elicited changes on resting-state functional networks (RSFNs) are not well understood. This study investigated the treatment effect of methylphenidate using a variety of RSFN analyses and explored the collaborative influences of treatment-relevant RSFN changes in children with ADHD. Resting-state functional magnetic resonance imaging was acquired from 20 medication-naïve ADHD children before methylphenidate treatment and twelve weeks later. Changes in large-scale functional connectivity were defined using independent component analysis with dual regression and graph theoretical analysis. The amplitude of low frequency fluctuation (ALFF) was measured to investigate local spontaneous activity alteration. Finally, significant findings were recruited to random forest regression to identify the feature subset that best explains symptom improvement. After twelve weeks of methylphenidate administration, large-scale connectivity was increased between the left fronto-parietal RSFN and the left insula cortex and the right fronto-parietal and the brainstem, while the clustering coefficient (CC) of the global network and nodes, the left fronto-parietal, cerebellum, and occipital pole-visual network, were decreased. ALFF was increased in the bilateral superior parietal cortex and decreased in the right inferior fronto-temporal area. The subset of the local and large-scale RSFN changes, including widespread ALFF changes, the CC of the global network and the cerebellum, could explain the 27.1% variance of the ADHD Rating Scale and 13.72% of the Conner's Parent Rating Scale. Our multivariate approach suggests that the neural mechanism of methylphenidate treatment could be associated with alteration of spontaneous activity in the superior parietal cortex or widespread brain regions as well as functional segregation of the large-scale intrinsic functional

OROS Methylphenidate in Adolescents with ADHD

Directory of Open Access Journals (Sweden)

J Gordon Millichap

2006-01-01

Full Text Available The efficacy and tolerability of osmotic-release oral system (OROS methylphenidate in adolescents with attention deficit hyperactivity disorder (ADHD were evaluated in a multisite controlled study at the Massachusetts General Hospital, Boston, and other centers in the United States.

A pilot study for augmenting atomoxetine with methylphenidate: safety of concomitant therapy in children with attention-deficit/hyperactivity disorder

Directory of Open Access Journals (Sweden)

Ball Susan

2007-09-01

Full Text Available Abstract Background This study examined augmenting atomoxetine with extended-release methylphenidate in children whose attention-deficit/hyperactivity disorder (ADHD previously failed to respond adequately to stimulant medication. Methods Children with ADHD and prior stimulant treatment (N = 25 received atomoxetine (1.2 mg/kg/day plus placebo. After 4 weeks, patients who were responders (n = 4 were continued on atomoxetine/placebo while remaining patients were randomly assigned to either methylphenidate (ATX/MPH (1.1 mg/kg/day or placebo augmentation (ATX/PB for another 6 weeks. Patients and sites were blind to timing of active augmentation. Safety measures included vital signs, weight, and adverse events. Efficacy was assessed by ADHD rating scales. Results Categorical increases in vital signs occurred for 5 patients (3 patients in ATX/MPH, 2 patients in ATX/PBO. Sixteen percent discontinued the study due to AE, but no difference between augmentation groups. Atomoxetine treatment was efficacious on outcome measures (P ≤ .001, but methylphenidate did not enhance response. Conclusion Methylphenidate appears to be safely combined with atomoxetine, but conclusions limited by small sample. With atomoxetine treatment, 43% of patients achieved normalization on ADHD ratings.

Diacylglycerol kinase β knockout mice exhibit attention-deficit behavior and an abnormal response on methylphenidate-induced hyperactivity.

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Mitsue Ishisaka

Full Text Available BACKGROUND: Diacylglycerol kinase (DGK is an enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. DGKβ is one of the subtypes of the DGK family and regulates many intracellular signaling pathways in the central nervous system. Previously, we demonstrated that DGKβ knockout (KO mice showed various dysfunctions of higher brain function, such as cognitive impairment (with lower spine density, hyperactivity, reduced anxiety, and careless behavior. In the present study, we conducted further tests on DGKβ KO mice in order to investigate the function of DGKβ in the central nervous system, especially in the pathophysiology of attention deficit hyperactivity disorder (ADHD. METHODOLOGY/PRINCIPAL FINDINGS: DGKβ KO mice showed attention-deficit behavior in the object-based attention test and it was ameliorated by methylphenidate (MPH, 30 mg/kg, i.p.. In the open field test, DGKβ KO mice displayed a decreased response to the locomotor stimulating effects of MPH (30 mg/kg, i.p., but showed a similar response to an N-methyl-d-aspartate (NMDA receptor antagonist, MK-801 (0.3 mg/kg, i.p., when compared to WT mice. Examination of the phosphorylation of extracellular signal-regulated kinase (ERK, which is involved in regulation of locomotor activity, indicated that ERK1/2 activation induced by MPH treatment was defective in the striatum of DGKβ KO mice. CONCLUSIONS/SIGNIFICANCE: These findings suggest that DGKβ KO mice showed attention-deficit and hyperactive phenotype, similar to ADHD. Furthermore, the hyporesponsiveness of DGKβ KO mice to MPH was due to dysregulation of ERK phosphorylation, and that DGKβ has a pivotal involvement in ERK regulation in the striatum.

[Methylphenidate and short-term memory in young females with attention deficit hyperactivity disorder. A study using functional magnetic resonance imaging].

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Gonzalez-Garrido, A A; Barrios, F A; de la Serna-Tuya, J M; Cocula-León, H; Gómez-Velázquez, F R

Attention deficit/hyperactivity disorder (ADHD) is a common behavioral disorder found mainly in males, thus current knowledge on its clinical expression in female adults is extremely limited. AIM. To evaluate the behavioral and neural substrates associated with the performance of a short-term memory task in female ADHD adults, with and without methylphenidate exposure, with respect to a control group. Two groups of eight young right-handed, female, university students with ADHD and healthy controls matched by age, gender, handedness and academic level, voluntarily participated. All subjects performed twice an easy auditory short-term memory task (ADHD group without, and 90 minutes post-intake of methylphenidate 0.4 mg/kg in a counterbalanced order). The BOLD-fMRI response was used as a measure of neural activity during task performance. ADHD subjects showed a tendency to improve their performances under medication, showing an increased widespread functional activation, especially relevant over left frontal and cerebellar areas, in comparison with control subjects. Methylphenidate slightly improves short-term memory task performance in adult female ADHD subjects by modifying underlying neural functioning patterns.

Methylphenidate, cognition, and epilepsy: A 1-month open-label trial.

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Adams, Jesse; Alipio-Jocson, Valerie; Inoyama, Katherine; Bartlett, Victoria; Sandhu, Saira; Oso, Jemima; Barry, John J; Loring, David W; Meador, Kimford J

2017-12-01

Cognitive difficulties are common in epilepsy. Beyond reducing seizures and adjusting antiepileptic medications, no well-validated treatment exists in adults. Methylphenidate is used effectively in children with epilepsy and attention-deficit/hyperactivity disorder, but its effects in adults have not been systematically evaluated. We hypothesized that methylphenidate can safely improve cognition in adults with epilepsy. We detail here the open-label follow-up to a double-blind, placebo-controlled, single-dose study. Thirty epilepsy patients entered a 1-month open-label methylphenidate trial after a double-blind phase. Doses were titrated according to clinical practice and patient tolerance, ranging 20-40 mg/day. Primary measures included: Conners' Continuous Performance Test (CPT), Symbol-Digit Modalities Test (SDMT), and Medical College of Georgia Memory Test (MCG). Secondary measures were: Beck Depression Inventory, 2nd Edition (BDI-II), Beck Anxiety Inventory, Apathy Evaluation Scale (AES), Stimulant Side-Effect Checklist, Adverse Events Profile, Quality of Life in Epilepsy-89 (QOLIE-89), and seizure frequency. Fourteen healthy, nonmedicated controls were tested concurrently. Twenty-eight participants with epilepsy (13 men/15 women) completed the trial. Withdrawals occurred due to anxiety (n = 1) and fatigue (n = 1). Mean age was 36.4 years (range = 20-60). Epilepsy types were: focal (n = 21), generalized (n = 6), or unclassified (n = 1). Mean epilepsy duration was 12.3 years. Mean baseline seizure frequency was 2.8/month. There were significant improvements on methylphenidate for SDMT, MCG, CPT (the ability to discriminate between targets and nontargets [d'] hits, hit reaction time standard deviation, omissions, and commissions), and QOLIE subscales (energy/fatigue, attention/concentration, memory, and language; paired t tests; p ≤ 0.002). BDI-II and additional subscales also improved, at a lower level of statistical significance. Effect

Anxiety and methylphenidate in attention deficit hyperactivity disorder: a double-blind placebo-drug trial.

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Moshe, Keren; Karni, Avi; Tirosh, Emanuel

2012-09-01

To examine the relationship between attention and anxiety and the response to methylphenidate in children with attention deficit hyperactivity disorder (ADHD), a total of 57 boys, between the ages of 7-12 years, were assessed for their attention and level of anxiety. Methylphenidate was administered for a week in a randomized double-blind drug/placebo-drug cross-over design. The levels of anxiety were evenly distributed between the inattentive and hyperactive/impulsive types. Anxiety was significantly correlated with the attention as reported by both teachers and parents. The response to methylphenidate was inversely correlated with the reported anxiety level only in boys with the hyperactive/impulsive and combined types. The higher the level of anxiety, the lower level of response to methylphenidate was observed. In the assessment and treatment of children with ADHD, the level of anxiety should be evaluated and taken into account while planning and monitoring treatment regiment.

Methylphenidate poisoning: an evidence-based consensus guideline for out-of-hospital management.

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Scharman, Elizabeth J; Erdman, Andrew R; Cobaugh, Daniel J; Olson, Kent R; Woolf, Alan D; Caravati, E Martin; Chyka, Peter A; Booze, Lisa L; Manoguerra, Anthony S; Nelson, Lewis S; Christianson, Gwenn; Troutman, William G

2007-01-01

the equivalent amount of a modified-release formulation that has been chewed) should be referred to an emergency department (Grade C). 9) If a patch has been swallowed, consider the entire contents of the patch (not just the labeled dose of the patch) to have been ingested. Patients who ingest more than 2 mg/kg or 60 mg, whichever is less should be referred to an emergency department. If it is known that the patch has been chewed only briefly, and the patch remains intact, significant toxicity is unlikely and emergency department referral is not necessary (Grade D). 10) Patients who ingest more than 4 mg/kg or 120 mg, whichever is less, of an intact modified-release formulation should be referred to an emergency department (Grade D). 11) For oral exposures, do not induce emesis (Grade D). 12) Pre-hospital activated charcoal administration, if available, should only be carried out by health professionals and only if no contraindications are present. Do not delay transportation in order to administer activate charcoal (Grade D). 13) Benzodiazepines can be administered by EMS personnel if agitation, dystonia, or convulsions are present and if authorized by EMS medical direction expressed by written treatment protocol or policy or direct medical oversight (Grade C). 14) Standard advanced cardiac life support (ACLS) measures should be administered by EMS personnel if respiratory arrest, cardiac dysrhythmias, or cardiac arrest are present and if authorized by EMS medical direction expressed by written treatment protocol or policy or direct medical oversight (Grade C).

An Open-Label, Randomized Trial of Methylphenidate and Atomoxetine Treatment in Children with Attention-Deficit/Hyperactivity Disorder.

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Shang, Chi-Yung; Pan, Yi-Lei; Lin, Hsiang-Yuan; Huang, Lin-Wan; Gau, Susan Shur-Fen

2015-09-01

The efficacy of both methylphenidate and atomoxetine has been established in placebo-controlled trials. The present study aimed to directly compare the efficacy of methylphenidate and atomoxetine in improving symptoms among children with attention-deficit/hyperactivity disorder (ADHD). The study sample included 160 drug-naïve children and adolescents 7-16 years of age, with DSM-IV-defined ADHD, randomly assigned to osmotic-release oral system methylphenidate (OROS-methylphenidate) (n=80) and atomoxetine (n=80) in a 24 week, open-label, head-to-head clinical trial. The primary efficacy measure was the score of the ADHD Rating Scale-IV Parents Version: Investigator Administered and Scored (ADHD-RS-IV). The secondary efficacy measures included the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) and Chinese Swanson, Nolan, and Pelham IV scale (SNAP-IV), based on the ratings of investigators, parents, teachers, and subjects. At week 24, mean changes in ADHD-RS-IV Inattention scores were 13.58 points (Cohen's d, -3.08) for OROS-methylphenidate and 12.65 points (Cohen's d, -3.05) for atomoxetine; and mean changes in ADHD-RS-IV Hyperactivity-Impulsivity scores were 10.16 points (Cohen's d, -1.75) for OROS-methylphenidate and 10.68 points (Cohen's d, -1.87) for atomoxetine. In terms of parent-, teacher-, and self-ratings on behavioral symptoms, both of the two treatment groups significantly decreased on the SNAP-IV scores at the end-point, with effect sizes ranging from 0.9 to 0.96 on the Inattention subscale and from 0.61 to 0.8 on the Hyperactivity/Impulsivity subscale for OROS-methylphenidate; and from 0.51 to 0.88 on the Inattention subscale and from 0.29 to 0.57 on the Hyperactivity/Impulsivity subscale for atomoxetine. No statistically significant differences between treatment groups were observed on the outcome measures. Vomiting, somnolence, and dizziness were reported more often for atomoxetine than for OROS-methylphenidate, whereas insomnia was reported

Mass Spectrometry Imaging Shows Cocaine and Methylphenidate Have Opposite Effects on Major Lipids in Drosophila Brain.

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Philipsen, Mai H; Phan, Nhu T N; Fletcher, John S; Malmberg, Per; Ewing, Andrew G

2018-03-20

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to study the effects of cocaine versus methylphenidate administration on both the localization and abundance of lipids in Drosophila melanogaster brain. A J105 ToF-SIMS with a 40 keV gas cluster primary ion source enabled us to probe molecular ions of biomolecules on the fly with a spatial resolution of ∼3 μm, giving us unique insights into the effect of these drugs on molecular lipids in the nervous system. Significant changes in phospholipid composition were observed in the central brain for both. Principal components image analysis revealed that changes occurred mainly for phosphatidylcholines, phosphatidylethanolamines, and phosphatidylinositols. When the lipid changes caused by cocaine were compared with those induced by methylphenidate, it was shown that these drugs exert opposite effects on the brain lipid structure. We speculate that this might relate to the molecular mechanism of cognition and memory.

Methylphenidate Enhances Extinction of Contextual Fear

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Abraham, Antony D.; Cunningham, Christopher L.; Lattal, K. Matthew

2012-01-01

Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show…

Long Withdrawal of Methylphenidate Induces a Differential Response of the Dopaminergic System and Increases Sensitivity to Cocaine in the Prefrontal Cortex of Spontaneously Hypertensive Rats.

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Maurício dos Santos Pereira

Full Text Available Methylphenidate (MPD is one of the most prescribed drugs for alleviating the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD. However, changes in the molecular mechanisms related to MPD withdrawal and susceptibility to consumption of other psychostimulants in normal individuals or individuals with ADHD phenotype are not completely understood. The aims of the present study were: (i to characterize the molecular differences in the prefrontal dopaminergic system of SHR and Wistar strains, (ii to establish the neurochemical consequences of short- (24 hours and long-term (10 days MPD withdrawal after a subchronic treatment (30 days with Ritalin® (Methylphenidate Hydrochloride; 2.5 mg/kg orally, (iii to investigate the dopaminergic synaptic functionality after a cocaine challenge in adult MPD-withdrawn SHR and Wistar rats. Our results indicate that SHR rats present reduced [3H]-Dopamine uptake and cAMP accumulation in the prefrontal cortex (PFC and are not responsive to dopaminergic stimuli in when compared to Wistar rats. After a 24-hour withdrawal of MPD, SHR did not present any alterations in [3H]-Dopamine Uptake, [3H]-SCH 23390 binding and cAMP production; nonetheless, after a 10-day MPD withdrawal, the results showed a significant increase of [3H]-Dopamine uptake, of the quantity of [3H]-SCH 23390 binding sites and of cAMP levels in these animals. Finally, SHR that underwent a 10-day MPD withdrawal and were challenged with cocaine (10 mg/kg i.p. presented reduced [3H]-Dopamine uptake and increased cAMP production. Wistar rats were affected by the 10-day withdrawal of MPD in [3H]-dopamine uptake but not in cAMP accumulation; in addition, cocaine was unable to induce significant modifications in [3H]-dopamine uptake and in cAMP levels after the 10-day withdrawal of MPD. These results indicate a mechanism that could explain the high comorbidity between ADHD adolescent patients under methylphenidate treatment and substance abuse in adult

Deviant patterns of methylphenidate use in adults

DEFF Research Database (Denmark)

Rasmussen, Lotte; Zoëga, Helga; Hallas, Jesper

2015-01-01

of drugs used in addictive disorders (OR2 2.08) or opioids (OR2 1.75). Sensitivity analyses revealed that the number of different prescribers alone does not seem to effectively identify deviant users of methylphenidate. CONCLUSION: We have identified characteristics associated with deviant patterns...

Prescribing Patterns of Methylphenidate and Atomoxetine for ...

African Journals Online (AJOL)

Purpose: To determine the prescribing pattern of methylphenidate and atomoxetine to patients with. Attention-Deficit/Hyperactivity Disorder (ADHD) in South Africa. Methods: A retrospective, cross-sectional pharmacoepidemiological study was conducted based on the data from a medical aid administrator in South Africa for ...

Prescribing Patterns of Methylphenidate and Atomoxetine for ...

African Journals Online (AJOL)

Purpose: To determine the prescribing pattern of methylphenidate and atomoxetine to patients with Attention-Deficit/Hyperactivity Disorder (ADHD) in South Africa. Methods: A retrospective, cross-sectional pharmacoepidemiological study was conducted based on the data from a medical aid administrator in South Africa for ...

Methylphenidate Has Superior Efficacy Over Parent-Child Interaction Therapy for Preschool Children with Disruptive Behaviors.

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van der Veen-Mulders, Lianne; van den Hoofdakker, Barbara J; Nauta, Maaike H; Emmelkamp, Paul; Hoekstra, Pieter J

2018-02-01

To compare the effectiveness between parent-child interaction therapy (PCIT) and methylphenidate in preschool children with attention-deficit/hyperactivity disorder (ADHD) symptoms and disruptive behaviors who had remaining significant behavior problems after previous behavioral parent training. We included 35 preschool children, ranging in age between 3.4 and 6.0 years. Participants were randomized to PCIT (n = 18) or methylphenidate (n = 17). Outcome measures were maternal ratings of the intensity and number of behavior problems and severity of ADHD symptoms. Changes from pretreatment to directly posttreatment were compared between groups using two-way mixed analysis of variance. We also made comparisons of both treatments to a nonrandomized care as usual (CAU) group (n = 17) regarding intensity and number of behavior problems. All children who started one of the treatments were included in the analyses. Mothers reported a significantly more decreased intensity of behavior problems after methylphenidate (pre-post effect size d = 1.50) compared with PCIT (d = 0.64). ADHD symptoms reduced significantly over time only after methylphenidate treatment (d = 0.48) and not after PCIT. Changes over time of children in the CAU treatment were nonsignificant. Although methylphenidate was more effective than PCIT, both interventions may be effective in the treatment of preschool children with disruptive behaviors. Our findings are preliminary as our sample size was small and the use of methylphenidate in preschool children lacks profound safety data as reflected by its off-label status. More empirical support is needed from studies with larger sample sizes.

Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task

International Nuclear Information System (INIS)

Goldstein, R.Z.; Woicik, P.A.; Maloney, T.; Tomasi, D.; Alia-Klein, N.; Shan, J.; Honorario, J.; Samaras, D.; Wang, R.; Telang, F.; Wang, G.-J.; Volkow, N.D.

2010-01-01

Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.

Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task

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Goldstein, R.Z.; Goldstein, R.Z.; Woicik, P.A.; Maloney, T.; Tomasi, D.; Alia-Klein, N.; Shan, J.; Honorario, J.; Samaras, d.; Wang, R.; Telang, F.; Wang, G.-J.; Volkow, N.D.

2010-09-21

Anterior cingulate cortex (ACC) hypoactivations during cognitive demand are a hallmark deficit in drug addiction. Methylphenidate (MPH) normalizes cortical function, enhancing task salience and improving associated cognitive abilities, in other frontal lobe pathologies; however, in clinical trials, MPH did not improve treatment outcome in cocaine addiction. We hypothesized that oral MPH will attenuate ACC hypoactivations and improve associated performance during a salient cognitive task in individuals with cocaine-use disorders (CUD). In the current functional MRI study, we used a rewarded drug cue-reactivity task previously shown to be associated with hypoactivations in both major ACC subdivisions (implicated in default brain function) in CUD compared with healthy controls. The task was performed by 13 CUD and 14 matched healthy controls on 2 d: after ingesting a single dose of oral MPH (20 mg) or placebo (lactose) in a counterbalanced fashion. Results show that oral MPH increased responses to this salient cognitive task in both major ACC subdivisions (including the caudal-dorsal ACC and rostroventromedial ACC extending to the medial orbitofrontal cortex) in the CUD. These functional MRI results were associated with reduced errors of commission (a common impulsivity measure) and improved task accuracy, especially during the drug (vs. neutral) cue-reactivity condition in all subjects. The clinical application of such MPH-induced brain-behavior enhancements remains to be tested.

Atomoxetine/Methylphenidate Effects on Social Play Behavior

Directory of Open Access Journals (Sweden)

J Gordon Millichap

2015-02-01

Full Text Available Researchers at Utrecht University, The Netherlands, and University “Roma Tre,” Rome, Italy, studied the neural substrates of the previously identified social play-suppressant effects of methylphenidate (MPH and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD.

Methylphenidate use and poly-substance use among ...

African Journals Online (AJOL)

2016-03-22

Mar 22, 2016 ... Methylphenidate hydrochloride (MPH) is used in the treatment of attention deficit hyperactivity disorder (ADHD). Prescriptions for and usage of MPH products have increased sharply since the early 1990s with accompanying concerns about potential misuse.1,2,3 While peer pressure and experimentation ...

Topiramate via NMDA, AMPA/kainate, GABAA and Alpha2 receptors and by modulation of CREB/BDNF and Akt/GSK3 signaling pathway exerts neuroprotective effects against methylphenidate-induced neurotoxicity in rats.

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Motaghinejad, Majid; Motevalian, Manijeh; Fatima, Sulail; Beiranvand, Tabassom; Mozaffari, Shiva

2017-11-01

Chronic abuse of methylphenidate (MPH) often causes neuronal cell death. Topiramate (TPM) carries neuroprotective effects, but its exact mechanism of action remains unclear. In the present study, the role of various doses of TPM and its possible mechanisms, receptors and signaling pathways involved against MPH-induced hippocampal neurodegeneration were evaluated in vivo. Thus, domoic acid (DOM) was used as AMPA/kainate receptor agonist, bicuculline (BIC) as GABA A receptor antagonist, ketamine (KET) as NMDA receptor antagonist, yohimbine (YOH) as α 2 adrenergic receptor antagonist and haloperidol (HAL) was used as dopamine D 2 receptor antagonist. Open field test (OFT) was used to investigate the disturbances in motor activity. Hippocampal neurodegenerative parameters were evaluated. Protein expressions of CREB/BDNF and Akt/GSK3 signaling pathways were also evaluated. Cresyl violet staining was performed to show and confirm the changes in the shape of the cells. TPM (70 and 100 mg/kg) reduced MPH-induced rise in lipid peroxidation, oxidized form of glutathione (GSSG), IL-1β and TNF-α levels, Bax expression and motor activity disturbances. In addition, TPM treatment increased Bcl-2 expression, the level of reduced form of glutathione (GSH) and the levels and activities of superoxide dismutase, glutathione peroxidase and glutathione reductase enzymes. TPM also inhibited MPH-induced hippocampal degeneration. Pretreatment of animals with DOM, BIC, KET and YOH inhibited TPM-induced neuroprotection and increased oxidative stress, neuroinflammation, neuroapoptosis and neurodegeneration while reducing CREB, BDNF and Akt protein expressions. Also pretreatment with DOM, BIC, KET and YOH inhibited TPM-induced decreases in GSK3. It can be concluded that the mentioned receptors by modulation of CREB/BDNF and Akt/GSK3 pathways, are involved in neuroprotection of TPM against MPH-induced neurodegeneration.

Acute effects of methylphenidate on impulsivity and attentional behavior among adolescents comorbid for ADHD and conduct disorder.

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Dougherty, Donald M; Olvera, Rene L; Acheson, Ashley; Hill-Kapturczak, Nathalie; Ryan, Stacy R; Mathias, Charles W

2016-12-01

Adolescents with Attention Deficit Hyperactivity Disorder (ADHD) and Conduct Disorder (CD) experience deficits in neuropsychological measures of attention, inhibition, and reward processes. Methylphenidate treatment for ADHD and CD has acute effects on these processes. Some of these same aspects of performance are separately described in the Behavioral Model of Impulsivity, which uses a modified approach to measurement. This study characterized the acute effects of methylphenidate attention, initiation, inhibition, and reward processes described in this model of impulsivity. Thirty-one adolescents from the United States of America with comorbid ADHD and CD completed measures of impulsivity (response initiation, response inhibition, and consequence) and attention following placebo, 20 mg, and 40 mg of a long-acting dose of methylphenidate. Methylphenidate effects on attentional performance was more robust than on any of the measures of impulsivity. Adolescent performance from this behavioral perspective is interpreted in the context of divergence from previous neuropsychological tests of acute methylphenidate effects. Copyright © 2016 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Metabolism of methylphenidate in dog and rat

International Nuclear Information System (INIS)

Egger, H.; Bartlett, F.; Dreyfuss, R.; Karliner, J.

1981-01-01

The urinary metabolites of methylphenidate in the dog and rat were investigated. After oral administration of 14C-labeled methylphenidate, approximately 86% and 63% of the dose was recovered in the urine of the dog and rat, respectively. Less than 1% of the dose was excreted as unchanged drug. Metabolism involved oxidation, hydrolysis, and conjugation processes. The primary hydrolytic product was alpha-phenyl-2-piperidineacetic acid (24%, dog; 35-40%, rat). The primary metabolites of oxidation were methyl 6-oxo-alpha-phenyl-2-piperidineacetate (3%, dog; 1.5%, rat) and the glucuronide of alpha-(p-hydroxyphenyl)-2-piperidineacetic acid (10%, rat). The former also underwent extensive biotransformation, including: 1) hydrolysis to the lactam acid (27%, dog; 7-10%, rat) and subsequent carboxylic acid O-glucuronidation (15%, dog); or 2) hydroxylation at the 5-position (1%, dog; 2%, rat) and subsequent hydrolysis (4%, dog; 15-17%, rat); or 3) 5-O-glucuronidation (12%, dog). Additional minor metabolites from methyl-6-oxo-alpha-phenyl-2-piperidineacetate were the phenolic O-glucuronide of methyl alpha-(p-hydroxyphenyl)-6-oxo-2-piperidineacetate (1%, dog), and the 4-O-glucuronide of methyl 4-hydroxy-6-oxo-alpha-phenyl-2-piperidineacetate (1%, dog), and the taurine amide conjugate of alpha-(p-hydroxyphenyl)-6-oxo-2-piperidineacetic acid (1%, dog). Additional products from methylphenidate conjugation included methyl 1-carbamoyl-alpha-phenyl-2-piperidineacetate (1%, dog or rat) and its carboxylic acid hydrolysis product (1%, rat). The chirality of the major metabolites isolated from dog urine showed that metabolism was partially stereoselective in all investigated cases, except in the formation of alpha-phenyl-2-piperidineacetic acid

Attention-deficit/hyperactivity disorder: the impact of methylphenidate on working memory, inhibition capacity and mental flexibility.

Science.gov (United States)

Bolfer, Cristiana; Pacheco, Sandra Pasquali; Tsunemi, Miriam Harumi; Carreira, Walter Souza; Casella, Beatriz Borba; Casella, Erasmo Barbante

2017-04-01

To compare children with attention-deficit/hyperactivity disorder (ADHD), before and after the use of methylphenidate, and a control group, using tests of working memory, inhibition capacity and mental flexibility. Neuropsychological tests were administrated to 53 boys, 9-12 years old: the WISC-III digit span backward, and arithmetic; Stroop Color; and Trail Making Tests. The case group included 23 boys with ADHD, who were combined type, treatment-naive, and with normal intelligence without comorbidities. The control group (n = 30) were age and gender matched. After three months on methylphenidate, the ADHD children were retested. The control group was also retested after three months. Before treatment, ADHD children had lower scores than the control group on the tests (p ≤ 0.001) and after methylphenidate had fewer test errors than before (p ≤ 0.001). Methylphenidate treatment improves the working memory, inhibitory control and mental flexibility of ADHD boys.

Management of attention-deficit hyperactivity disorder in adults: focus on methylphenidate hydrochloride

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Rajasree Nair

2009-08-01

Full Text Available Rajasree Nair, Shannon B MossBaylor Family Medicine Residency at Garland, Garland, Texas, USAAbstract: Attention-deficit hyperactivity disorder (ADHD is one of the most common psychiatric disorders in young adults and causes significant psychosocial impairment and economic burden to society. Because of the paucity of long-term evidence and lack of national guidelines for diagnosis and management of adult ADHD, most of the data are based on experience derived from management of childhood ADHD. This article reviews the current evidence for the diagnosis and management of adult ADHD with special emphasis on the role of methylphenidate hydrochloride preparations in its treatment. Methylphenidate hydrochloride, a stimulant that acts through the dopaminergic and adrenergic pathways, has shown more than 75% efficacy in controlling the symptoms of adult ADHD. Although concern for diversion of the drug exists, recent data have shown benefits in preventing substance use disorders in patients with adult ADHD.Keywords: adult ADHD, treatment, stimulants, methylphenidate hydrochloride

Methylphenidate intoxications in children and adults: exposure circumstances and evidence-based dose threshold for pre-hospital triage

NARCIS (Netherlands)

Hondebrink, Laura; Rietjens, Saskia J; Hunault, Claudine C; Pereira, Rob R; Kelleci, Nuriye; Yasar, Gulhan; Ghebreslasie, Ariam; Lo-A-Foe, Cindy; De Vries, Irma; Meulenbelt, Jan

2015-01-01

CONTEXT: Methylphenidate intoxications mostly have a relatively mild course, although serious complications can occur. OBJECTIVE: We aimed to characterize methylphenidate exposures and reassess our current dose threshold for hospital referral (2 mg/kg). METHODS: In a prospective follow-up study, we

Methylphenidate intoxications in children and adults : Exposure circumstances and evidence-based dose threshold for pre-hospital triage

NARCIS (Netherlands)

Hondebrink, Laura; Rietjens, Saskia J.; Hunault, Claudine C.; Pereira, Rob R.; Kelleci, Nuriye; Yasar, Gulhan; Ghebreslasie, Ariam; Lo-A-Foe, Cindy; De Vries, Irma; Meulenbelt, Jan

Context. Methylphenidate intoxications mostly have a relatively mild course, although serious complications can occur. Objective. We aimed to characterize methylphenidate exposures and reassess our current dose threshold for hospital referral (2 mg/kg). Methods. In a prospective follow-up study, we

Use of methylphenidate among medical students: a systematic review

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Guilherme Finger

2013-06-01

Full Text Available OBJECTIVE: To review the effects of methylphenidate on cognitive enhancement, memory, and performance in medical students. METHODS: A review of four databases (LILACS, PubMed, ScienceDirect, and SciELO, analyzing the title and of all articles published between 1990 and 2012 in English, Portuguese, and Spanish. Selected articles were read in entirety, including in the review those that met the established criteria. RESULTS: The prevalence of use among medical students reached 16%, with no gender difference. Most students began using the drug after entering the university, and the reasons cited to justify it are related to enhancing academic performance. CONCLUSION: There is no evidence in the literature that the use of methylphenidate is beneficial in terms of memory or learning. The drug simply increases wakefulness and alertness, reducing the time of sleep.

Cost-Effectiveness of Extended-Release Methylphenidate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder Sub-Optimally Treated with Immediate Release Methylphenidate

NARCIS (Netherlands)

van der Schans, Jurjen; Kotsopoulos, Niko; Hoekstra, Pieter J.; Hak, Eelko; Postma, Maarten J.

2015-01-01

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH) is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at

Synthesis of the racemate and individual enantiomers of [11C]methylphenidate for studying presynaptic dopaminergic neutron with positron emission tomography

International Nuclear Information System (INIS)

Ding, Y.-S.; Sugano, Y.; Fowler, J.S.; Salata, C.

1994-01-01

Carbon-11 labeled dl-threo-methylphenidate (methyl-2-phenyl-2-(2-piperidyl)acetate, Ritalin), a psychostimulant drug widely used to treat attention deficit hyperactivity disorder, was prepared in two steps: O-methylation of the N-protected dl-threo-ritalinic acid derivative with [ 11 C]methyl iodide followed by deprotection. The same strategy was applied for the preparation of C-11 labeled individual enantiomers of threo-methylphenidate from N-protected d-threo-l-threo-ritalinic acid. The subsequent C18 sep-pak and reverse-phase HPLC purification resulted in ca. 40% radiochemical yield with a total synthesis time of 40 minutes and an average specific activity of 1.5 Ci/μmole (at EOB). (author)

Safety of Methylphenidate and Atomoxetine in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): Data from the Italian National ADHD Registry.

Science.gov (United States)

Cortese, Samuele; Panei, Pietro; Arcieri, Romano; Germinario, Elena A P; Capuano, Annalisa; Margari, Lucia; Chiarotti, Flavia; Curatolo, Paolo

2015-01-01

The aim of this study was to assess the type and frequency of adverse events (AEs) in children with attention-deficit/hyperactivity disorder (ADHD) treated with methylphenidate or atomoxetine over a 5-year period in a large naturalistic study. We draw on data from the Italian ADHD Registry, a national database for postmarketing phase IV pharmacovigilance of ADHD medications across 90 centers. AEs were defined as severe or mild as per the classification of the Italian Medicines Agency. AE frequency in the two treatment groups was compared using incidence rates per 100 person-years (IR100PY) and incidence rate ratios (IRRs). Mantel-Haenszel adjusted IRRs were calculated to control for psychiatric comorbidity. A total of 1350 and 753 participants (aged 6-18 years, mean age 10.7 ± 2.8) were treated with methylphenidate and atomoxetine, respectively, from 2007 to 2012. Ninety participants (7 %) were switched from methylphenidate to atomoxetine, and 138 (18 %) from atomoxetine to methylphenidate. Thirty-seven children treated with atomoxetine and 12 with methylphenidate had their medication withdrawn. Overall, 645 patients (26.8 %) experienced at least one mild AE (including decreased appetite and irritability, for both drugs) and 95 patients (3.9 %) experienced at least one severe AE (including severe gastrointestinal events). IR100PY were significantly higher in the atomoxetine-treated group compared with the methylphenidate-treated group for a number of mild and severe AEs and for any severe or mild AEs. After controlling for comorbidities, IRR was still significantly higher in the atomoxetine group compared with the methylphenidate group for a number of mild (decreased appetite, weight loss, abdominal pain, dyspepsia, stomach ache, irritability, mood disorder and dizziness) and severe (gastrointestinal, neuropsychiatric, and cardiovascular) AEs. In this naturalistic study, methylphenidate had a better safety profile than atomoxetine.

Prescribing patterns of methylphenidate in a South African patient ...

African Journals Online (AJOL)

ADHD) in children. The primary aim of the study was to investigate the prescribing patterns of methylphenidate of a medical aid patient population in a private sector and to compare the results with previous studies. An exposure cohort drug ...

Methylphenidate enhances extinction of contextual fear

OpenAIRE

Abraham, Antony D.; Cunningham, Christopher L.; Lattal, K. Matthew

2012-01-01

Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show that MPH, administered before or immediately following extinction of contextual fear, will enhance extinction retention in C57BL/6 mice. Animals that ...

Comparison of duloxetine and methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder

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Nasrin Dodangi

2016-06-01

Full Text Available Background: Attention-deficit/hyperactivity disorder (ADHD is a common and mostly chronic mental health condition that affects children, adolescents, and adults. Stimulants and atomoxetine are first-line agents for the treatment of ADHD. Despite the impressive track record of stimulants in the treatment of ADHD, they fail in 25% of patients due to lack of efficacy or the emergence of unwanted side effects. Accordingly, this study carried out to compare efficacy and safety of duloxetine (a serotonin and norepinephrine reuptake inhibitor and methylphenidate (a short acting stimulant in the treatment of children with attention-deficit/hyperactivity disorder. Methods: Twenty-four children diagnosed with ADHD participated in this 6 weeks open clinical trial. Patients were between 6 to 11 years old that had been referred to psychiatry clinic at Akhavan and Rofide Medical and Rehabilitation Center in Tehran from September 2012 to July 2014. Diagnosis was made by two child psychiatrist according to DSM-IV TR criteria. Thirteen patients received duloxetine and others received methylphenidate. Conner’ parent rating scale-revised-short form (CPRS-RS and ADHD-rating scale (ADHD-RS were used at the beginning and then each two weeks to assess efficacy of treatment. Routine laboratory tests and electrocardiogram (ECG was carried out in the beginning and end of the trial. Results: Twenty children with ADHD completed the study (Ten in methylphenidate and ten in duloxetine group. In both groups, scales of CPRS-RS and ADHD-RS were reduced from baseline to endpoint, but this reduction in methylphenidate group was significantly greater than duloxetine group (P= 0.000. The most common side effect was gastrointestinal problems in duloxetine group and anorexia in methylphenidate group. No serious side effects and no changes in laboratory and ECG indexes were seen in both groups. Conclusion: Duloxetine is not efficacious as well as methylphenidate in treatment of

Dextroamphetamine and Methylphenidate in the Treatment of Hyperactive/Agressive Children

Science.gov (United States)

Winsberg, Bertrand G.; And Others

1974-01-01

Studied was the comparative effectiveness of dextroamphetamine and methylphenidate for the treatment of severe behavior disorders among 18 children (from 5 to 10 1/2 years of age) hospitalized for neuropsychiatric conditions. (Author)

ADHD in childhood epilepsy: Clinical determinants of severity and of the response to methylphenidate.

Science.gov (United States)

Rheims, Sylvain; Herbillon, Vania; Villeneuve, Nathalie; Auvin, Stéphane; Napuri, Silvia; Cances, Claude; Berquin, Patrick; Castelneau, Pierre; Nguyen The Tich, Sylvie; Villega, Frédéric; Isnard, Hervé; Nabbout, Rima; Gaillard, Ségolène; Mercier, Catherine; Kassai, Behrouz; Arzimanoglou, Alexis

2016-07-01

Attention-deficit/hyperactivity disorder (ADHD) is commonly observed in children with epilepsy. However, factors associated with the development of ADHD and which might help to guide its therapeutic management, remain an issue of debate. We conducted a multicenter prospective observational study that included children, aged 6-16 years, with both epilepsy and ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. After inclusion, patients entered a 12-16 week follow-up period during which they were either treated with methylphenidate or they did not receive specific ADHD treatment. ADHD was evaluated with the ADHD Rating Scale-IV. One hundred sixty-seven patients were included, of which 91 were seizure-free during the preinclusion baseline period. At inclusion, the ADHD Rating Scale-IV total score was 30.4 ± (standard deviation) 9.2, the inattentive subscore was 17.3 ± 4.4, and the hyperactive subscore was 13.2 ± 6.6. We did not detect any difference of ADHD Rating Scale-IV scores across patients' age or gender, age at epilepsy onset, epilepsy syndrome, seizure frequency, or number of ongoing antiepileptic drugs. Methylphenidate was initiated in 61 patients, including 55 in whom a follow-up evaluation was available. At the last follow-up, 41 patients (75%) treated with methylphenidate and 39 (42%) of those who did not received ADHD therapy demonstrated ≥25% decrease of ADHD Rating Scale-IV total score (p < 0.001). Response to methylphenidate was greater in girls but was not influenced by any epilepsy-related variables. We did not detect any epilepsy-related factor associated with the severity of ADHD. Twenty-five percent of patients did not respond to methylphenidate. A better understanding of the pathologic process that underlies ADHD development in childhood epilepsy might be required to improve therapeutic strategies. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

First-Trimester In Utero Exposure to Methylphenidate

DEFF Research Database (Denmark)

Dideriksen, Dorthe; Pottegård, Anton; Hallas, Jesper

2013-01-01

published, and safety during pregnancy has not been established. We systematically reviewed available data on birth outcome after human in utero exposure to methylphenidate. Systematic searches in PubMed/Embase were performed from origin to August 2012, and data from Michigan Medicaid recipients...

Non-medical use of methylphenidate among medical students of the University of the Free State

OpenAIRE

Jain, Roshini; Chang, Chiech; Koto, Mpho; Geldenhuys, Alden; Nichol, Richard; Joubert, Gina

2017-01-01

Background: Faced with demanding training programmes, medical students may be more prone to use methylphenidate for non-medical purposes in order to improve concentration, alertness and academic performance. Aim: The study aimed to investigate the prevalence of the non-medical use of methylphenidate and knowledge of this drug among undergraduate medical students of the University of the Free State. Methods: This was a cross-sectional study. A self-administered, anonymous questionnaire...

The effects of surgical and chemical lesions on striatal [3H]threo-(+-)-methylphenidate binding: correlation with [3H]dopamine uptake

International Nuclear Information System (INIS)

Janowsky, A.; Berger, P.; Long, R.; Paul, S.M.; Schweri, M.M.; Skolnick, P.

1985-01-01

The specific binding of [ 3 H]threo-(+-)-methylphenidate to membranes prepared from rat striatum was significantly reduced following either surgical lesions of the medial forebrain bundle or intracerebroventricular administration of 6-hydroxydopamine. The decrease in the density of [ 3 H]threo-(+-)-methylphenidate binding sites in striatum following chemical or surgical denervation was highly correlated with the decrease in [ 3 H]dopamine uptake. In contrast, intracerebroventricular administration of 5,7-dihydroxytryptamine, AF64A, or chronic parenteral administration of reserpine did not alter either the number or apparent affinity of [ 3 H]threo-(+-)-methylphenidate binding sites. These data suggest that the specific binding sites for [ 3 H]threo-(+-)-methylphenidate in striatum are localized to dopaminergic nerve terminals, and may be associated with the dopamine transport complex. (orig.)

Effects of methylphenidate on memory functions of adults with ADHD

NARCIS (Netherlands)

Fuermaier, Anselm B M; Tucha, Lara; Koerts, Janneke; Weisbrod, Matthias; Lange, Klaus W; Aschenbrenner, Steffen; Tucha, Oliver

2017-01-01

Neuropsychological research on adults with attention deficit hyperactivity disorder (ADHD) revealed considerable impairments in memory functions related to executive control. However, only limited evidence exists supporting the effects of pharmacological treatment using methylphenidate (MPH) on

Synthesis of the racemate and individual enantiomers of [[sup 11]C]methylphenidate for studying presynaptic dopaminergic neutron with positron emission tomography

Energy Technology Data Exchange (ETDEWEB)

Ding, Y -S; Sugano, Y; Fowler, J S; Salata, C [Brookhaven National Lab., Upton, NY (United States)

1994-10-01

Carbon-11 labeled dl-threo-methylphenidate (methyl-2-phenyl-2-(2-piperidyl)acetate, Ritalin), a psychostimulant drug widely used to treat attention deficit hyperactivity disorder, was prepared in two steps: O-methylation of the N-protected dl-threo-ritalinic acid derivative with [[sup 11]C]methyl iodide followed by deprotection. The same strategy was applied for the preparation of C-11 labeled individual enantiomers of threo-methylphenidate from N-protected d-threo-l-threo-ritalinic acid. The subsequent C18 sep-pak and reverse-phase HPLC purification resulted in ca. 40% radiochemical yield with a total synthesis time of 40 minutes and an average specific activity of 1.5 Ci/[mu]mole (at EOB). (author).

Short-Term Effects of Methylphenidate on Math Productivity in Children With Attention-Deficit/Hyperactivity Disorder are Mediated by Symptom Improvements: Evidence From a Placebo-Controlled Trial.

Science.gov (United States)

Kortekaas-Rijlaarsdam, Anne Fleur; Luman, Marjolein; Sonuga-Barke, Edmund; Bet, Pierre M; Oosterlaan, Jaap

2017-04-01

Although numerous studies report positive effects of methylphenidate on academic performance, the mechanism behind these improvements remains unclear. This study investigates the effects of methylphenidate on academic performance in children with attention-deficit/hyperactivity disorder (ADHD) and the mediating and moderating influence of ADHD severity, academic performance, and ADHD symptom improvement. Sixty-three children with ADHD participated in a double-blind placebo-controlled crossover study comparing the effects of long-acting methylphenidate and placebo. Dependent variables were math, reading, and spelling performance. The ADHD group performance was compared with a group of 67 typically developing children. Methylphenidate improved math productivity and accuracy in children with ADHD. The effect of methylphenidate on math productivity was partly explained by parent-rated symptom improvement, with greater efficacy for children showing more symptom improvement. Further, children showing below-average math performance while on placebo profited more from methylphenidate than children showing above-average math performance. The results from this study indicate positive effects of methylphenidate on academic performance, although these were limited to math abilities. In light of these results, expectations of parents, teachers, and treating physicians about the immediate effects of methylphenidate on academic improvement should be tempered. Moreover, our results implicate that positive effects of methylphenidate on math performance are in part due directly to effects on math ability and in part due to reductions in ADHD symptoms.

Severe Recurrent Pancreatitis in a Child with ADHD after Starting Treatment with Methylphenidate (Ritalin

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Suheil Artul

2014-01-01

Full Text Available We present a case of a 10-year-old boy, who had severe relapsing pancreatitis, three times in two months within 3 weeks after starting treatment with methylphenidate (Ritalin due to attention deficit hyperactivity disorder (ADHD. Pancreatitis due to the use of (methylphenidate Ritalin was never published before. Attention must be made by the physicians regarding this possible complication, and this complication should be taken into consideration in every patient with abdominal pain who was newly treated with Ritalin.

Buspirone versus Methylphenidate in the Treatment of Attention Deficit Hyperactivity Disorder: A Double-Blind and Randomized Trial

Science.gov (United States)

Davari-Ashtiani, Rozita; Shahrbabaki, Mahin Eslami; Razjouyan, Katayoon; Amini, Homayoun; Mazhabdar, Homa

2010-01-01

The efficacy and side effects of buspirone compared with methylphenidate (MPH) in the treatment of children with attention-deficit/hyperactivity disorder (ADHD). A total of 34 children with ADHD as defined by DSM-IV-TR were randomized to buspirone or methylphenidate dosed on weight-adjusted basis at buspirone (0.5 mg/kg/day) and methylphenidate…

Motivational effects of methylphenidate are associated with GABRA2 variants conferring addiction risk

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Theodora eDuka

2015-11-01

Full Text Available Background: Variations in the GABRA2 gene, encoding α2 subunits of GABAA receptors, have been associated with risk for addiction to several drugs, but the mechanisms by which variations in non-coding regions of GABRA2 increase risk for addictions are not understood. Mice with deletion of Gabra2 show deficits in the ability of psychostimulants to facilitate responding for conditioned reinforcers, offering a potential explanation. Methods: We report human and mouse studies investigating a potential endophenotype underlying this association. Healthy human volunteers carrying either cocaine-addiction risk or protective GABRA2 SNPs were tested for their subjective responses to methylphenidate, and methylphenidate’s ability to facilitate conditioned reinforcement (CRf for visual stimuli (CS+ associated with monetary reward. In parallel, methylphenidate’s ability to facilitate responding for a visual CRf was studied in wildtype and α2 knockout (α2-/- mice. Results: Methylphenidate increased the number of CS+ presentations obtained by human subjects carrying protective, but not risk SNPs. In mice, methylphenidate increased responding for a CS+ in wildtype, but not α2-/- mice. Human subjects carrying protective SNPs felt stimulated, aroused and restless following methylphenidate, while individuals carrying risk SNPs did not. Conclusion: Human risk SNP carriers were insensitive to methylphenidate’s effects on mood or in facilitating CRf. That mice with the gene deletion were also insensitive to methylphenidate’s ability to increase responding for CRf, suggests a potential mechanism whereby low α2-subunit levels increase risk for addictions. Circuits employing GABAA-α2 subunit-containing receptors may protect against risk for addictions.

The role of the polymorphic efflux transporter P-glycoprotein on the brain accumulation of d-methylphenidate and d-amphetamine.

Science.gov (United States)

Zhu, Hao-Jie; Wang, Jun-Sheng; DeVane, C Lindsay; Williard, Robin L; Donovan, Jennifer L; Middaugh, Lawrence D; Gibson, Brian B; Patrick, Kennerly S; Markowitz, John S

2006-07-01

The psychostimulant medications methylphenidate (MPH) and amphetamine (AMP), available in various ratios or enantiopure formulations of their respective active dextrorotary isomers, constitute the majority of agents used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Substantial interindividual variability occurs in their pharmacokinetics and tolerability. Little is known regarding the potential role of drug transporters such as P-glycoprotein (P-gp) in psychostimulant pharmacokinetics and response. Therefore, experiments were carried out in P-gp knockout (KO) mice versus wild-type (WT) mice after intraperitoneal dosing (2.5 mg/kg) of d-MPH or (3.0 mg/kg) of d-AMP. After the administration of each psychostimulant, locomotor activity was assessed at 30-min intervals for 2 h. Total brain-to-plasma drug concentration ratios were determined at 10-, 30-, and 80-min postdosing time-points. The results showed no statistically supported genotypic difference in d-AMP-induced locomotor activity stimulation or in brain-to-plasma ratio of d-AMP. As for d-MPH, the P-gp KO mice had 33% higher brain concentrations (p brain-to-plasma ratios (p brain concentrations, d-MPH-induced locomotor activity increase was attenuated for P-gp compared with that for WT mice. These data indicate that P-gp has no apparent effect on the pharmacokinetics and pharmacodynamics of d-AMP. In addition, d-MPH is a relatively weak P-gp substrate, and its entry into the brain may be limited by P-gp. Furthermore, the mechanism by which d-MPH-induced locomotor activity was attenuated in P-gp KO mice remains to be elucidated.

Possible involvements of glutamate and adrenergic receptors on acute toxicity of methylphenidate in isolated hippocampus and cerebral cortex of adult rats.

Science.gov (United States)

Motaghinejad, Majid; Motevalian, Manijeh; Shabab, Behnaz

2017-04-01

Neurodegeneration induced by methylphenidate (MPH), as a central stimulant with unknown long-term consequences, in adult rats' brain and the possible mechanisms involved were studied. Rats were acutely treated with MPH in the presence and absence of some receptor antagonists such as ketamine, topiramate, yohimbine, and haloperidol. Motor activity and anxiety level in rats were monitored. Antioxidant and inflammatory parameters were also measured in isolated hippocampus and cerebral cortex. MPH-treated groups (10 and 20 mg/kg) demonstrated anxiety-like behavior and increased motor activity. MPH significantly increased lipid peroxidation, GSSG content, IL-1β and TNF-α levels in isolated tissues, and also significantly reduced GSH content, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) activities in hippocampus and cerebral cortex. Pretreatment of animals by receptor antagonists caused inhibition of MPH-induced motor activity disturbances and anxiety-like behavior. Pretreatment of animals by ketamine, topiramate, and yohimbine inhibited the MPH-induced oxidative stress and inflammation; it significantly decreased lipid peroxidation, GSSG level, IL-1β and TNF-α levels and increased GSH content, SOD, GPx, and GR activities in hippocampus and cerebral cortex of acutely MPH-treated rats. Pretreatment with haloperidol did not cause any change in MPH-induced oxidative stress and inflammation. In conclusion, acute administration of high doses of MPH can cause oxidative and inflammatory changes in brain cells and induce neurodegeneration in hippocampus and cerebral cortex of adult rats and these changes might probably be mediated by glutamate (NMDA or AMPA) and/or α 2 -adrenergic receptors. © 2016 Société Française de Pharmacologie et de Thérapeutique.

Dextroamphetamine (but Not Atomoxetine Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.

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Jonathan D Kenny

Full Text Available Methylphenidate induces reanimation (active emergence from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each. When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6. After a single dose of propofol (8 mg/kg i.v., the mean emergence times for rats that received normal saline (vehicle and dextroamphetamine (1 mg/kg i.v. were 641 sec and 404 sec, respectively (n = 8 each. The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8, this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1-4 Hz to θ (4-8 Hz during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation

Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence

Science.gov (United States)

Kenny, Jonathan D.; Taylor, Norman E.; Brown, Emery N.; Solt, Ken

2015-01-01

Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg IV), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg IV) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1–4 Hz) to θ (4–8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes

Dextroamphetamine (but Not Atomoxetine) Induces Reanimation from General Anesthesia: Implications for the Roles of Dopamine and Norepinephrine in Active Emergence.

Science.gov (United States)

Kenny, Jonathan D; Taylor, Norman E; Brown, Emery N; Solt, Ken

2015-01-01

Methylphenidate induces reanimation (active emergence) from general anesthesia in rodents, and recent evidence suggests that dopaminergic neurotransmission is important in producing this effect. Dextroamphetamine causes the direct release of dopamine and norepinephrine, whereas atomoxetine is a selective reuptake inhibitor for norepinephrine. Like methylphenidate, both drugs are prescribed to treat Attention Deficit Hyperactivity Disorder. In this study, we tested the efficacy of dextroamphetamine and atomoxetine for inducing reanimation from general anesthesia in rats. Emergence from general anesthesia was defined by return of righting. During continuous sevoflurane anesthesia, dextroamphetamine dose-dependently induced behavioral arousal and restored righting, but atomoxetine did not (n = 6 each). When the D1 dopamine receptor antagonist SCH-23390 was administered prior to dextroamphetamine under the same conditions, righting was not restored (n = 6). After a single dose of propofol (8 mg/kg i.v.), the mean emergence times for rats that received normal saline (vehicle) and dextroamphetamine (1 mg/kg i.v.) were 641 sec and 404 sec, respectively (n = 8 each). The difference was statistically significant. Although atomoxetine reduced mean emergence time to 566 sec (n = 8), this decrease was not statistically significant. Spectral analysis of electroencephalogram recordings revealed that dextroamphetamine and atomoxetine both induced a shift in peak power from δ (0.1-4 Hz) to θ (4-8 Hz) during continuous sevoflurane general anesthesia, which was not observed when animals were pre-treated with SCH-23390. In summary, dextroamphetamine induces reanimation from general anesthesia in rodents, but atomoxetine does not induce an arousal response under the same experimental conditions. This supports the hypothesis that dopaminergic stimulation during general anesthesia produces a robust behavioral arousal response. In contrast, selective noradrenergic stimulation causes

Influence of Methylphenidate on Motor Performance and Attention in Children with Developmental Coordination Disorder and Attention Deficit Hyperactive Disorder

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Bart, Orit; Daniel, Liron; Dan, Orrie; Bar-Haim, Yair

2013-01-01

Individuals with attention deficit hyperactive disorder (ADHD) often have coexisting developmental coordination disorder (DCD). The positive therapeutic effect of methylphenidate on ADHD symptoms is well documented, but its effects on motor coordination are less studied. We assessed the influence of methylphenidate on motor performance in children…

Prescribing of methylphenidate to children and adolescents in South ...

African Journals Online (AJOL)

2008-11-13

Nov 13, 2008 ... Background: Pharmacoepidemiological studies on ADHD are limited in South Africa. The primary aim was to analyse the prescribing of methylphenidate to patients aged 18 years and younger in the private health care sector. Methods: Data for a one-month period in 2004 were obtained from a large ...

Prescribing of methylphenidate to children and adolescents in South ...

African Journals Online (AJOL)

Background: Pharmacoepidemiological studies on ADHD are limited in South Africa. The primary aim was to analyse the prescribing of methylphenidate to patients aged 18 years and younger in the private health care sector. Methods: Data for a one-month period in 2004 were obtained from a large medical aid ...

Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis

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Hanwella Raveen

2011-11-01

Full Text Available Abstract Background Psychostimulants and non stimulants are effective in the treatment of ADHD. Efficacy of both methylphenidate and atomoxetine has been established in placebo controlled trials. Direct comparison of efficacy is now possible due to availability of results from several head-to-head trials of these two medications. Methods All published, randomized, open label or double blind trials, comparing efficacy of methylphenidate with atomoxetine, in treatment of ADHD in children, diagnosed using DSM-IV™ criteria were included. The outcome studied was ADHDRS-IVParent:Inv score. The standardized mean difference (SMD was used as a measure of effect size. Results Nine randomized trials comparing methylphenidate and atomoxetine, with a total of 2762 participants were included. Meta-analysis did not find a significant difference in efficacy between methylphenidate and atomoxetine (SMD = 0.09, 95% CI -0.08-0.26 (Z = 1.06, p = 0.29. Synthesis of data from eight trials found no significant difference in response rates (RR = 0.93 95% CI 0.76-1.14, p = 0.49. Sub group analysis showed a significant standardized mean difference favouring OROS methylphenidate (SMD = 0.32, 95% CI 0.12-0.53 (Z = 3.05, p I2 = 67%. Subgroup analysis demonstrated the heterogeneity to be due to the open label trials (p = 0.001, I2 = 81%. Conclusions In general atomoxetine and methylphenidate have comparable efficacy and equal acceptability in treatment of ADHD in children and adolescents. However OROS methylphenidate is more effective than atomoxetine and may be considered as first line treatment in treatment of ADHD in children and adolescents.

Enantioselective determination of methylphenidate and ritalinic acid in whole blood from forensic cases using automated solid-phase extraction and liquid chromatography-tandem mass spectrometry

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Thomsen, Ragnar; B. Rasmussen, Henrik; Linnet, Kristian

2012-01-01

A chiral liquid chromatography tandem mass spectrometry (LC–MS-MS) method was developed and validated for quantifying methylphenidate and its major metabolite ritalinic acid in blood from forensic cases. Blood samples were prepared in a fully automated system by protein precipitation followed...... methylphenidate was not determined to be related to the cause of death, the femoral blood concentration of d-methylphenidate ranged from 5 to 58 ng/g, and from undetected to 48 ng/g for l-methylphenidate (median d/l-ratio 5.9). Ritalinic acid was present at concentrations 10–20 times higher with roughly equal...

Autonomic correlates at rest and during evoked attention in children with attention-deficit/hyperactivity disorder and effects of methylphenidate.

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Negrao, Bianca Lee; Bipath, Priyesh; van der Westhuizen, Deborah; Viljoen, Margaretha

2011-01-01

The aim of this study was to assess autonomic nervous system functioning in children with attention-deficit/hyperactivity disorder (ADHD) and to examine the effects of methylphenidate and focussed attention. Children with ADHD (n = 19) were tested while they were stimulant free and during a period in which they were on stimulants. On both occasions, autonomic nervous system functioning was tested at baseline and during focussed attention. Autonomic nervous system functioning of control subjects was also tested at baseline and during focussed attention. Autonomic nervous system activity was determined by means of heart rate variability (HRV) and skin conductivity analyses. Attention was evoked by means of the BioGraph Infiniti biofeedback apparatus. HRV was determined by time domain, frequency domain and Poincaré analysis of RR interval data. Skin conductivity was determined by the BioGraph Infiniti biofeedback apparatus. The main findings of this study were (a) that stimulant-free children with ADHD showed a sympathetic underarousal and parasympathetic overarousal of the sympathovagal balance relative to control subjects; (b) methylphenidate shifted the autonomic balance of children with ADHD towards normal levels; however, a normal autonomic balance was not reached, and (c) stimulant-free children with ADHD exhibited a shift in the sympathovagal balance towards the sympathetic nervous system from baseline to focussed attention; however, methylphenidate appeared to abolish this shift. Stimulant-free children with ADHD have a parasympathetic dominance of the autonomic balance, relative to control subjects. Methylphenidate attempts to restore the normal autonomic balance in children with ADHD, but inhibits the normal autonomic nervous system response to a cognitive challenge. These results indicate that methylphenidate may have a suppressive effect on the normal stress response. Although this may be of benefit to those who interact with children who suffer from ADHD

High dose methylphenidate treatment in adult attention deficit hyperactivity disorder: a case report

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Liebrenz Michael

2012-05-01

Full Text Available Abstract Introduction Stimulant medication improves hyperactivity, inattention, and impulsivity in both pediatric and adult populations with Attention Deficit Hyperactivity Disorder (ADHD. However, data regarding the optimal dosage in adults is still limited. Case presentation We report the case of a 38-year-old Caucasian patient who was diagnosed with Attention Deficit Hyperactivity Disorder when he was nine years old. He then received up to 10 mg methylphenidate (Ritalin® and 20 mg sustained-release methylphenidate (Ritalin SR® daily. When he was 13, his medication was changed to desipramine (Norpramin®, and both Ritalin® and Ritalin SR® were discontinued; and at age 18, when he developed obsessive-compulsive symptoms, his medication was changed to clomipramine (Anafranil® 75 mg daily. Still suffering from inattention and hyperactivity, the patient began college when he was 19, but did not receive stimulant medication until three years later, when Ritalin® 60 mg daily was re-established. During the 14 months that followed, he began to use Ritalin® excessively, both orally and rectally, in dosages from 4800-6000 mg daily. Four years ago, he was referred to our outpatient service, where his Attention Deficit Hyperactivity Disorder was re-evaluated. At that point, the patient’s daily Ritalin® dosage was reduced to 200 mg daily orally, but he still experienced pronounced symptoms of, Attention Deficit Hyperactivity Disorder so this dosage was raised again. The patient’s plasma levels consistently remained between 60–187 nmol/l—within the recommended range—and signs of his obsessive-compulsive symptoms diminished with fluoxetine 40 mg daily. Finally, on a dosage of 378 mg extended-release methylphenidate (Concerta®, his symptoms of Attention Deficit Hyperactivity Disorder have improved dramatically and no further use of methylphenidate has been recorded during the 24 months preceding this report. Conclusions Symptoms of

A Comparison of Effectiveness of Parent Behavioral Management Training and Methylphenidate on Reduction of Symptomsof Attention Deficit Hyperactivity Disorder

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Mohammad Reza Mohammadi

2016-09-01

Full Text Available Attention deficit hyperactivity disorder (ADHD is one of the most common psychological disorders of childhood. Methylphenidate is highly effective in the treatment of ADHD. This study aimed to determine the effectiveness of combined Parent behavioral management training (PBMT and medication treatment (Methylphenidate in reducing ADHD symptoms in 6-12-year-old children, using randomized sampling. A total of 50 children with ADHD were assigned into two groups: an experimental group of PBMT and a control group of medication treatment (Methylphenidate without other interventions. Conners’ Parent Rating Scale (CPRS-48 was employed before and after interventions to determine the effects. Descriptive Statistics method (consisting of Mean and Standard deviation and Statistical inference method, (including t-test and Levene's Test were used for data analysis.  Findings revealed that the combined behavioral intervention of PBMT and methylphenidate treatment is more effective in reduction of ADHD in children. The difference of means between pre-test and post-test of CPRS in the experimental group was equal to 10.77, and it was equal to 1.88 in the control group. In addition, PBMT was more effective in the case of younger parents (P<0.025. However, parents’ education level did not affect the behavioral intervention (P<0.025.The findings suggest that combined intervention of PBMT and methylphenidate is effective in reducing the symptoms of ADHD in children.

The Effects of Methylphenidate on Goal-Directed Behavior in a Rat Model of ADHD

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Joman Y. Natsheh

2015-11-01

Full Text Available Although attentional and motor alterations in Attention Deficit Hyperactivity Disorder (ADHD have been well characterized, less is known about how this disorder impacts goal-directed behavior. To investigate whether there is a misbalance between goal-directed and habitual behaviors in an animal model of ADHD, we tested adult [P75-P105] Spontaneously Hypertensive Rats (SHR (ADHD rat model and Wistar-Kyoto rats (WKY, the normotensive control strain, on an instrumental conditioning paradigm with two phases: a free-operant training phase in which rats separately acquired two distinct action-outcome contingencies, and a choice test conducted in extinction prior to which one of the food outcomes was devalued through specific satiety. To assess the effects of Methylphenidate, a commonly used ADHD medication, on goal-directed behavior, we injected rats with either Methylphenidate or saline prior to the choice test. Both rat strains acquired an instrumental response, with SHR responding at greater rates over the course of training. During the choice test WKY demonstrated goal-directed behavior, responding more frequently on the lever that delivered, during training, the still-valued outcome. In contrast, SHR showed no goal-directed behavior, responding equally on both levers. However, methylphenidate administration prior to the choice test restored goal-directed behavior in SHR, and disrupted this behavior in WKY rats. This study provides the first experimental evidence for selective impairment in goal-directed behavior in rat models of ADHD, and how methylphenidate acts differently on SHR and WKY animals to restore or impair this behavior, respectively.

The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): study protocol for a randomized controlled trial.

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Scherer, Roberta W; Drye, Lea; Mintzer, Jacobo; Lanctôt, Krista; Rosenberg, Paul; Herrmann, Nathan; Padala, Prasad; Brawman-Mintzer, Olga; Burke, William; Craft, Suzanne; Lerner, Alan J; Levey, Allan; Porsteinsson, Anton; van Dyck, Christopher H

2018-01-18

Alzheimer's disease (AD) is characterized not only by cognitive and functional decline, but also often by the presence of neuropsychiatric symptoms. Apathy, which can be defined as a lack of motivation, is one of the most prevalent neuropsychiatric symptoms in AD and typically leads to a worse quality of life and greater burden for caregivers. Treatment options for apathy in AD are limited, but studies have examined the use of the amphetamine, methylphenidate. The Apathy in Dementia Methylphenidate Trial (ADMET) found that treatment of apathy in AD with methylphenidate was associated with significant improvement in apathy in two of three outcome measures, some evidence of improvement in global cognition, and minimal adverse events. However, the trial only enrolled 60 participants who were followed for only 6 weeks. A larger, longer-lasting trial is required to confirm these promising findings. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is a phase III, placebo-controlled, masked, 6-month, multi-center, randomized clinical trial targeted to enroll 200 participants with AD and apathy. Participants are randomly assigned 1:1 to 20 mg methylphenidate per day prepared as four over-encapsulated tablets or to matching placebo. The primary outcomes include (1) the mean difference in the Neuropsychiatric Inventory Apathy subscale scores measured as change from baseline to 6 months, and (2) the odds of having a given rating or better on the modified AD Cooperative Study Clinical Global Impression of Change ratings at month 6 compared with the baseline rating. Other outcomes include change in cognition, safety, and cost-effectiveness measured at monthly follow-up visits up to 6 months. Given the prevalence of apathy in AD and its impact on both patients and caregivers, an intervention to alleviate apathy would be of great benefit to society. ADMET 2 follows on the promising results from the original ADMET to evaluate the efficacy of methylphenidate as a

Cognitive enhancement with methylphenidate and modafinil: conceptual advances and societal implications

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Dubljević V

2015-08-01

Full Text Available Veljko Dubljević,1 Christopher James Ryan2 1Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; 2Discipline of Psychiatry and the Centre for Values, Ethics and the Law in Medicine, University of Sydney, Sydney, NSW, Australia Abstract: “Cognition enhancement” (CE drugs are pharmaceuticals taken by healthy people with the aim of sustaining attention, augmenting memory, or improving other cognitive capacities. This paper focuses on two CE drugs – methylphenidate and modafinil. It analyzes their mechanism of action, the evidence for their efficacy in nonsleep deprived individuals, and reviews their adverse effects. It then addresses the normative stances and social issues surrounding CE drug use. Currently, there is little evidence that either methylphenidate or modafinil provide any useful cognitive enhancement to well-rested users. However, it is very possible that future research may reveal cognitive benefits for these agents or for other pharmaceuticals. Public attitudes on CE mirror those evident in academic debate. Even though the majority seem to be opposed to enhancement based on issues of authenticity, utility, and fairness, a steady minority take the view that cognitive enhancer usage is both acceptable and fair. Current legal regimes do not adequately address the social phenomenon of CE use. While the United Nations Convention on Psychotropic Substances defines limits of methylphenidate use across the globe, no such guide exists for modafinil. Keywords: cognitive enhancement, psychopharmacological neuroenhancement, Ritalin, Provigil, neuroethics

Effects of Methylphenidate and Atomoxetine on Cortical Inhibition in ADHD

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J Gordon Millichap

2006-09-01

Full Text Available The effects of methylphenidate (MPH, a psychostimulant, and atomoxetine (ATX, a selective norepinephrine reuptake inhibitor, on short interval-cortical inhibition (SICI were measured in motor cortex with transcranial magnetic stimulation, in a study at Cincinnati Children’s Medical Center, OH, and other centers.

Combined methylphenidate and atomoxetine pharmacotherapy in attention deficit hyperactivity disorder.

Science.gov (United States)

Ozbaran, Burcu; Kose, Sezen; Yuzuguldu, Onur; Atar, Burcu; Aydin, Cahide

2015-01-01

Pharmacological treatment of attention deficit hyperactivity disorder (ADHD) includes stimulant and non-stimulant medications. Our purpose in this study is to investigate efficacy, safety and tolerability of combined methylphenidate and atomoxetine pharmacotherapy. We included 12 patients of the 824 patients with ADHD using methylphenidate and atomoxetine combined therapy between the years 2010 and 2014. Kiddie-SADS, Turgay DSM-IV Based Child and Adolescent Behavior Disorders Screening and Rating Scale, Child Behavior Checklist, Clinic Global Impression Scale Severity and Impression (CGIS-S-I) scales were used. Patients were between the ages of 7 and 17 years. Before combined pharmacotherapy the CGIS-S score mean was 5.08. Mean CGIS-S score after the combined pharmacotherapy was 3.08 (P = 0.03; -2,980). The most common side effects were irritability (n = 5, 41.6%), appetite reduction (n = 3, 25%), palpitations (n = 2, 16.7%), headache (n = 1, 8.3%). Nine of these 12 patients showed significant improvement in their symptoms, combined therapy enhanced the effectiveness of monotherapy.

Anxiety and depression symptoms and response to methylphenidate in children with attention-deficit hyperactivity disorder and tic disorder.

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Gadow, Kenneth D; Nolan, Edith E; Sverd, Jeffrey; Sprafkin, Joyce; Schwartz, Joseph

2002-06-01

This study examined response to methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD) and chronic multiple tic disorder. The primary goal was to determine if children with anxiety or depression symptoms showed a less favorable response to treatment. Subjects were 38 prepubertal children who participated in an 8-week, double-blind, placebo-controlled, methylphenidate crossover evaluation. Treatment effects were assessed with direct observations of child behavior in public school and clinic settings; rating scales completed by parents, teachers, and clinicians; and laboratory analogue tasks. There was little evidence (group data) that children with anxiety or depression symptoms responded in a clinically different manner to methylphenidate than youngsters who did not exhibit these symptoms, particularly in school observations of the core features of ADHD. Seeming differences between children with and without comorbid anxiety or depression symptoms and drug response are likely explained by differences in pretreatment levels of negativistic behaviors (i.e., symptoms of oppositional defiant disorder or conduct disorder). Methylphenidate appears to be effective for the management of ADHD behaviors in children with mild to moderate anxiety or depression symptoms; nevertheless, much research remains to be performed in this area.

Methylphenidate in Treatment of ADHD and Comorbid Chronic Tic Disorder

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J Gordon Millichap

2007-07-01

Full Text Available The safety and efficacy of immediate-release methylphenidate (MPH-IR for the treatment of attention deficit hyperactivity disorder (ADHD in children (ages 6-12 years with Tourette's syndrome (96% or chronic motor tic disorder (4% were evaluated at State University of New York, Stony Brook.

Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)

DEFF Research Database (Denmark)

Storebø, Ole Jakob; Ramstad, Erica; Krogh, Helle B

2015-01-01

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive.Methylphenidate is the drug most often prescribed...

A network meta-analysis of atomoxetine and osmotic release oral system methylphenidate in the treatment of attention-deficit/hyperactivity disorder in adult patients.

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Bushe, Chris; Day, Kathleen; Reed, Victoria; Karlsdotter, Kristina; Berggren, Lovisa; Pitcher, Ashley; Televantou, Foula; Haynes, Virginia

2016-05-01

The lack of head-to-head clinical studies powered to compare atomoxetine and osmotic release oral system (OROS) methylphenidate necessitates treatment comparison by methods that include indirect evidence such as network meta-analysis (NMA). A NMA assessing the relative treatment effects of atomoxetine and OROS methylphenidate in adults with attention-deficit/hyperactivity disorder (ADHD) was conducted. Studies were identified by systematic literature review. Analyses summarised improvements in efficacy, measured by ADHD-specific scales, using Cohen'sdto calculate the standardised mean difference (SMD), and all cause discontinuations. Results showed effect sizes (SMD, 95% credible interval (CrI)) relative to placebo that did not differ significantly between atomoxetine (0.46, 0.36-0.56) and OROS methylphenidate (0.51, 0.40-0.63) in clinical studies of up to 12 weeks' duration (SMD, 95% CrI for atomoxetine versus OROS methylphenidate: -0.05, -0.18-0.08). Patients treated with these medications responded better than those given placebo across all analyses. There was also no significant difference in discontinuation rates between atomoxetine and OROS methylphenidate (odds ratio, 95% CrI: 0.85, 0.53-1.35). Between-study heterogeneity was low overall. Results of this NMA suggest that the efficacy of atomoxetine and OROS methylphenidate in adults does not differ significantly. Clinical guidelines may require amendment to reflect these recent data. © The Author(s) 2016.

Hiccup Due to Aripiprazole Plus Methylphenidate Treatment in an Adolescent with Attention Deficit and Hyperactivity Disorder and Conduct Disorder: A Case Report.

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Kutuk, Meryem Ozlem; Guler, Gulen; Tufan, Ali Evren; Kutuk, Ozgur

2017-11-30

Our case had hiccups arising in an adolescent with the attention deficit and hyperactivity disorder (ADHD) and conduct disorder (CD) after adding aripiprazole treatment to extended-release methylphenidate. Actually, antipsychotics are also used in the treatment of hiccups, but studies suggest that they can cause hiccups as well. Within 12 hours of taking 2.5 mg aripiprazole added to extended-release methylphenidate at a dose of 54 mg/day, 16-year-old boy began having hiccups in the morning, which lasted after 3-4 hours. As a result, aripiprazole was discontinued and methylphenidate was continued alone because we could not convince the patient to use another additional drug due to this side effect. Subsequently, when his behavior got worsened day by day, his mother administered aripiprazole alone again at the dose of 2.5 mg/day at the weekend and continued treatment because hiccup did not occur again. But when it was administered with methylphenidate on Monday, hiccup started again next morning and lasted one hour at this time. In conclusion, we concluded that concurrent use of methylphenidate and aripiprazole in this adolescent led to hiccups.

Comparative Efficacy of Iranian and Foreign Methylphenidate in Children with Attention Deficit Hyperactive Disorder

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M Karahmadi

2008-04-01

Full Text Available ABSTRACT: Introduction & Objective: Methylphenidate is one of the basic drugs in treating ADHD. According to many clinical studies, the foreign form of methylphenidate (ritalin is more efficient than the Iranian form of the drug (stimidate. This study aimed to compare the efficacy of stimidate and Ritalin in the treatment of attention deficit hyperactive disorder. Materials & Methods: In this double blind, randomized clinical trial, 200 children with attention deficit hyperactive disorder who referred to Isfahan psychiatric clinics were studied. For 100 of these patients ritalin was prescribed while others received stimidate. After 4 weeks, changes in severity of symptoms were evaluated with parental form of Conner's questionnaire. Results: After 4 weeks of treatment, the mean decrease of Conner's number in Ritalin group was 19.63±13.5 and in Stimidate group was 3.29±7.2. Ritalin had effectiveness in treatment of 83.3 percent of the patients ( 6 reduction in Conner's number, but Stimidate was only effective in treating 37.5 percent of the patients. Conclusion: This study showed that foreign methylphenidate (ritalin is more effective than the Iranian form of the medicine (stimidate.

Effect of vitamin D supplementation as adjunctive therapy to methylphenidate on ADHD symptoms: A randomized, double blind, placebo-controlled trial.

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Mohammadpour, Nakisa; Jazayeri, Shima; Tehrani-Doost, Mehdi; Djalali, Mahmoud; Hosseini, Mostafa; Effatpanah, Mohammad; Davari-Ashtiani, Rozita; Karami, Elham

2018-04-01

Previous studies have shown that serum levels of vitamin D were lower in attention deficit hyperactivity disorder (ADHD) children compared to healthy controls. The aim of the study was to determine the effect of vitamin D supplementation as adjunctive therapy to methylphenidate on symptoms of children with ADHD. Sixty-two children aged 5-12 years with a diagnosis of ADHD based on DSM-IV criteria were randomly assigned into two groups to receive either 2000IU vitamin D or placebo in addition to methylphenidate for 8 weeks. Symptoms severity was assessed by Conner's Parent Rating Scale-Revised[S] (CPRS), ADHD rating scale-IV (ADHD-RS), and Weekly Parent Ratings of Evening and Morning Behavior (WPREMB) at weeks 0, 4, and 8. Serum levels of 25(OH)D were measured at baseline and after 8 weeks. Anthropometric variables, dietary intake, physical activity, sun exposure, and side effects were assessed. Fifty-four participants completed the trial. After 8 weeks of supplementation, serum levels of 25(OH)D significantly increased in the vitamin D group. ADHD symptoms decreased significantly in both groups (P D supplementation as adjunctive therapy to methylphenidate improved ADHD evening symptoms. Future research is needed to clarify vitamin D effects as monotherapy in ADHD and its mechanism. The trial was registered in www.irct.ir is (IRCT201404222394N10).

A hidden Markov model to assess drug-induced sleep fragmentation in the telemetered rat.

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Diack, C; Ackaert, O; Ploeger, B A; van der Graaf, P H; Gurrell, R; Ivarsson, M; Fairman, D

2011-12-01

Drug-induced sleep fragmentation can cause sleep disturbances either via their intended pharmacological action or as a side effect. Examples of disturbances include excessive daytime sleepiness, insomnia and nightmares. Developing drugs without these side effects requires insight into the mechanisms leading to sleep disturbance. The characterization of the circadian sleep pattern by EEG following drug exposure has improved our understanding of these mechanisms and their translatability across species. The EEG shows frequent transitions between specific sleep states leading to multiple correlated sojourns in these states. We have developed a Markov model to consider the high correlation in the data and quantitatively compared sleep disturbance in telemetered rats induced by methylphenidate, which is known to disturb sleep, and of a new chemical entity (NCE). It was assumed that these drugs could either accelerate or decelerate the transitions between the sleep states. The difference in sleep disturbance of methylphenidate and the NCE were quantitated and different mechanisms of action on rebound sleep were identified. The estimated effect showed that both compounds induce sleep fragmentation with methylphenidate being fivefold more potent compared to the NCE.

Non-medical use of methylphenidate: a review Uso não terapêutico do metilfenidato: uma revisão

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Luana Freese

2012-01-01

Full Text Available INTRODUCTION: Methylphenidate is a psychostimulant medication used for the treatment of attention deficit hyperactivity disorder and narcolepsy. However, it has also been used for non-medical purposes, e.g. to produce euphoria, to increase self-esteem, and to achieve the so-called neurocognitive enhancement, decreasing the feeling of tiredness and increasing focus and attention. OBJECTIVE: To describe, from theoretical and contextual points of view, the potential for abuse and non-medical use of methylphenidate. METHOD: The PubMed, SciELO and Cochrane databases were searched using the following keywords in Portuguese: metilfenidato, transtorno do déficit de atenção com hiperatividade, facilitadores dos processos cognitivos or agentes nootrópicos, and abuso de substâncias; and in English: methylphenidate, attention deficit disorder with hyperactivity, cognitive enhancement or nootropic agents, and substance abuse. Studies published between 1990 and 2010 were selected for review. RESULTS: Non-medical use of methylphenidate is a relevant topic that raises important ethical and scientific questions in several areas, e.g. pharmacological and neurobiological characteristics, evidence of methylphenidate use, forms of non-medical use of methylphenidate, mechanisms of action, and therapeutic application of methylphenidate. According to the review, methylphenidate can generally influence performance as a result of its stimulatory effect. Notwithstanding, evidence does not support the conclusion that it can enhance cognitive performance. CONCLUSION: Health professionals need to acquire expert knowledge and inform patients and their families on the methylphenidate potential for abuse when used with non-medical purposes.INTRODUÇÃO: O metilfenidato é um medicamento psicoestimulante usado no tratamento do transtorno de déficit de atenção e hiperatividade e da narcolepsia. No entanto, a droga também vem sendo utilizada com fins não terap

Methylphenidate-Related Improvements in Math Performance Cannot Be Explained by Better Cognitive Functioning or Higher Academic Motivation : Evidence From a Randomized Controlled Trial

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Kortekaas-Rijlaarsdam, Anne Fleur; Luman, Marjolein; Sonuga-Barke, Edmund; Bet, Pierre; Oosterlaan, Jaap

2017-01-01

OBJECTIVE: This study investigated whether improvements in working memory, reaction time, lapses of attention, interference control, academic motivation, and perceived competence mediated effects of methylphenidate on math performance. METHOD: Sixty-three children (ADHD diagnosis; methylphenidate

Effects of methylphenidate during emotional processing in amphetamine users: preliminary findings.

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Bottelier, M A; Schouw, M L J; de Ruiter, M B; Ruhe, H G; Lindauer, R J L; Reneman, L

2015-12-01

D-amphetamine (dAMPH) and methylphenidate (MPH) are stimulants used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Preclinical studies have shown that in healthy animals, dAMPH induces dopamine (DA) dysfunction, as evidenced for instance by loss of DA levels and its transporters. It has also been suggested that DA plays an important role in emotional processing, and that altered DA-ergic intervention may modulate amygdala function. To explore the role of the DA system in emotional processing we examined emotional processing using functional magnetic resonance imaging (fMRI) in eight male recreational users of dAMPH and eight male healthy controls. We compared brain activation between both groups during an emotional face-processing task with and without an oral MPH challenge. All subjects were abstinent for at least 2 weeks during the baseline scan. The second scan was performed on the same day 1½ hours after receiving an oral dose of 35 mg MPH. A significant Valence*Group interaction (p = .037) indicated amygdala hyperreactivity to fearful facial expressions in dAMPH users that was robust against adjustment for age (p = .015). Furthermore, duration of amphetamine use in years was positively correlated with amygdala reactivity in dAMPH users (r = .76; p = .029). These exploratory findings are in line with previous findings suggesting that DA plays a role in emotional processing.

Virtual Remediation Versus Methylphenidate to Improve Distractibility in Children With ADHD: A Controlled Randomized Clinical Trial Study.

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Bioulac, Stéphanie; Micoulaud-Franchi, Jean-Arthur; Maire, Jenna; Bouvard, Manuel P; Rizzo, Albert A; Sagaspe, Patricia; Philip, Pierre

2018-03-01

Virtual environments have been used to assess children with ADHD but have never been tested as therapeutic tools. We tested a new virtual classroom cognitive remediation program to improve symptoms in children with ADHD. In this randomized clinical trial, 51 children with ADHD (7-11 years) were assigned to a virtual cognitive remediation group, a methylphenidate group, or a psychotherapy group. All children were evaluated before and after therapy with an ADHD Rating Scale, a Continuous Performance Test (CPT), and a virtual classroom task. After therapy by virtual remediation, children exhibited significantly higher numbers of correct hits on the virtual classroom and CPT. These improvements were equivalent to those observed with methylphenidate treatment. Our study demonstrates for the first time that a cognitive remediation program delivered in a virtual classroom reduces distractibility in children with ADHD and could replace methylphenidate treatment in specific cases.

Effects of Methylphenidate on Working Memory Components: Influence of Measurement

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Bedard, Anne-Claude; Jain, Umesh; Hogg-Johnson, Sheilah; Tannock, Rosemary

2007-01-01

Background: To investigate the effects of methylphenidate (MPH) on components of working memory (WM) in attention-deficit hyperactivity disorder (ADHD) and determine the responsiveness of WM measures to MPH. Methods: Participants were a clinical sample of 50 children and adolescents with ADHD, aged 6 to 16 years old, who participated in an acute…

Animal Model of Methylphenidate's Longterm Memory-Enhancing Effects

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Carmack, Stephanie A.; Howell, Kristin K.; Rasaei, Kleou; Reas, Emilie T.; Anagnostaras, Stephan G.

2014-01-01

Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a…

Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

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Froehlich, Tanya E.; Epstein, Jeffery N.; Nick, Todd G.; Melguizo Castro, Maria S.; Stein, Mark A.; Brinkman, William B.; Graham, Amanda J.; Langberg, Joshua M.; Kahn, Robert S.

2011-01-01

Objective: Because of significant individual variability in attention-deficit/hyperactivity disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examined the role of four catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response. Method:…

Effects of Methylphenidate on performance of a practical pistol shooting task: a quantitative electroencephalography (qEEG study

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Paes Flávia

2011-02-01

Full Text Available Abstract Background The present study examined absolute alpha power using quantitative electroencephalogram (qEEG in bilateral temporal and parietal cortices in novice soldiers under the influence of methylphenidate (MPH during the preparatory aiming period in a practical pistol-shooting task. We anticipated higher bi-hemispheric cortical activation in the preparatory period relative to pre-shot baseline in the methylphenidate group when compared with the control group because methylphenidate has been shown to enhance task-related cognitive functions. Methods Twenty healthy, novice soldiers were equally distributed in control (CG; n = 10 and MPH groups 10 mg (MG; n = 10 using a randomized, double blind design. Subjects performed a pistol-shooting task while electroencephalographic activity was acquired. Results We found main effects for group and practice blocks on behavioral measures, and interactions between group and phases on electroencephalographic measures for the electrodes T3, T4, P3 and P4. Regarding the behavioral measures, the MPH group demonstrated significantly poorer in shooting performance when compared with the control and, in addition, significant increases in the scores over practice blocks were found on both groups. In addition, regarding the electroencephalographic data, we observed a significant increase in alpha power over practice blocks, but alpha power was significantly lower for the MPH group when compared with the placebo group. Moreover, we observed a significant decrease in alpha power in electrodes T4 and P4 during PTM. Conclusion Although we found no correlation between behavioral and EEG data, our findings show that MPH did not prevent the learning of the task in healthy subjects. However, during the practice blocks (PBs it also did not favor the performance when compared with control group performance. It seems that the CNS effects of MPH demanded an initial readjustment period of integrated operations relative

Selegiline in Comparison with Methylphenidate in Treatment of Adults with Attention Deficit yperactivity Disorder: A Double-blind, Randomized Trial

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Farbod Fadai

2009-12-01

Full Text Available  Objective: "n "nAttention-Deficit/Hyperactivity Disorder (ADHD is one of the most common mental disorders in childhood and it continues to adulthood without proper treatment. Stimulants have been used in treatment of ADHD for many years and the efficacy of methylphenidate (MPH in the treatment of adults with ADHD has been proven to be acceptable according to meta-analysis studies. However, there are some concerns about stimulants. Finding other effective medications for the treatment of adult ADHD seems necessary. We tried a monoamine oxidase inhibitor, Selegiline, as there are some theoretical and experimental evidences for the efficacy of this medication . "nMethod: Forty patients were randomized to receive Selegiline or methylphenidate in an equal ratio for an 8-week double-blind clinical trial. Each patient filled the CAARS self report screening form before starting to take the medication and in weeks 2-4-6 and 8. Patients were also assessed by a psychiatrist at the baseline and on each 14 days up to the 8 weeks period. "nResults: The mean score of the two groups- receiving Selegiline or methylphenidate- decreased over the 8 weeks. There was not a significant difference between the two groups. The most prevalent side-effect of methylphenidate was decrease of appetite and for Selegiline change in sleep pattern . "nConclusion: Selegiline is as effective as methylphenidate in the treatment of adults with Attention-Deficit/Hyperactivity Disorder. Selegiline can be an alternative medication for the treatment of adult ADHD If its clinical efficacy is proven by other larger studies .

The effects of methylphenidate on prepulse inhibition during attended and ignored prestimuli among boys with attention-deficit hyperactivity disorder.

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Hawk, Larry W; Yartz, Andrew R; Pelham, William E; Lock, Thomas M

2003-01-01

The present study investigated attentional modification of prepulse inhibition of startle among boys with and without attention-deficit hyperactivity disorder (ADHD). Two hypotheses were tested: (1) whether ADHD is associated with diminished prepulse inhibition during attended prestimuli, but not ignored prestimuli, and (2) whether methylphenidate selectively increases prepulse inhibition to attended prestimuli among boys with ADHD. Participants were 17 boys with ADHD and 14 controls. Participants completed a tone discrimination task in each of two sessions separated by 1 week. ADHD boys were administered methylphenidate (0.3 mg/kg) in one session and placebo in the other session in a randomized, double-blind fashion. During each series of 72 tones (75 dB; half 1200-Hz, half 400-Hz), participants were paid to attend to one pitch and ignore the other. Bilateral eyeblink electromyogram startle responses were recorded in response to acoustic probes (50-ms, 102-dB white noise) presented following the onset of two-thirds of tones, and during one-third of intertrial intervals. Relative to controls, boys with ADHD exhibited diminished prepulse inhibition 120 ms after onset of attended but not ignored prestimuli following placebo administration. Methylphenidate selectively increased prepulse inhibition to attended prestimuli at 120 ms among boys with ADHD to a level comparable to that of controls, who did not receive methylphenidate. These data are consistent with the hypothesis that ADHD involves diminished selective attention and suggest that methylphenidate ameliorates the symptoms of ADHD, at least in part, by altering an early attentional mechanism.

Anxiety, Methylphenidate Response, and Working Memory in Children with ADHD

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Bedard, Anne-Claude; Tannock, Rosemary

2008-01-01

Objective: To investigate the effects of methylphenidate (MPH) on components of working memory (WM) in children with ADHD and determine whether MPH produces differential effects on WM in children with comorbid anxiety (ANX). Method: Participants were a clinical sample of 130 children with ADHD, aged 6 to 12 years old (32% comorbid ANX). Each child…

Depressive symptoms as a side effect of the sustained release form of methylphenidate in a 7-year-old boy with attention-deficit hyperactivity disorder

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Lakić Aneta

2012-01-01

symptoms were withdrawed. Conclusion. Manifestation of depressive symptomatology after dose increasement of sustained release form of methylphenidate in a 7-year-old boy with ADHD represents an uncommon side effect. Precise drug activity mechanisms responsible for the appearance of these symptoms remains to be explained.

A systematic review of randomized controlled trials of bupropion versus methylphenidate in the treatment of attention-deficit/hyperactivity disorder

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Maneeton N

2014-08-01

Full Text Available Narong Maneeton,1 Benchalak Maneeton,1 Suthi Intaprasert,1 Pakapan Woottiluk2 1Department of Psychiatry, Faculty of Medicine, 2Psychiatric Nursing Division, Faculty of Nursing, Chiang Mai University, Chiang Mai, ThailandBackground: Some trials have suggested that bupropion, as well as methylphenidate, is bene­ficial in the treatment of attention-deficit/hyperactivity disorder (ADHD.Objectives: The purpose of this systematic review was to summarize the efficacy, acceptability, and tolerability of bupropion in comparison with methylphenidate for ADHD treatment. Included studies were randomized controlled trials (RCTs that compared bupropion and methylphenidate. Clinical studies conducted between January 1991 and January 2014 were reviewed.Data sources: MEDLINE®, EMBASE™, CINAHL, PsycINFO®, and the Cochrane Controlled Trials Register were searched in January 2014. Additionally, clinical trials were identified from the databases of ClinicalTrials.gov and the EU Clinical Trials Register.Study eligible criteria, participants, and interventions: All RCTs of bupropion and methylphenidate reporting final outcomes relevant to 1 ADHD severity, 2 response or remission rates, 3 overall discontinuation rate, or 4 discontinuation rate due to adverse events. Language restriction was not applied.Study appraisal and synthesis methods: The relevant clinical trials were examined and the data of interest were extracted. Additionally, the risks of bias were also inspected. The efficacy outcomes were the mean changed scores of ADHD rating scales, the overall response rate, and the overall remission rates. The overall discontinuation rate and the discontinuation rate due to adverse events were determined. Relative risks and weighted mean differences or standardized mean differences with 95% confidence intervals were estimated using a random effect model.Results: A total of 146 subjects in four RCTs comparing bupropion with methylphenidate in the treatment of

Methylphenidate use and school performance among primary school children : a descriptive study

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van der Schans, Jurjen; Cicek, Rukiye; Vardar, Sefike; Bos, Jens H. J.; de Vries, Tjalling W.; Hoekstra, Pieter J.; Hak, Eelko

2017-01-01

Background: There is no conclusive evidence that stimulants have beneficial effects on major associated outcome parameters, particularly school performance. We assessed the differences in school performance among children using methylphenidate at the end of primary school in relation to various

Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clincal Trial

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Schrantee, A.; Tamminga, H.G.H.; Bouziane, C.; Bottelier, M.A.; Bron, E.E.; Mutsaerts, H.-J.M.M.; Zwinderman, A.H.; Groote, I.R.; Rombouts, S.A.R.B.; Lindauer, R.J.L.; Klein, S.; Niessen, W.J.; Opmeer, B.C.; Boer, F.; Lucassen, P.J.; Andersen, S.L.; Geurts, H.M.; Reneman, L.

2016-01-01

Importance: Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. Objectives: To determine whether

Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder

DEFF Research Database (Denmark)

Holmskov, Mathilde; Storebø, Ole Jakob; Moreira-Maia, Carlos R

2017-01-01

OBJECTIVES: To study in more depth the relationship between type, dose, or duration of methylphenidate offered to children and adolescents with attention deficit hyperactivity disorder and their risks of gastrointestinal adverse events based on our Cochrane systematic review. METHODS AND FINDINGS...... differences in the risk according to type, dose, or duration of administration. The required information size was achieved in three out of four outcomes. CONCLUSION: Methylphenidate increases the risks of decreased appetite, weight loss, and abdominal pain in children and adolescents with attention deficit...... hyperactivity disorder. No differences in the risks of gastrointestinal adverse events according to type, dose, or duration of administration were found....

Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial

NARCIS (Netherlands)

Schrantee, Anouk; Tamminga, Hyke G. H.; Bouziane, Cheima; Bottelier, Marco A.; Bron, Esther E.; Mutsaerts, Henk-Jan M. M.; Zwinderman, Aeilko H.; Groote, Inge R.; Rombouts, Serge A. R. B.; Lindauer, Ramon J. L.; Klein, Stefan; Niessen, Wiro J.; Opmeer, Brent C.; Boer, Frits; Lucassen, Paul J.; Andersen, Susan L.; Geurts, Hilde M.; Reneman, Liesbeth

2016-01-01

Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. To determine whether the effects of

Rationalising polymer selection for supersaturated film forming systems produced by an aerosol spray for the transdermal delivery of methylphenidate.

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Edwards, A; Qi, S; Liu, F; Brown, M B; McAuley, W J

2017-05-01

Film forming systems offer a number of advantages for topical and transdermal drug delivery, in particular enabling production of a supersaturated state which can greatly improve drug absorption and bioavailability. However the suitability of individual film forming polymers to stabilise the supersaturated state and optimise delivery of drugs is not well understood. This study reports the use of differential scanning calorimetry (DSC) to measure the solubility of methylphenidate both as the free base and as the hydrochloride salt in two polymethacrylate copolymers, Eudragit RS (EuRS) and Eudragit E (EuE) and relates this to the ability of films formed using these polymers to deliver methylphenidate across a model membrane. EuRS provided greater methylphenidate delivery when the drug was formulated as the free base in comparison EuE because the lower solubility of the drug in EuRS provided a higher degree of drug saturation in the polymeric film. In contrast EuE provided greater delivery of methylphenidate hydrochloride as EuRS could not prevent its crystallisation from a supersaturated state. Methylphenidate flux across the membrane could be directly related to degree of saturation of the drug in the film formulation as estimated by the drug solubility in the individual polymers demonstrating the importance of drug solubility in the polymer included in film forming systems for topical/transdermal drug delivery. In addition DSC has been demonstrated to be a useful tool for determining the solubility of drugs in polymers used in film forming systems and the approaches outlined here are likely to be useful for predicting the suitability of polymers for particular drugs in film forming transdermal drug delivery systems. Copyright © 2017. Published by Elsevier B.V.

First-Trimester Exposure to Methylphenidate

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Pottegård, Anton; Hallas, Jesper; Andersen, Jon T

2014-01-01

conducted this study to estimate the risk of major congenital malformations following first-trimester in utero exposure to methylphenidate. METHOD: Data from 2005 to 2012 were extracted from the Danish National Patient Register, the Danish National Prescription Registry, the Medical Birth Registry...... subjects with respect to maternal age, smoking status, body mass index, length of education, calendar year of completion of pregnancy, and concomitant use of antipsychotics, antidepressants, anxiolytics, and nonsteroidal anti-inflammatory drugs. RESULTS: We included 222 exposed and 2,220 unexposed...... pregnancies in the analysis. There was no statistically significant increase in major malformations (point prevalence ratio = 0.8; 95% CI, 0.3-1.8) or cardiac malformations (point prevalence ratio = 0.9; 95% CI, 0.2-3.0). Sensitivity analyses using different definitions of exposure or previous users...

Cognitive Improvement of Attention and Inhibition in the Late Afternoon in Children With Attention-Deficit Hyperactivity Disorder (ADHD) Treated With Osmotic-Release Oral System Methylphenidate.

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Slama, Hichem; Fery, Patrick; Verheulpen, Denis; Vanzeveren, Nathalie; Van Bogaert, Patrick

2015-07-01

Long-acting medications have been developed and approved for use in the treatment of attention-deficit hyperactivity disorder (ADHD). These compounds are intended to optimize and maintain symptoms control throughout the day. We tested prolonged effects of osmotic-release oral system methylphenidate on both attention and inhibition, in the late afternoon. A double-blind, randomized, placebo-controlled study was conducted in 36 boys (7-12 years) with ADHD and 40 typically developing children. The ADHD children received an individualized dose of placebo or osmotic-release oral system methylphenidate. They were tested about 8 hours after taking with 2 continuous performance tests (continuous performance test-X [CPT-X] and continuous performance test-AX [CPT-AX]) and a counting Stroop. A positive effect of osmotic-release oral system methylphenidate was present in CPT-AX with faster and less variable reaction times under osmotic-release oral system methylphenidate than under placebo, and no difference with typically developing children. In the counting Stroop, we found a decreased interference with osmotic-release oral system methylphenidate but no difference between children with ADHD under placebo and typically developing children. © The Author(s) 2014.

Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of harmful effects in non-randomised studies

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Jakob, Storebø Ole; Nadia, Pedersen; Erica, Ramstad

2016-01-01

This is the protocol for a review and there is no abstract. The objectives are as follows:To assess the harmful effects of methylphenidate treatment for children and adolescents with attention deficit hyperactivity disorder (ADHD) in non-randomised studies.......This is the protocol for a review and there is no abstract. The objectives are as follows:To assess the harmful effects of methylphenidate treatment for children and adolescents with attention deficit hyperactivity disorder (ADHD) in non-randomised studies....

Methylphenidate does not influence smoking-reinforced responding or attentional performance in adult smokers with and without attention deficit hyperactivity disorder (ADHD).

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Kollins, Scott H; Schoenfelder, Erin; English, Joseph S; McClernon, F Joseph; Dew, Rachel E; Lane, Scott D

2013-10-01

Individuals with Attention Deficit Hyperactivity Disorder (ADHD) smoke cigarettes at rates higher than the general population and questions have been raised about how stimulant drugs-the frontline pharmacological treatment for ADHD-influence smoking risk and behavior in those with ADHD. In the present study adult regular smokers with (n = 16) and without (n = 17) ADHD participated in 3 experimental sessions in which they completed a Progressive Ratio (PR) task to measure the relative reinforcing effects of cigarette smoking and money after oral administration of placebo and 2 active doses of methylphenidate (10 mg and 40 mg). We also measured attention and inhibitory control via a Continuous Performance Test (CPT). Methylphenidate had no effect on smoking-reinforced responding, attention, or inhibitory control in either group. Attention and inhibitory control were associated with smoking-reinforced responding, but unsystematically and only in the non-ADHD group. Several design features, such as the value of the monetary response option, the PR schedule, and the potential effects of smoking on attention and inhibitory control, could have contributed to the negative findings and are discussed as such. Although inconsistent with some previous human laboratory studies of stimulant drugs and smoking, results are consistent with recent trials of stimulant drugs as adjuncts for smoking cessation in adult smokers with ADHD. In general, methylphenidate at mild and moderate doses did not influence the relative reinforcing effects of cigarette smoking in adults with and without ADHD. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Conditioned place preference and locomotor activity in response to methylphenidate, amphetamine and cocaine in mice lacking dopamine D4 receptors

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Thanos, P.K.; Thanos, P.K.; Bermeo, C.; Rubinstein, M.; Suchland, K.L.; Wang, G.-J.; Grandy, D.K.; Volkow, N.D.

2010-05-01

Methylphenidate (MP) and amphetamine (AMPH) are the most frequently prescribed medications for the treatment of attention-deficit/hyperactivity disorder (ADHD). Both drugs are believed to derive their therapeutic benefit by virtue of their dopamine (DA)-enhancing effects, yet an explanation for the observation that some patients with ADHD respond well to one medication but not to the other remains elusive. The dopaminergic effects of MP and AMPH are also thought to underlie their reinforcing properties and ultimately their abuse. Polymorphisms in the human gene that codes for the DA D4 receptor (D4R) have been repeatedly associated with ADHD and may correlate with the therapeutic as well as the reinforcing effects of responses to these psychostimulant medications. Conditioned place preference (CPP) for MP, AMPH and cocaine were evaluated in wild-type (WT) mice and their genetically engineered littermates, congenic on the C57Bl/6J background, that completely lack D4Rs (knockout or KO). In addition, the locomotor activity in these mice during the conditioning phase of CPP was tested in the CPP chambers. D4 receptor KO and WT mice showed CPP and increased locomotor activity in response to each of the three psychostimulants tested. D4R differentially modulates the CPP responses to MP, AMPH and cocaine. While the D4R genotype affected CPP responses to MP (high dose only) and AMPH (low dose only) it had no effects on cocaine. Inasmuch as CPP is considered an indicator of sensitivity to reinforcing responses to drugs these data suggest a significant but limited role of D4Rs in modulating conditioning responses to MP and AMPH. In the locomotor test, D4 receptor KO mice displayed attenuated increases in AMPH-induced locomotor activity whereas responses to cocaine and MP did not differ. These results suggest distinct mechanisms for D4 receptor modulation of the reinforcing (perhaps via attenuating dopaminergic signalling) and locomotor properties of these stimulant drugs

Methylphenidate Transdermal System in Adult ADHD and Impact on Emotional and Oppositional Symptoms

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Marchant, Barrie K.; Reimherr, Frederick W.; Robison, Reid J.; Olsen, John L.; Kondo, Douglas G.

2011-01-01

Objective: This trial evaluated the effect of methylphenidate transdermal system (MTS) on the full spectrum of adult symptoms (attention-disorganization, hyperactivity-impulsivity, emotional dysregulation [ED], and oppositional-defiant disorder [ODD]) found in this disorder. Method: This placebo-controlled, double-blind, flexible-dose, crossover…

Methylphenidate Improves Visual-Spatial Memory in Children with Attention-Deficit- hyperactivity Disorder

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Bedard, Anne-Claude; Martinussen, Rhonda; Ickowicz, Abel; Tannock, Rosemary

2004-01-01

Objective: To investigate the effect of methylphenidate (MPH) on visual-spatial memory, as measured by subtests of the Cambridge Neuropsychological Testing Automated Battery (CANTAB), in children with attention-deficit/hyperactivity disorder (ADHD). Visual-spatial memory is a core component of working memory that has been shown to be impaired in…

Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment

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Dresel, S.; LaFougere, C.; Brinkbaeumer, K.; Hahn, K.; Tatsch, K.; Krause, J.; Krause, K.-H.; Kung, H.F.

2000-01-01

Involvement of the dopaminergic system has been suggested in patients suffering from attention deficit hyperactivity disorder (ADHD) since the symptoms can be successfully treated with methylphenidate, a potent blocker of the dopamine transporter (DAT). This study reports the findings on the status of the DAT in adults with ADHD before and after commencement of treatment with methylphenidate, as measured using [ 99m Tc]TRODAT-1. Seventeen patients (seven males, ten females, aged 21-64 years, mean 38 years) were examined before and after the initiation of methylphenidate treatment (3 x 5 mg/day). All subjects were injected with 800 MBq [ 99m Tc]TRODAT-1 and imaged 3 h p.i. Single-photon emission tomography (SPET) scans were acquired using a triple-headed gamma camera. For semi-quantitative evaluation of the DAT, transverse slices corrected for attenuation were used to calculate specific binding in the striatum, with the cerebellum used as background [(STR-BKG)/BKG]. Data were compared with an age-matched control group. It was found that untreated patients presented with a significantly increased specific binding of [ 99m Tc]TRODAT-1 to the DAT as compared with normal controls [(STR-BKG)/BKG: 1.43±0.18 vs 1.22±0.06, P<0.001]. Under treatment with methylphenidate, specific binding decreased significantly in all patients [(STR-BKG)/BKG: 1.00±0.14, P<0.001]. Our findings suggest that the number of DAT binding sites is higher in drug-naive patients suffering from ADHD than in normal controls. The decrease in available DAT binding sites under treatment with methylphenidate correlates well with the improvement in clinical symptoms. The data of this study help to elucidate the complex dysregulation of the dopaminergic neurotransmitter system in patients suffering from ADHD and the effect of treatment with psychoactive drugs. (orig.)

78 FR 40484 - Determination That METADATE ER (Methylphenidate Hydrochloride) Extended-Release Tablet, 10...

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2013-07-05

... marketing for reasons other than safety or effectiveness. ANDAs that refer to METADATE ER (methylphenidate... Withdrawn From Sale for Reasons of Safety or Effectiveness AGENCY: Food and Drug Administration, HHS. ACTION... safety or effectiveness. This determination will allow FDA to approve abbreviated new drug applications...

The role of the dopaminergic system in mood, motivation and cognition in Parkinson's disease: a double blind randomized placebo-controlled experimental challenge with pramipexole and methylphenidate.

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Drijgers, Rosa L; Verhey, Frans R J; Tissingh, Gerrit; van Domburg, Peter H M F; Aalten, Pauline; Leentjens, Albert F G

2012-09-15

In Parkinson's disease (PD) reduced dopaminergic activity in the mesocorticolimbic pathway is implied in the pathophysiology of several non-motor symptoms related to mood, motivation and cognition. Insight in the pathophysiology of these syndromes may pave the way for more rational treatments. In a double-blind, randomized, placebo controlled, crossover design with three arms, we studied the effects of a direct dopaminergic challenge with the dopamine 2 receptor agonist pramipexole, an indirect challenge with the dopamine reuptake inhibitor methylphenidate, and placebo on measures of mood, motivation and cognition in 23 agonist-naïve PD patients and 23 healthy controls. Acute challenge with pramipexole had a negative effect on mood and fatigue in both patients and controls. In addition, challenge with pramipexole led to increased anger, fatigue, vigor and tension in healthy control subjects, but not in PD patients. Challenge with methylphenidate had a positive effect on anhedonia and vigor in PD patients. Due to its side effects after a single administration, pramipexole is probably less suitable for acute challenge studies. The acute effects of a methylphenidate challenge on anhedonia and vigor in PD patients make this drug an interesting choice for further studies of the treatment of mood and motivational disorders in this population. Copyright © 2012 Elsevier B.V. All rights reserved.

Buspirone Versus Methylphenidate in the Treatment of Children with Attention- Deficit/ Hyperactivity Disorder: Randomized Double-Blind Study

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Shahin Akhondzadeh

2012-11-01

Full Text Available A recent randomized clinical trial showed buspirone efficacy in the treatment of attention-deficit/hyperactivity disorder (ADHD in children. However, results from a recent multi-site controlled clinical trial of transdermal buspirone failed to separate it from placebo in a large sample of children with ADHD. Therefore, due to these inconsistent findings, this study was designed to assess the efficacy of buspirone in the treatment of children with ADHD compared to methylphenidate in a double blind randomized clinical trial. Forty outpatients with a DSM-IV-TR diagnosis of ADHD were study population of this trial. Subjects were recruited from an outpatient child and adolescent clinic for a 6 week double blind, randomized clinical trial. All study subjects were randomly assigned to receive treatment using tablet of buspirone at a dose of 20-30 mg/day depending on weight (20 mg/day for 30kg (group 1 or methylphenidate at a dose of 20-30 mg/day depending on weight (20 mg/day for 30kg (group 2 for a 6 week double blind, randomized clinical trial. The principal measure of outcome was the Teacher and Parent ADHD Rating Scale IV. Patients were assessed at baseline and at 21 and 42 days after the medication started. Significant differences were observed between the two groups on the Parent and Teacher Rating Scale scores. The changes at the endpoint compared to baseline were: -8.95±8.73 (mean±SD and -15.60±7.81 (mean±SD for buspirone and methyphenidate, for Parent ADHD Rating Scale. The changes at the endpoint compared to baseline were: -9.80 ±7.06 (mean±SD and -22.40±9.90 (mean±SD for buspirone and methyphenidate, respectively for Teacher ADHD Rating Scale. The difference between the buspirone and methylphenidate groups in the frequency of side effects was not significant except for decreased appetite, headache and insomnia that were observed more frequently in the methylphenidate group. The results of this study suggest that administration of

Melatonin Effects in Methylphenidate Treated Children with Attention Deficit Hyperactivity Disorder: A Randomized Double Blind Clinical Trial

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Mohammad Reza Mohammadi

2012-06-01

Full Text Available Objective: The aim of this study was to determine melatonin effects on sleep patterns, symptoms of hyperactivity and attention deficiency in children with attention-deficit hyperactivity disorder (ADHD.Methods: Children with age range of 7-12 years who had a combined form of ADHD were randomly divided in to 2 groups according to gender blocks. One group took melatonin (3 or 6mg combined with methylphenidate (Ritalin (1mg/kg, and the other group took placebo combined with methylphenidate (1mg/kg. ADHD rating scale and sleep patterns questionnaires were completed. Research hypotheses were assessed at the baseline, the second, fourth and eighth weeks after the treatment.Results: The mean sleep latency and total sleep disturbance scores were reduced in melatonin group, while the scores increased in the placebo group (p≥0.05. Data analysis, using ANOVA with repeated measures, did not show any statistically significant differences between the two groups in ADHD scores.Conclusion: Administration of melatonin along with methylphenidate can partially improve symptoms of sleep disturbance. However, it does not seem to reduce attention deficiency and hyperactivity behavior of children with ADHD.

Treating nicotine dependence by targeting attention-deficit/ hyperactivity disorder (ADHD) with OROS methylphenidate: the role of baseline ADHD severity and treatment response.

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Nunes, Edward V; Covey, Lirio S; Brigham, Gregory; Hu, Mei-Chen; Levin, Frances R; Somoza, Eugene C; Winhusen, Theresa M

2013-10-01

To determine whether treatment of attention-deficit/hyperactivity disorder (ADHD) with osmotic-release oral system (OROS) methylphenidate promotes abstinence from smoking among smokers with ADHD who have greater severity of ADHD symptoms at baseline or greater improvement in ADHD during treatment. This is a secondary analysis of data from a randomized, double-blind, 11-week trial conducted between December 2005 and January 2008 at 6 clinical sites; the original trial was sponsored by the National Drug Abuse Clinical Trials Network. Adult cigarette smokers (aged 18-55 years) who met DSM-IV criteria for ADHD were randomly assigned to OROS methylphenidate (72 mg/d) (n = 127) or matching placebo (n = 128). All participants received nicotine patches (21 mg/d) and weekly individual smoking cessation counseling. Logistic regression was used to model prolonged abstinence from smoking (ascertained by self-report and breath carbon monoxide testing) as a function of treatment, baseline ADHD Rating Scale-IV (ADHD-RS) score, change in ADHD-RS score during treatment, and their interactions. Treatment interacted with both ADHD-RS score at baseline (P = .01) and change in ADHD-RS score during treatment (P = .008). Among patients with higher ADHD-RS scores (> 36) at baseline and the most improvement in ADHD during treatment (ADHD-RS change score ≥ 24), 70.0% of those who took OROS methylphenidate achieved abstinence from smoking compared to 36.8% of those who took placebo (P = .02). In contrast, among patients with the lowest ADHD-RS baseline scores (≤ 30), 30.3% of those who took OROS methylphenidate achieved abstinence from smoking compared to 60.7% of those who took placebo (P = .02). OROS methylphenidate, in combination with nicotine patch, may be an effective treatment for nicotine dependence among smokers with more severe ADHD and more robust response of ADHD symptoms to medication. OROS methylphenidate may be counterproductive among smokers with lower severity of ADHD

Predicting Response of ADHD Symptoms to Methylphenidate Treatment Based on Comorbid Anxiety

Science.gov (United States)

Blouin, Brittany; Maddeaux, Cindy; Stanley Firestone, Jill; van Stralen, Judy

2010-01-01

Objective: In this small pilot study, the association of comorbid anxiety with the treatment of ADHD is studied. Methods: Eighteen volunteers from a pediatric clinic are tested for ADHD and anxiety and assessed for behavioral and cognitive ADHD symptomology. Response to methylphenidate as treatment for ADHD symptoms is measured 2 to 3 weeks, and…

Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder

DEFF Research Database (Denmark)

Holmskov, Mathilde; Storebø, Ole Jakob; Moreira-Maia, Carlos R

2017-01-01

: We use data from our review including 185 randomised clinical trials. Randomised parallel-group trials and cross-over trials reporting gastrointestinal adverse events associated with methylphenidate were included. Data were extracted and quality assessed according to Cochrane guidelines. Data were...... summarised as risk ratios (RR) with 95% confidence intervals (CI) using the inverse variance method. Bias risks were assessed according to domains. Trial Sequential Analysis (TSA) was used to control random errors. Eighteen parallel group trials and 43 cross-over trials reported gastrointestinal adverse...... differences in the risk according to type, dose, or duration of administration. The required information size was achieved in three out of four outcomes. CONCLUSION: Methylphenidate increases the risks of decreased appetite, weight loss, and abdominal pain in children and adolescents with attention deficit...

Attention deficit hyperactivity disorder: binding of [{sup 99m}Tc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment

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Dresel, S; LaFougere, C; Brinkbaeumer, K; Hahn, K; Tatsch, K [Dept. of Nuclear Medicine, Univ. of Munich (Germany); Krause, J; Krause, K -H [Inst. for Psychiatry and Psychotherapy, Ottobrunn (Germany); Friedrich Baur Inst., Univ. of Munich (Germany); Kung, H F [Dept. of Radiology, Univ. of Pennsylvania (United States)

2000-10-01

Involvement of the dopaminergic system has been suggested in patients suffering from attention deficit hyperactivity disorder (ADHD) since the symptoms can be successfully treated with methylphenidate, a potent blocker of the dopamine transporter (DAT). This study reports the findings on the status of the DAT in adults with ADHD before and after commencement of treatment with methylphenidate, as measured using [{sup 99m}Tc]TRODAT-1. Seventeen patients (seven males, ten females, aged 21-64 years, mean 38 years) were examined before and after the initiation of methylphenidate treatment (3 x 5 mg/day). All subjects were injected with 800 MBq [{sup 99m}Tc]TRODAT-1 and imaged 3 h p.i. Single-photon emission tomography (SPET) scans were acquired using a triple-headed gamma camera. For semi-quantitative evaluation of the DAT, transverse slices corrected for attenuation were used to calculate specific binding in the striatum, with the cerebellum used as background [(STR-BKG)/BKG]. Data were compared with an age-matched control group. It was found that untreated patients presented with a significantly increased specific binding of [{sup 99m}Tc]TRODAT-1 to the DAT as compared with normal controls [(STR-BKG)/BKG: 1.43{+-}0.18 vs 1.22{+-}0.06, P<0.001]. Under treatment with methylphenidate, specific binding decreased significantly in all patients [(STR-BKG)/BKG: 1.00{+-}0.14, P<0.001]. Our findings suggest that the number of DAT binding sites is higher in drug-naive patients suffering from ADHD than in normal controls. The decrease in available DAT binding sites under treatment with methylphenidate correlates well with the improvement in clinical symptoms. The data of this study help to elucidate the complex dysregulation of the dopaminergic neurotransmitter system in patients suffering from ADHD and the effect of treatment with psychoactive drugs. (orig.)

Methylphenidate for ADHD in children and adolescents: throwing the baby out with the bathwater

NARCIS (Netherlands)

Banaschewski, T.; Buitelaar, J.K.; Chui, C.S.; Coghill, D.; Cortese, S.; Simonoff, E.; Wong, I.C.

2016-01-01

A recent Cochrane review assessed the efficacy of methylphenidate for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. Notwithstanding the moderate-to-large effect sizes for ADHD symptom reduction found in the meta-analysis, the authors concluded that the quality of the

Behavioral and stimulant treatment of hyperactive children: a therapy study with methylphenidate probes in a within-subject design.

Science.gov (United States)

Pelham, W E; Schnedler, R W; Bologna, N C; Contreras, J A

1980-01-01

Eight hyperactive children were treated with a behavioral intervention focusing on teacher and parent training over a period of 5 months. Three times, before therapy and after 3 weeks and 13 weeks of intervention, children received methylphenidate during 3-week probe periods. Each week in a probe they received either a placebo, .25 mg/kg, or .75 mg/kg methylphenidate. Classroom observation of on-task behavior suggested that effectiveness of the behavioral intervention was between that of the two dosages of medication before therapy. Both dosages resulted in higher levels of on-task behavior when administered after 13 weeks of behavioral intervention than when administered before therapy. Teacher rating data showed equivalent effects of therapy and the low dosage of methylphenidate alone but a stronger effect of the high dose alone; only the high dose resulted in improved behavior after 13 weeks of behavioral intervention. As a group, only when they received the high dose of methylphenidate after 13 weeks of behavioral intervention did children reach the level of appropriate behavior shown by nonhyperactive controls. However, this level was also reached by two children with the low dose and by one child without medication, and it was not reached by one child. The results suggest that the combination of psychostimulant medication and behavior therapy may be more effective in the short-term than either treatment alone for hyperactive children in school settings. In addition, parent ratings and clinic observation of parent-child interactions suggested that children had improved in the home setting, high-lighting the importance of behavioral parent training in the treatment of hyperactivity.

Methylphenidate Transdermal System in Adults with Past Stimulant Misuse: An Open-Label Trial

Science.gov (United States)

McRae-Clark, Aimee L.; Brady, Kathleen T.; Hartwell, Karen J.; White, Kathleen; Carter, Rickey E.

2011-01-01

Objective: This 8-week, open-label trial assessed the efficacy of methylphenidate transdermal system (MTS) in 14 adult individuals diagnosed with ADHD and with a history of stimulant misuse, abuse, or dependence. Method: The primary efficacy endpoint was the Wender-Reimherr Adult ADHD Scale (WRAADS), and secondary efficacy endpoints included the…

Differential effects of psychomotor stimulants on attentional performance in rats: nicotine, amphetamine, caffeine and methylphenidate.

Science.gov (United States)

Bizarro, L; Patel, S; Murtagh, C; Stolerman, I P

2004-05-01

Nicotine can improve attentional performance in the rat as assessed by a modified five-choice serial reaction time task (5-CSRTT), but it is not known if the effect is shared with other psychomotor stimulants. This study compared the effects of nicotine, amphetamine, caffeine and methylphenidate on performance in the 5-CSRTT and determined whether presenting stimuli at unpredictable times by using variable inter-trial intervals (ITI) influenced the sensitivity of the task to the drugs. One group of male hooded rats was trained to obtain food reinforcers by nose-poking in response to 1 s light stimuli presented randomly in one of five apertures, with fixed ITI; for a second group of rats, ITI varied randomly (n=12 per group). As observed previously, nicotine (tested in doses of 0.05-0.2 mg/kg) produced dose-related improvements in accuracy, reduced omission errors and response latencies, but increased anticipatory responding. Amphetamine (0.1-0.8 mg/kg) and methylphenidate (2.5-10 mg/kg) increased accuracy and reduced response latency, and decreased anticipatory responding. Caffeine (2.5-20 mg/kg) did not improve performance except at a small dose that decreased omission errors only. Training at different levels of stimulus predictability influenced performance in the undrugged state but had little impact on profiles of responses to the drugs. The findings with methylphenidate support the potential value of the 5-CSRTT for testing drugs that may be useful in the treatment of attention deficit hyperactivity disorder.

Rapid response to methylphenidate as an add-on therapy to mirtazapine in the treatment of major depressive disorder in terminally ill cancer patients: a four-week, randomized, double-blinded, placebo-controlled study.

Science.gov (United States)

Ng, Chong Guan; Boks, Marco P M; Roes, Kit C B; Zainal, Nor Zuraida; Sulaiman, Ahmad Hatim; Tan, Seng Beng; de Wit, Niek J

2014-04-01

This is a 4 week, randomized, double-blind, placebo-controlled study to examine the effects of methylphenidate as add-on therapy to mirtazapine compared to placebo for treatment of depression in terminally ill cancer patients. It involved 88 terminally ill cancer patients from University of Malaya Medical Centre, Kuala Lumpur, Malaysia. They were randomized and treated with either methylphenidate or placebo as add on to mirtazapine. The change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 3 was analyzed by linear regression. Changes of MADRS and Clinical Global Impression-Severity Scale (CGI-S) over 28 days were analyzed using mixed model repeated measures (MMRM). Secondary analysis of MADRS response rates, defined as 50% or more reduction from baseline score. A significantly larger reduction of Montgomery-Åsberg Depression Rating Scale (MADRS) score in the methylphenidate group was observed from day 3 (B=4.14; 95% CI=1.83-6.45). Response rate (defined as 50% or more reduction from baseline MADRS score) in the methylphenidate treated group was superior from day 14. Improvement in Clinical Global Impression-Severity Scale (CGI-S) was greater in the methylphenidate treated group from day 3 until day 28. The drop-out rates were 52.3% in the methylphenidate group and 59.1% in the placebo group (relative risk=0.86, 95%CI=0.54-1.37) due to cancer progression. Nervous system adverse events were more common in methylphenidate treated subjects (20.5% vs 9.1%, p=0.13). In conclusions, methylphenidate as add on therapy to mirtazapine demonstrated an earlier antidepressant response in terminally ill cancer patients, although at an increased risk of the nervous system side effects. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Immediate-Release Methylphenidate for ADHD in Children with Comorbid Chronic Multiple Tic Disorder

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Gadow, Kenneth D.; Sverd, Jeffrey; Nolan, Edith E.; Sprafkin, Joyce; Schneider, Jayne

2007-01-01

Objective: To examine the safety and efficacy of immediate-release methylphenidate (MPH-IR) for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children (ages 6-12 years) with Tourette's syndrome (96%) or chronic motor tic disorder (4%). Method: Two cohorts of prepubertal children (N = 71) received placebo and three doses of…

Randomized, 6-Week, Placebo-Controlled Study of Treatment for Adult Attention-Deficit/Hyperactivity Disorder: Individualized Dosing of Osmotic-Release Oral System (OROS) Methylphenidate With a Goal of Symptom Remission.

Science.gov (United States)

Goodman, David W; Starr, H Lynn; Ma, Yi-Wen; Rostain, Anthony L; Ascher, Steve; Armstrong, Robert B

2017-01-01

To evaluate the efficacy and safety of individualized dosing within the approved dose range for osmotic-release oral system (OROS) methylphenidate hydrochloride in adults with attention-deficit/hyperactivity disorder (ADHD). A double-blind, 6-week trial was conducted between July 2009 and February 2010 at 35 US sites. Adults with ADHD (DSM-IV diagnostic criteria) and a screening ADHD Investigator Symptom Rating Scale (AISRS) score > 24 were randomly assigned to OROS methylphenidate 18 mg or matching placebo. Treatment dose could be increased at 18 mg increments, up to 72 mg/d, until an optimal dose was achieved. AISRS score changes from baseline to end point (primary outcome) were analyzed using analysis of covariance. At baseline, the intent-to-treat population of 169 OROS methylphenidate and 172 placebo subjects (mean age = 35.8 years) had mean (standard deviation [SD]) AISRS scores of 37.8 (6.94) and 37.0 (7.51), respectively. OROS methylphenidate-treated subjects exhibited a significantly greater mean (SD) AISRS score improvement than placebo subjects (-17.1 [12.44] vs -11.7 [13.30]; P ADHD. OROS methylphenidate treatment with individualized doses titrated to achieve symptom remission demonstrated greater ADHD symptom reduction than placebo treatment. These data support the overall efficacy of OROS methylphenidate treatment in the management of adults with ADHD and provide new possibilities for additional intervention. ClinicalTrials.gov identifier: NCT00937040. © Copyright 2017 Physicians Postgraduate Press, Inc.

Differential Effects of Methylphenidate on Attentional Functions in Children with Attention-Deficit-Hyperactivity Disorder

Science.gov (United States)

Konrad, Kerstin; Gunther, Thomas; Hanisch, Charlotte; Herpertz-Dahlmann, Beate

2004-01-01

Objective: To examine the effects of methylphenidate on different attentional functions and behavior in children with attention-deficit-hyperactivity disorder (ADHD). Method: A total of 60 ADHD children aged between 8 and 12 years completed a randomized, double-blind, placebo-controlled, within-subject crossover trial with two doses of…

The association between methylphenidate treatment and the risk for fracture among young ADHD patients: A nationwide population-based study in Taiwan.

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Vincent Chin-Hung Chen

Full Text Available Attention-deficit hyperactivity disorder (ADHD is associated with higher risk for fracture. Whether the medical treatment for ADHD would mitigate the risk remains unclear. In this study, we sought to investigate the effect of methylphenidate treatment on risk for fracture, as well the moderational role of treatment duration on the risk of fracture, in a large national sample. Cases less than 18 years old were identified from Taiwan's National Health Insurance Research Database with a new primary diagnosis of ADHD (ICD-9:314 between 1996 and 2013. A total of 6201 cases with ADHD were included as the study cohort. The cases were divided into 3 groups according to the duration of methylphenidate treatment (0, 1-180, and more than 180 days. All groups were followed until the end of 2013 for first diagnoses of fracture (ICD-9 codes 800 to 829. Cox proportional hazards models were applied. Compared to the group without methylphenidate treatment, the risk for fracture was lower among the group treated for more than 180 days. The adjusted hazard ratio was 0.77 (95% Confidence interval: 0.63-0.94. The groups treated for 180 days or fewer had no significant difference in the risk for fracture. In conclusion, methylphenidate treatment was associated with lower risk for fracture among ADHD patients. The association was evident only in the cohort treated for more than 180 days.

The Cochrane Collaboration withdraws a review on methylphenidate for adults with attention deficit hyperactivity disorder

DEFF Research Database (Denmark)

Boesen, Kim; Saiz, Luis Carlos; Erviti, Juan

2017-01-01

A Cochrane systematic review on immediate-release methylphenidate for adults with attention deficit hyperactivity disorder (ADHD) was withdrawn from the Cochrane Library on 26 May 2016 after substantial criticism of its methods and flawed conclusions. Retraction of scientific papers on this basis...

The effect of methylphenidate on three forms of response inhibition in boys with AD/HD

NARCIS (Netherlands)

Scheres, A.; Oosterlaan, J.; Swanson, J.; Morein-Zamir, S.; Meiran, N.; Schut, H.; Vlasveld, L.; Sergeant, J.A.

2003-01-01

The current study was aimed at (a) investigating the effect of three doses methylphenidate (MPH) and placebo on inhibition of a prepotent response, inhibition of an ongoing response, and interference control in Attention Deficit/Hyperactivity Disorder (AD/HD), and (b) studying dose-response

Methylphenidate Improves Working Memory and Set-Shifting in AD/HD: Relationships to Baseline Memory Capacity

Science.gov (United States)

Mehta, Mitul A.; Goodyer, Ian M.; Sahakian, Barbara J.

2004-01-01

Objective: Catecholamine stimulant drugs are highly efficacious treatments for attention deficit/hyperactivity disorders (AD/HD). Catecholamine modulation in humans influences performance of numerous cognitive tasks, including tests of attention and working memory (WM). Clear delineation of the effects of methylphenidate upon such cognitive…

Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial.

Science.gov (United States)

Franke, Andreas G; Gränsmark, Patrik; Agricola, Alexandra; Schühle, Kai; Rommel, Thilo; Sebastian, Alexandra; Balló, Harald E; Gorbulev, Stanislav; Gerdes, Christer; Frank, Björn; Ruckes, Christian; Tüscher, Oliver; Lieb, Klaus

2017-03-01

Stimulants and caffeine have been proposed for cognitive enhancement by healthy subjects. This study investigated whether performance in chess - a competitive mind game requiring highly complex cognitive skills - can be enhanced by methylphenidate, modafinil or caffeine. In a phase IV, randomized, double-blind, placebo-controlled trial, 39 male chess players received 2×200mg modafinil, 2×20mg methylphenidate, and 2×200mg caffeine or placebo in a 4×4 crossover design. They played twenty 15-minute games during two sessions against a chess program (Fritz 12; adapted to players' strength) and completed several neuropsychological tests. Marked substance effects were observed since all three substances significantly increased average reflection time per game compared to placebo resulting in a significantly increased number of games lost on time with all three treatments. Treatment effects on chess performance were not seen if all games (n=3059) were analysed. Only when controlling for game duration as well as when excluding those games lost on time, both modafinil and methylphenidate enhanced chess performance as demonstrated by significantly higher scores in the remaining 2876 games compared to placebo. In conjunction with results from neuropsychological testing we conclude that modifying effects of stimulants on complex cognitive tasks may in particular result from more reflective decision making processes. When not under time pressure, such effects may result in enhanced performance. Yet, under time constraints more reflective decision making may not improve or even have detrimental effects on complex task performance. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Cost-effectiveness of extended-release methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder sub-optimally treated with immediate release methylphenidate.

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Jurjen van der Schans

Full Text Available Attention-Deficit/Hyperactivity Disorder (ADHD is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at school often leads to reduced compliance, sub-optimal treatment, and therefore economic loss. Replacement of IR-MPH with a single-dose extended release (ER-MPH formulation may improve drug response and economic efficiency.To evaluate the cost-effectiveness from a societal perspective of a switch from IR-MPH to ER-MPH in patients who are sub-optimally treated.A daily Markov-cycle model covering a time-span of 10 years was developed including four different health states: (1 optimal response, (2 sub-optimal response, (3 discontinued treatment, and (4 natural remission. ER-MPH options included methylphenidate osmotic release oral system (MPH-OROS and Equasym XL/Medikinet CR. Both direct costs and indirect costs were included in the analysis, and effects were expressed as quality-adjusted life years (QALYs. Univariate, multivariate as well as probabilistic sensitivity analysis were conducted and the main outcomes were incremental cost-effectiveness ratios.Switching sub-optimally treated patients from IR-MPH to MPH-OROS or Equasym XL/Medikinet CR led to per-patient cost-savings of €4200 and €5400, respectively, over a 10-year treatment span. Sensitivity analysis with plausible variations of input parameters resulted in cost-savings in the vast majority of estimations.This study lends economic support to switching patients with ADHD with suboptimal response to short-acting IR-MPH to long-acting ER-MPH regimens.

Evidence on methylphenidate in children and adolescents with ADHD is in fact of ‘very low quality’

DEFF Research Database (Denmark)

Storebø, O. J.; Zwi, Morris; Krogh, Helle B

2016-01-01

Banaschewski and colleagues from the European Attention Deficit Hyperactivity Disorder (ADHD) guideline group make a number of critical comments regarding our systematic review on methylphenidate for children and adolescents with ADHD. In this article, we present our views, showing that our trial...... selection was not flawed and was undertaken with scientific justification. Similarly, our data collection and interpretation was systematic and correct. We have followed a sound methodology for assessing risk of bias and our conclusions are not misleading. We acknowledge that different researchers might...... such errors and to engage in debate on methodological and ethical issues. In terms of clinical implications, we are advocating that clinicians, patients and their relatives should weight carefully risks and benefits of methylphenidate. Clinical experience seems to suggest that there are people who benefit...

How Oppositionality, Inattention, and Hyperactivity Affect Response to Atomoxetine versus Methylphenidate: A Pooled Meta-Analysis

Science.gov (United States)

van Wyk, Gregory W.; Hazell, Philip L.; Kohn, Michael R.; Granger, Renee E.; Walton, Richard J.

2012-01-01

Objective: To assess how threshold oppositional defiant disorder (ODD), inattention, and hyperactivity-impulsivity affect the response to atomoxetine versus methylphenidate. Method: Systematic review of randomized controlled trials (RCTs; greater than or equal to 6 weeks follow-up). The primary measure was core symptom response--greater than or…

Predicting methylphenidate response in attention deficit hyperactivity disorder: a preliminary study.

Science.gov (United States)

Johnston, Blair A; Coghill, David; Matthews, Keith; Steele, J Douglas

2015-01-01

Methylphenidate (MPH) is established as the main pharmacological treatment for patients with attention deficit hyperactivity disorder (ADHD). Whilst MPH is generally a highly effective treatment, not all patients respond, and some experience adverse reactions. Currently, there is no reliable method to predict how patients will respond, other than by exposure to a trial of medication. In this preliminary study, we sought to investigate whether an accurate predictor of clinical response to methylphenidate could be developed for individual patients, using sociodemographic, clinical and neuropsychological measures. Of the 43 boys with ADHD included in this proof-of-concept study, 30 were classed as responders and 13 as non-responders to MPH, with no significant differences in age nor verbal intelligence quotient (IQ) between the groups. Here we report the application of a multivariate analysis approach to the prediction of clinical response to MPH, which achieved an accuracy of 77% (p = 0.005). The most important variables to the classifier were performance on a 'go/no go' task and comorbid conduct disorder. This preliminary study suggested that further investigation is merited. Achieving a highly significant accuracy of 77% for the prediction of MPH response is an encouraging step towards finding a reliable and clinically useful method that could minimise the number of children needlessly being exposed to MPH. © The Author(s) 2014.

Quantitation of dopamine transporter blockade by methylphenidate: first in vivo investigation using [123I]FP-CIT and a dedicated small animal SPECT

International Nuclear Information System (INIS)

Nikolaus, Susanne; Wirrwar, Andreas; Antke, Christina; Arkian, Shahram; Mueller, Hans-Wilhelm; Larisch, Rolf; Schramm, Nils

2005-01-01

The aim of this study was to investigate the feasibility of assessing dopamine transporter binding after treatment with methylphenidate in the rat using a recently developed high-resolution small animal single-photon emission computed tomograph (TierSPECT) and [ 123 I]FP-CIT. [ 123 I]FP-CIT was administered intravenously 1 h after intraperitoneal injection of methylphenidate (10 mg/kg) or vehicle. Animals underwent scanning 2 h after radioligand administration. The striatum was identified by superimposition of [ 123 I]FP-CIT scans with bone metabolism and perfusion scans obtained with 99m Tc-DPD and 99m Tc-tetrofosmin, respectively. As these tracers do not pass the blood-brain barrier, their distribution permits the identification of extracerebral anatomical landmarks such as the orbitae and the harderian glands. The cerebellum was identified by superimposing [ 123 I]FP-CIT scans with images of brain perfusion obtained with 99m Tc-HMPAO. Methylphenidate-treated animals and vehicle-treated animals yielded striatal equilibrium ratios (V '' 3 ) of 0.24±0.26 (mean ± SD) and 1.09±0.42, respectively (ttest, two-tailed, p '' 3 values amounted to 0.05±0.28 (methylphenidate) and 0.3±0.39 (saline, p=0.176). This first in vivo study of rat dopamine transporter binding after pre-treatment with methylphenidate showed a mean reduction of 78% in striatal [ 123 I]FP-CIT accumulation. The results can be interpreted in terms of a pharmacological blockade in the rat striatum and show that in vivo quantitation of dopamine transporter binding is feasible with [ 123 I]FP-CIT and the TierSPECT. This may be of future relevance for in vivo investigations on rat models of attention deficit/hyperactivity disorder. Furthermore, our findings suggest that investigations in other animal models, e.g. of Parkinson's and Huntington's disease, may be feasible using SPECT radioligands and small animal imaging systems. (orig.)

Risperidone Versus Methylphenidate in Treatment of Preschool Children With Attention-Deficit Hyperactivity Disorder.

Science.gov (United States)

Arabgol, Fariba; Panaghi, Leily; Nikzad, Vahid

2015-02-01

Attention Deficit Hyperactivity Disorder (ADHD) is a common psychiatric diagnosis among preschool children. The aim of this study was to examine the Risperidone treatment compared to Methylphenidate (MPH) in preschool children with ADHD. Thirty three outpatient preschool children, aged 3-6 years, diagnosed with ADHD (The diagnosis of ADHD was established by two child and adolescent psychiatrists according to the DSM-IV-TR criteria), participated in a 6-week, double-blind clinical trial with risperidone (0.5-1.5 mg/d) and methylphenidate (5-20 mg/d), in two divided doses. Treatment outcomes were assessed using the Parent ADHD Rating Scale and Conners Rating Scale. Patients were assessed by a child psychiatrist at baseline, 2, 4 and 6 weeks after the medication started. Side effects were also rated by side effects questionnaire. There were no significant differences between the two protocols on the Parent ADHD Rating Scale scores (P > 0.05) and Parent Conners Rating Scale scores (P > 0.05). Both groups showed a significant improvement in ADHD symptoms over the 6 weeks of treatment for parent ADHD Rating Scale (P benefits and adverse effects in long term use and comorbid conditions.

The impact of methylphenidate and its enantiomers on dopamine synthesis and metabolism in vitro

DEFF Research Database (Denmark)

Bartl, Jasmin; Palazzesi, Ferruccio; Parrinello, Michele

2017-01-01

Methylphenidate (MPH), a psychostimulant, is an effective first-line treatment for the symptoms associated with Attention-Deficit/Hyperactivity Disorder (ADHD). Although most MPH formulations are composed of the racemic 1:1 mixture of the two enantiomers (d- and l-threo), converging lines of evid...... to the stereoselectivity of the investigated enzymes and pharmacological effects of MPH enantiomers....

Treatment outcomes after methylphenidate in adults with attention-deficit/hyperactivity disorder treated with lisdexamfetamine dimesylate or atomoxetine

Directory of Open Access Journals (Sweden)

Joseph A

2016-03-01

Full Text Available Alain Joseph,1 Martin Cloutier,2 Annie Guérin,2 Roy Nitulescu,2 Vanja Sikirica3 1Global HEOR and Epidemiology, Shire, Zählerweg, Zug, Switzerland; 2Analysis Group, Inc., Montreal, Quebec, Canada; 3Global HEOR and Epidemiology, Shire, Wayne, PA, USA Purpose: To compare treatment adherence, discontinuation, add-on, and daily average consumption (DACON among adults with attention-deficit/hyperactivity disorder receiving second-line lisdexamfetamine dimesylate (LDX or atomoxetine (ATX, following methylphenidate.Patients and methods: A retrospective cohort study using US commercial claims databases (Q2/2009–Q3/2013.Results: At month 12, the LDX cohort (N=2,718 had a higher adherence level (proportion of days covered: 0.48 versus 0.30, P<0.001 and was less likely to discontinue (Kaplan–Meier estimate: 63% versus 85%, P<0.001 than the ATX cohort (N=674. There were no statistical differences in treatment add-on rates between cohorts (Kaplan–Meier estimate: 26% versus 25%, P=0.297. The LDX cohort had a lower DACON (1.10 versus 1.31, P<0.001 and was less likely to have a DACON >1 (adjusted odds ratio: 0.20, 95% confidence interval: 0.15–0.25, P<0.001 than the ATX cohort.Conclusion: Adults with attention-deficit/hyperactivity disorder treated with LDX following methylphenidate had a higher treatment adherence and lower discontinuation and DACON relative to those treated with ATX following methylphenidate. Keywords: ADHD, adult, adherence, lisdexamfetamine dimesylate, atomoxetine

Methylphenidate and Comorbid Anxiety Disorder in Children with both Chronic Multiple Tic Disorder and ADHD

Science.gov (United States)

Gadow, Kenneth D.; Nolan, Edith E.

2011-01-01

Objective: To determine if comorbid anxiety disorder is associated with differential response to immediate release methylphenidate (MPH-IR) in children with both ADHD and chronic multiple tic disorder (CMTD). Method: Children with (n = 17) and without (n = 37) diagnosed anxiety disorder (ANX) were evaluated in an 8-week, placebo-controlled trial…

Long-term oral methylphenidate treatment in adolescent and adult rats: differential effects on brain morphology and function

NARCIS (Netherlands)

Marel, K. van der; Klomp, A.; Meerhoff, G.F.; Schipper, P.; Lucassen, P.J.; Homberg, J.R.; Dijkhuizen, R.M.; Reneman, L.

2014-01-01

Methylphenidate is a widely prescribed psychostimulant for treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents, which raises questions regarding its potential interference with the developing brain. In the present study, we investigated effects of 3 weeks oral

The effectiveness of methylphenidate in the treatment of encopresis independent from attention-deficit hyperactivity disorder symptoms.

Science.gov (United States)

Akça, Ömer Faruk; Yılmaz, Savaş

2015-01-01

Several medications are reported to be effective in treatment of encopresis. However, mechanisms of action related to these drugs are not known. We report a patient with ADHD and encopresis whose encopretic signs have disappeared with long acting methylphenidate while they have not changed with atomoxetine.

The Effectiveness of Methylphenidate in the Treatment of Encopresis Independent from Attention-Deficit Hyperactivity Disorder Symptoms

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Ak?a, ?mer Faruk; Y?lmaz, Sava?

2015-01-01

Several medications are reported to be effective in treatment of encopresis. However, mechanisms of action related to these drugs are not known. We report a patient with ADHD and encopresis whose encopretic signs have disappeared with long acting methylphenidate while they have not changed with atomoxetine.

Quantitation of dopamine transporter blockade by methylphenidate: first in vivo investigation using [{sup 123}I]FP-CIT and a dedicated small animal SPECT

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Nikolaus, Susanne; Wirrwar, Andreas; Antke, Christina; Arkian, Shahram; Mueller, Hans-Wilhelm; Larisch, Rolf [Heinrich-Heine University, Clinic of Nuclear Medicine, Duesseldorf (Germany); Schramm, Nils [Research Center Juelich, Central Laboratory for Electronics, Juelich (Germany)

2005-03-01

The aim of this study was to investigate the feasibility of assessing dopamine transporter binding after treatment with methylphenidate in the rat using a recently developed high-resolution small animal single-photon emission computed tomograph (TierSPECT) and [{sup 123}I]FP-CIT. [{sup 123}I]FP-CIT was administered intravenously 1 h after intraperitoneal injection of methylphenidate (10 mg/kg) or vehicle. Animals underwent scanning 2 h after radioligand administration. The striatum was identified by superimposition of [{sup 123}I]FP-CIT scans with bone metabolism and perfusion scans obtained with {sup 99m}Tc-DPD and {sup 99m}Tc-tetrofosmin, respectively. As these tracers do not pass the blood-brain barrier, their distribution permits the identification of extracerebral anatomical landmarks such as the orbitae and the harderian glands. The cerebellum was identified by superimposing [{sup 123}I]FP-CIT scans with images of brain perfusion obtained with {sup 99m}Tc-HMPAO. Methylphenidate-treated animals and vehicle-treated animals yielded striatal equilibrium ratios (V''{sub 3}) of 0.24{+-}0.26 (mean {+-} SD) and 1.09{+-}0.42, respectively (ttest, two-tailed, p<0.0001). Cortical V''{sub 3} values amounted to 0.05{+-}0.28 (methylphenidate) and 0.3{+-}0.39 (saline, p=0.176). This first in vivo study of rat dopamine transporter binding after pre-treatment with methylphenidate showed a mean reduction of 78% in striatal [{sup 123}I]FP-CIT accumulation. The results can be interpreted in terms of a pharmacological blockade in the rat striatum and show that in vivo quantitation of dopamine transporter binding is feasible with [{sup 123}I]FP-CIT and the TierSPECT. This may be of future relevance for in vivo investigations on rat models of attention deficit/hyperactivity disorder. Furthermore, our findings suggest that investigations in other animal models, e.g. of Parkinson's and Huntington's disease, may be feasible using SPECT radioligands and

Risperidone Versus Methylphenidate in Treatment of Preschool Children With Attention-Deficit Hyperactivity Disorder

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Arabgol, Fariba; Panaghi, Leily; Nikzad, Vahid

2015-01-01

Background: Attention Deficit Hyperactivity Disorder (ADHD) is a common psychiatric diagnosis among preschool children. Objectives: The aim of this study was to examine the Risperidone treatment compared to Methylphenidate (MPH) in preschool children with ADHD. Patients and Methods: Thirty three outpatient preschool children, aged 3-6 years, diagnosed with ADHD (The diagnosis of ADHD was established by two child and adolescent psychiatrists according to the DSM-IV-TR criteria), participated i...

The effects of clinically relevant doses of amphetamine and methylphenidate on signal detection and DRL in rats

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Andrzejewski, Matthew E.; Spencer, Robert C.; Harris, Rachel L.; Feit, Elizabeth C.; McKee, Brenda L.; Berridge, Craig W.

2014-01-01

Low dose amphetamine (AMPH) and methylphenidate (MPH, Ritalin®) are the most widely prescribed and most effective pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Certain low, clinically relevant doses of MPH improve sustained attention and working memory in normal rats, in contrast to higher doses that impair cognitive ability and induce locomotor activity. However, the effects of AMPH of MPH on sustained attention and behavioral inhibition remain poorly characterized. The present experiments examined the actions of AMPH (0.1 and 0.25 mg/kg) and MPH (0.5 and 1.0 mg/kg) in a rat model of 1) sustained attention, where signal and blank trials were interspersed randomly and occurred at unpredictable times, and 2) behavioral inhibition, using a differential reinforcement of low rate (DRL) schedule. In a signal detection paradigm, both 0.5 mg/kg and 1.0 mg/kg MPH and 0.25 mg/kg AMPH improve sustained attention, however neither AMPH nor MPH improve behavioral inhibition on DRL. Taken together with other recent studies, it appears that clinically-relevant doses of AMPH and MPH may preferentially improve attention-related behavior while having little effect on behavioral inhibition. These observations provide additional insight into the basic behavioral actions of low-dose psychostimulants and further suggest that the use of sustained attention tasks may be important in the development of novel pharmacological treatments for ADHD. PMID:24467844

Caffeine induces differential cross tolerance to the amphetamine-like discriminative stimulus effects of dopaminergic agonists.

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Jain, Raka; Holtzman, Stephen G

2005-05-15

The purpose of this study was to determine if caffeine induces cross tolerance to the amphetamine-like discriminative stimulus effects of dopaminergic drugs that act through distinct mechanisms (e.g., release, uptake inhibition, direct activation of dopamine D(1)- or D(2)-family receptors). Rats were trained to discriminate 1.0 mg/kg d-amphetamine from saline in a two-choice discrete-trial procedure. Stimulus-generalization curves were generated by cumulative dosing for d-amphetamine (0.1-1.0 mg/kg), methylphenidate (0.3-5.6 mg/kg), SKF 81297 (0.3-3.0 mg/kg), and R-(-)-propylnorapomorphine (NPA; 0.001-1.78 mg/kg), as well as for caffeine (3.0-56 mg/kg); curves were re-determined after twice daily injections of caffeine (30 mg/kg) for 3.5 days. The rats generalized dose dependently to the four dopaminergic drugs, but only to a limited extent to caffeine. Twice daily injections of caffeine induced significant cross tolerance (i.e., increased ED(50)) to the amphetamine-like discriminative effects of methylphenidate and SKF 81297, attenuated non-significantly the effects of NPA, and did not alter the effects of amphetamine. Thus, caffeine produces differential cross tolerance to the amphetamine-like discriminative effects of dopaminergic drugs, a phenomenon in which the dopamine D(1) receptor appears to have an important role.

Methylphenidate for ADHD in children and adolescents: throwing the baby out with the bathwater.

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Banaschewski, Tobias; Buitelaar, Jan; Chui, Celine S L; Coghill, David; Cortese, Samuele; Simonoff, Emily; Wong, Ian C K

2016-11-01

A recent Cochrane review assessed the efficacy of methylphenidate for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. Notwithstanding the moderate-to-large effect sizes for ADHD symptom reduction found in the meta-analysis, the authors concluded that the quality of the evidence is low and therefore the true magnitude of these effects remains uncertain. We identified a number of major concerns with the review, in the domains of study inclusion, approaches to quality assessment and interpretation of data relating to serious adverse events as well as of the clinical implications of the reported effects. We also found errors in the extraction of data used to estimate the effect size of the primary outcome. Considering all the shortcomings, the conclusion in the Cochrane review that the status of the evidence is uncertain is misplaced. Professionals, parents and patients should refer to previous reviews and existing guidelines, which include methylphenidate as one of the safe and efficacious treatment strategies for ADHD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Quality of life of methylphenidate treatment-responsive adolescents with attention-deficit/hyperactivity disorder

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Pin-Chen Yang

2012-05-01

Full Text Available Quality of life (QOL in methylphenidate treatment-responsive adolescents with attention deficit/hyperactivity disorder (ADHD was assessed. Patients were 12- to 18-year-old adolescents with ADHD (total n = 45 who had been on methylphenidate treatment for at least 3 months and were clinically judged to be improved. The self-completed Taiwanese Quality of Life Questionnaire for Adolescents (TQOLQA was used, and the resulting measures were compared between adolescents with ADHD and: (1 community adolescents (n = 2316; (2 treatment-responsive adolescents with a chronic medical condition (i.e., adolescents with leukemia in its first and complete continuous remission for at least 3 years after chemotherapy (n = 39. Patients’ cognitive profile and their daily executive functioning were also obtained for analysis. The QOL of the treated adolescents with ADHD was reported to be worse than that of both the community healthy adolescents and the adolescent leukemia survivors in the self-reported TQOLQA domain of “psychological well-being”. Treated adolescents with ADHD still had impaired executive skills in natural, everyday environments, and the scores for daily executive abilities could predict the QOL measures. Factors besides pharmacotherapy should be explored to further improve the QOL of medication-treated adolescents with ADHD.

Effect of methylphenidate on ICU and hospital length of stay in patients with severe and moderate traumatic brain injury.

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Moein, Houshang; Khalili, Hossein A; Keramatian, Kamyar

2006-09-01

Traumatic brain injury is one of the major causes of death and disability among young people. Methylphenidate, a neural stimulant and protective drug, which has been mainly used for childhood attention deficit/hyperactivity disorder, has shown some benefits in late psychosocial problems in patients with traumatic brain injury. Its effect on arousal and consciousness has been also revealed in the sub-acute phase of traumatic brain injury. We studied its effect on the acute phase of moderate and severe traumatic brain injury (TBI) in relation to the length of ICU and hospital admission. Severely and moderately TBI patients (according to inclusion and exclusion criteria) were randomized to treatment and control groups. The treatment group received methylphenidate 0.3mg/kg per dose PO BID by the second day of admission until the time of discharge, and the control group received a placebo. Admission information and daily Glasgow Coma Scale (GCS) were recorded. Medical, surgical, and discharge plans for patients were determined by the attending physician, blinded to the study. Forty patients with severe TBI (GCS = 5-8) and 40 moderately TBI patients (GCS = 9-12) were randomly divided into treatment and control groups on the day of admission. In the severely TBI patients, both hospital and ICU length of stay, on average, were shorter in the treatment group compared with the control group. In the moderately TBI patients while ICU stay was shorter in the treatment group, there was no significant reduction of the period of hospitalization. There were no significant differences between the treatment and control groups in terms of age, sex, post resuscitation GCS, or brain CT scan findings, in either severely or moderately TBI patients. Methylphenidate was associated with reductions in ICU and hospital length of stay by 23% in severely TBI patients (P = 0.06 for ICU and P = 0.029 for hospital stay time). However, in the moderately TBI patients who received methylphenidate

Performance on a strategy set shifting task during adolescence in a genetic model of attention deficit/hyperactivity disorder: Methylphenidate vs. atomoxetine treatments

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Harvey, Roxann C; Jordan, Chloe J; Tassin, David H; Moody, Kayla R; Dwoskin, Linda P; Kantak, Kathleen M

2013-01-01

Research examining medication effects on set shifting in teens with attention deficit/hyperactivity disorder (ADHD) is lacking. An animal model of ADHD may be useful for exploring this gap. The Spontaneously Hypertensive Rat (SHR) is a commonly used animal model of ADHD. SHR and two comparator strains, Wistar-Kyoto (WKY) and Wistar (WIS), were evaluated during adolescence in a strategy set shifting task under conditions of a 0-sec or 15-sec delay to reinforcer delivery. The task had three phases: initial discrimination, set shift and reversal learning. Under 0-sec delays, SHR performed as well as or better than WKY and WIS. Treatment with 0.3 mg/kg/day atomoxetine had little effect, other than to modestly increase trials to criterion during set shifting in all strains. Under 15-sec delays, SHR had longer lever press reaction times, longer latencies to criterion and more trial omissions than WKY during set shifting and reversal learning. These deficits were not reduced systematically by 1.5 mg/kg/day methylphenidate or 0.3 mg/kg/day atomoxetine. Regarding learning in SHR, methylphenidate improved initial discrimination, whereas atomoxetine improved set shifting but disrupted initial discrimination. During reversal learning, both drugs were ineffective in SHR, and atomoxetine made reaction time and trial omissions greater in WKY. Overall, WIS performance differed from SHR or WKY, depending on phase. Collectively, a genetic model of ADHD in adolescent rats revealed that neither methylphenidate nor atomoxetine mitigated all deficits in SHR during the set shifting task. Thus, methylphenidate or atomoxetine monotherapy may not mitigate all set shift task-related deficits in teens with ADHD. PMID:23376704

Adding methylphenidate to prism-adaptation improves outcome in neglect patients. A randomized clinical trial.

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Luauté, Jacques; Villeneuve, Laurent; Roux, Adeline; Nash, Stuart; Bar, Jean-Yves; Chabanat, Eric; Cotton, François; Ciancia, Sophie; Sancho, Pierre-Olivier; Hovantruc, Patrick; Quelard, François; Sarraf, Thierry; Cojan, Yann; Hadj-Bouziane, Fadila; Farné, Alessandro; Janoly-Dumenil, Audrey; Boisson, Dominique; Jacquin-Courtois, Sophie; Rode, Gilles; Rossetti, Yves

2018-04-04

Spatial neglect is one of the main predictors of poor functional recovery after stroke. Many therapeutic interventions have been developed to alleviate this condition, but to date the evidence of their effectiveness is still scarce. The purpose of this study was to test whether combining prism adaptation (PA) and methylphenidate (MP) could enhance the recovery of neglect patients at a functional level. RITAPRISM is a multicentre, randomized, double-blind, placebo-controlled study comparing PA plus placebo (control) versus PA plus MP. 24 patients were prospectively enrolled (10 in the placebo group and 14 in the MP group). The main result is a long-term functional improvement (on the functional independence measure (FIM) and on Bergego's scale) induced by MP combined with PA. No serious adverse event occurred. The long-term benefit on activities of daily living (ADL) obtained in this randomized controlled trial set this intervention apart from previous attempts and supports with a high level of evidence the value of combining PA and MP in order to improve the autonomy of neglect patients. Further studies will be needed to clarify the mechanism of this improvement. Although not specifically assessed at this stage, a part of the improvement in ADL might be related to the collateral effect of MP on mood, executive functions or fatigue, and/or the combined effect of PA and MP on motor intentional bias of neglect patients. This study provides Class I evidence that adding MP to PA improves the functional outcome of neglect patients. EUCTR2008-000325-20-FR. Copyright © 2018 Elsevier Ltd. All rights reserved.

Behavioral Effects of Neurofeedback Compared to Stimulants and Physical Activity in Attention-Deficit/Hyperactivity Disorder: A Randomized Controlled Trial.

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Geladé, Katleen; Janssen, Tieme W P; Bink, Marleen; van Mourik, Rosa; Maras, Athanasios; Oosterlaan, Jaap

2016-10-01

The efficacy of neurofeedback as a treatment for attention-deficit/hyperactivity disorder (ADHD), and whether neurofeedback is a viable alternative for stimulant medication, is still an intensely debated subject. The current randomized controlled trial compared neurofeedback to (1) optimally titrated methylphenidate and (2) a semi-active control intervention, physical activity, to account for nonspecific effects. A multicenter 3-way parallel-group study with balanced randomization was conducted. Children with a DSM-IV-TR diagnosis of ADHD, aged 7-13 years, were randomly allocated to receive neurofeedback (n = 39), methylphenidate (n = 36), or physical activity (n = 37) over a period of 10-12 weeks. Neurofeedback comprised theta/beta training on the vertex (Cz). Physical activity consisted of moderate to vigorous intensity exercises. Neurofeedback and physical activity were balanced in terms of number (~30) and duration of sessions. A double-blind pseudorandomized placebo-controlled crossover titration procedure was used to determine an optimal dose in the methylphenidate intervention. Parent and teacher ratings on the Strengths and Difficulties Questionnaire (SDQ) and Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN) were used to assess intervention outcomes. Data collection took place between September 2010 and March 2014. Intention-to-treat analyses revealed an improvement in parent-reported behavior on the SDQ and the SWAN Hyperactivity/Impulsivity scale, irrespective of received intervention (ηp² = 0.21-0.22, P ≤ .001), whereas the SWAN Inattention scale revealed more improvement in children who received methylphenidate than neurofeedback and physical activity (ηp² = 0.13, P ≤ .001). Teachers reported a decrease of ADHD symptoms on all measures for methylphenidate, but not for neurofeedback or physical activity (range of ηp² = 0.14-0.29, P ADHD symptoms in children with ADHD. ClinicalTrials.gov identifier: NCT01363544. © Copyright

Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder: A systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials.

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Mathilde Holmskov

Full Text Available To study in more depth the relationship between type, dose, or duration of methylphenidate offered to children and adolescents with attention deficit hyperactivity disorder and their risks of gastrointestinal adverse events based on our Cochrane systematic review.We use data from our review including 185 randomised clinical trials. Randomised parallel-group trials and cross-over trials reporting gastrointestinal adverse events associated with methylphenidate were included. Data were extracted and quality assessed according to Cochrane guidelines. Data were summarised as risk ratios (RR with 95% confidence intervals (CI using the inverse variance method. Bias risks were assessed according to domains. Trial Sequential Analysis (TSA was used to control random errors. Eighteen parallel group trials and 43 cross-over trials reported gastrointestinal adverse events. All trials were at high risk of bias. In parallel group trials, methylphenidate decreased appetite (RR 3.66, 95% CI 2.56 to 5.23 and weight (RR 3.89, 95% CI 1.43 to 10.59. In cross-over trials, methylphenidate increased abdominal pain (RR 1.61, 95% CI 1.27 to 2.04. We found no significant differences in the risk according to type, dose, or duration of administration. The required information size was achieved in three out of four outcomes.Methylphenidate increases the risks of decreased appetite, weight loss, and abdominal pain in children and adolescents with attention deficit hyperactivity disorder. No differences in the risks of gastrointestinal adverse events according to type, dose, or duration of administration were found.

Methylphenidate and Atomoxetine Enhance Prefrontal Function through alpha[subscript 2]-Adrenergic and Dopamine D[subscript 1] Receptors

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Gamo, Nao J.; Wang, Min; Arnsten, Amy F. T.

2010-01-01

Objective: This study examined the effects of the attention-deficit/hyperactivity disorder treatments, methylphenidate (MPH) and atomoxetine (ATM), on prefrontal cortex (PFC) function in monkeys and explored the receptor mechanisms underlying enhancement of PFC function at the behavioral and cellular levels. Method: Monkeys performed a working…

Safety and tolerability of flexible dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder

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Jan K Buitelaar

2009-08-01

Full Text Available Jan K Buitelaar1, J Antoni Ramos-Quiroga2, Miguel Casas2, J J Sandra Kooij3, Asko Niemelä4, Eric Konofal5, Joachim Dejonckheere6, Bradford H Challis7, Rossella Medori81Department of Psychiatry, University Medical Center, St. Radboud and Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands; 2Department of Psychiatry, Hospital Universitari Vall d’Hebron and Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; 3PsyQ, Psycho-Medical Programs, Program Adult ADHD, Den Haag, The Netherlands; 4Oulu University Hospital, Department of Psychiatry, Oulu, Finland; 5Groupe Hospitalier Pitie-Salpetriere, Paris, France; 6SGS Life Sciences, Mechelen, Belgium; 7Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ, USA; 8Janssen-Cilag EMEA, Neuss, GermanyAbstract: The osmotic release oral system (OROS methylphenidate formulation is a prolonged-release medication for the treatment of attention-deficit/hyperactivity disorder (ADHD in children, adolescents, and adults. We conducted a seven-week open-label extension of a double-blind study to assess the safety and tolerability of OROS methylphenidate in a flexible dose regimen (18–90 mg daily for the treatment of adults diagnosed with ADHD (N = 370. Medication was adjusted to optimize efficacy and tolerability for each patient. Adverse events, vital signs, and laboratory parameters were assessed. Most patients (337; 91% completed the seven-week treatment and the final dispensed dose was 18 mg (8%, 36 mg (29%, 54 mg (34%, 72 mg (20%, or 90 mg (9%. Adverse events were reported in 253 (68% patients and most were mild or moderate in severity; most frequently reported included headache (17%, decreased appetite (13%, and insomnia (11%. Adverse events were rarely serious (<1%; 2/370. Small mean increases in systolic and diastolic blood pressure (both 2.4 mmHg and pulse (3.2 bpm were observed. Body weight decreased

Methylphenidate, Interstimulus Interval, and Reaction Time Performance of Children with Attention Deficit/Hyperactivity Disorder : A Pilot Study

NARCIS (Netherlands)

van der Meere, J. J.; Shalev, R. S.; Borger, N.; Wiersema, J.R

2009-01-01

Thirteen children with attention deficit/hyperactivity disorder (ADHD: DSM-IV-TR) participated in the pilot study. They carried out a Go/No-Go test with a short (2 seconds) and long (6 seconds) interstimulus interval (ISI) when on placebo and a therapeutic dose of methylphenidate (MPH). For the

Case Report: Testicular failure possibly associated with chronic use of methylphenidate [v1; ref status: indexed, http://f1000r.es/48z

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Ranjith Ramasamy

2014-09-01

Full Text Available Methylphenidate is a commonly prescribed treatment for attention deficit hyperactivity disorder (ADHD. However, little is known about its adverse effects on the male reproductive system. We report a 20-year-old male patient whose chief complaint was of delayed puberty. He spoke in a high-pitched voice and complained of lack of body hair, impaired libido, inadequate erectile function, chronic fatigue, and low energy. He had been treated with methylphenidate as an infant and had continued treatment for 17 years. On examination, the patient was lean and visibly lacked facial or body hair. He further explained that he had never been able to grow underarm or facial hair and that he was often mistakenly considered a young teenager rather than a 20-year-old. The patient’s genitalia were categorized as Tanner Stage 2. Laboratory studies confirmed low serum follicle-stimulating hormone (FSH, luteinizing hormone (LH, and testosterone levels. The patient was given exogenous testosterone supplementation with pellets and human chorionic gonadotropin to maintain testicular size. After 4 months his symptoms improved and he demonstrated signs of puberty. Our goal is to further elucidate the possible impact of methylphenidate on the male reproductive system.

Methylphenidate treatment of attention deficit hyperactivity disorder in young people with learning disability and difficult-to-treat epilepsy: Evidence of clinical benefit

Science.gov (United States)

Fosi, Tangunu; Lax-Pericall, Maria T; Scott, Rod C; Neville, Brian G; Aylett, Sarah E

2013-01-01

Purpose To establish the efficacy and safety of methylphenidate (MPH) treatment for attention deficit hyperactivity disorder (ADHD) in a group of children and young people with learning disability and severe epilepsy. Methods This retrospective study systematically reviewed the case notes of all patients treated with methylphenidate (MPH) for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) ADHD at a specialist epilepsy center between 1998 and 2005. Treatment efficacy was ascertained using clinical global impressions (CGI) scores, and safety was indexed by instances of >25% increase in monthly seizure count within 3 months of starting MPH. Key Findings Eighteen (18) patients were identified with refractory epilepsies (14 generalized, 4 focal), IQ <70, and ADHD. Male patients predominated (13:5) and ADHD was diagnosed at a median age of 11.5 years (range 6–18 years). With use of a combination of a behavioral management program and MPH 0.3–1 mg/kg/day, ADHD symptoms improved in 61% of patients (11/18; type A intraclass correlation coefficient of CGI 0.85, 95% confidence interval [CI] 0.69–0.94). Daily MPH dose, epilepsy variables, and psychiatric comorbidity did not relate to treatment response across the sample. MPH adverse effects led to treatment cessation in three patients (dysphoria in two, anxiety in one). There was no statistical evidence for a deterioration of seizure control in this group with the use of MPH. Significance Methylphenidate with behavioral management was associated with benefit in the management of ADHD in more than half of a group of children with severe epilepsy and additional cognitive impairments. Eighteen percent had significant side effects but no attributable increase in seizures. Methylphenidate is useful in this group and is likely to be under employed. PMID:24304474

Safety and tolerability of flexible dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder.

NARCIS (Netherlands)

Buitelaar, J.K.; Ramos-Quiroga, J.A.; Casas, M.; Kooij, J.J.; Niemela, A.; Konofal, E.; Dejonckheere, J.; Challis, B.H.; Medori, R.

2009-01-01

The osmotic release oral system (OROS) methylphenidate formulation is a prolonged-release medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. We conducted a seven-week open-label extension of a double-blind study to assess the safety

The Acute Effect of Methylphenidate in Brazilian Male Children and Adolescents with ADHD: A Randomized Clinical Trial

Science.gov (United States)

Szobot, C. M.; Ketzer, C.; Parente, M. A.; Biederman, J.; Rohde, L. A.

2004-01-01

Objective: To evaluate the acute efficacy of methylphenidate (MPH) in Brazilian male children and adolescents with ADHD. Method: In a 4-day, double-blind, placebo-controlled, randomized, fix dose escalating, parallel-group trial, 36 ADHD children and adolescents were allocated to two groups: MPH (n = 19) and placebo (n = 17). Participants were…

Age-dependent effects of acute methylphenidate on amygdala reactivity in stimulant treatment-naive patients with Attention Deficit/Hyperactivity Disorder

NARCIS (Netherlands)

Bottelier, Marco A.; Schrantee, Anouk; Ferguson, Bart; Tamminga, Hyke G. H.; Bouziane, Cheima; Kooij, J. J. Sandra; de Ruiter, Michiel B.; Reneman, Liesbeth

2017-01-01

In the present study, we investigate whether methylphenidate (MPH) affects emotional processing and whether this effect is modulated by age. We measured amygdala reactivity with functional Magnetic Resonance Imaging (fMRI) during processing of angry and fearful facial expressions in male stimulant

OROS-methylphenidate efficacy on specific executive functioning deficits in adults with ADHD: A randomized, placebo-controlled cross-over study

NARCIS (Netherlands)

Bron, T.I.; Bijlenga, D.; Boonstra, A. M.; Breuk, M.; Pardoen, W.F.H.; Beekman, A.T.F.; Kooij, J.J.S

2014-01-01

Attention-deficit/hyperactivity disorder (ADHD) is linked to impaired executive functioning (EF). This is the first study to objectively investigate the effects of a long-acting methylphenidate on neurocognitive test performance of adults with ADHD. Twenty-two adults with ADHD participated in a

Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies

DEFF Research Database (Denmark)

Storebø, Ole Jakob; Pedersen, Nadia; Ramstad, Erica

2018-01-01

Background: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used medication to treat it. Several studies have investigated the benefits of methylphenidate, showing possible favourable...... of the Diagnostic and Statistical Manual of Mental Disorders or the 9th or 10th edition of theInternational Classification of Diseases, with or without comorbid diagnoses. We required that at least 75% of participants had a normal intellectual capacity (intelligence quotient of more than 70 points) and were aged.......36, 95% confidence interval (CI) 1.17 to 1.57; 2 studies, 72,005 participants); any psychotic disorder (RR 1.36, 95% CI 1.17 to 1.57; 1 study, 71,771 participants); and arrhythmia (RR 1.61, 95% CI 1.48 to 1.74; 1 study, 1224 participants) compared to no intervention. In the non-comparative cohort studies...

Methylphenidate-induced improvements of various measures of attention in adults with attention deficit hyperactivity disorder.

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Tucha, O; Mecklinger, L; Laufkötter, R; Klein, H E; Walitza, S; Lange, K W

2006-10-01

The present study examined the effect of the stimulant medication methylphenidate (MPH) on attentional functioning of adults with ADHD. Sixteen adults with a diagnosed ADHD without comorbidity were assessed twice, at baseline off MPH and following MPH treatment. The assessment battery consisted of reaction time tasks of low complexity, including measures of alertness--subdivided into tonic and phasic alertness, vigilance, divided attention, flexibility and such aspects of selective attention as including focused attention, inhibition and integration of sensory information. In addition, 16 healthy participants who were matched to adults with ADHD according to sex, age, education level and intellectual functions were also assessed twice using the same test battery. The results of the present study suggest that adults with ADHD off stimulant medication are seriously impaired in various components of attention including vigilance, divided attention, selective attention and flexibility. These impairments of attention were observed primarily in regard to reaction time and its variability. Treatment of adults with ADHD using individually tailored doses of MPH has a positive effect on measures of alertness, vigilance, selective attention, divided attention and flexibility. However, even on MPH adults with ADHD displayed considerable deficits in vigilance and integration of sensory information. The present findings indicate that adults with ADHD are not differentially impaired in attentional processes but may suffer from a more global deficit of attention. Although MPH treatment has been found to be effective in the treatment of the attention deficit of adults with ADHD, additional treatment appears to be necessary.

Impact of Methylphenidate Delivery Profiles on Driving Performance of Adolescents with Attention-Deficit/hyperactivity Disorder: A Pilot Study

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Cox, Daniel J.; Merkel, R. Lawrence; Penberthy, Jennifer Kim; Kovatchev, Boris; Hankin, Cheryl S.

2004-01-01

Objective: Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at high risk for driving accidents. One dose of methylphenidate (MPH) improves simulator driving performances of ADHD-diagnosed adolescents at 1.5 hours post-dose. However, little is known about the effects of different MPH delivery profiles on driving performance…

Methylphenidate Ameliorates Depressive Comorbidity in ADHD Children without any Modification on Differences in Serum Melatonin Concentration between ADHD Subtypes

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Isabel Cubero-Millán

2014-09-01

Full Text Available The vast majority of Attention-deficit/hyperactivity disorder (ADHD patients have other associated pathologies, with depressive symptoms as one of the most prevalent. Among the mediators that may participate in ADHD, melatonin is thought to regulate circadian rhythms, neurological function and stress response. To determine (1 the serum baseline daily variations and nocturnal excretion of melatonin in ADHD subtypes and (2 the effect of chronic administration of methylphenidate, as well as the effects on symptomatology, 136 children with ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision: DSM-IV-TR criteria were divided into subgroups using the “Children’s Depression Inventory” (CDI. Blood samples were drawn at 20:00 and 09:00 h, and urine was collected between 21:00 and 09:00 h, at inclusion and after 4.61 ± 2.29 months of treatment. Melatonin and its urine metabolite were measured by radioimmunoassay RIA. Factorial analysis was performed using STATA 12.0. Melatonin was higher predominantly in hyperactive-impulsive/conduct disordered children (PHI/CD of the ADHD subtype, without the influence of comorbid depressive symptoms. Methylphenidate ameliorated this comorbidity without induction of any changes in the serum melatonin profile, but treatment with it was associated with a decrease in 6-s-melatonin excretion in both ADHD subtypes. Conclusions: In untreated children, partial homeostatic restoration of disrupted neuroendocrine equilibrium most likely led to an increased serum melatonin in PHI/CD children. A differential cerebral melatonin metabolization after methylphenidate may underlie some of the clinical benefit.

Effects of Methylphenidate and Bupropion on DHEA-S and Cortisol Plasma Levels in Attention-Deficit Hyperactivity Disorder

Science.gov (United States)

Lee, Moon-Soo; Yang, Jae-Won; Ko, Young-Hoon; Han, Changsu; Kim, Seung-Hyun; Lee, Min-Soo; Joe, Sook-Haeng; Jung, In-Kwa

2008-01-01

We evaluated plasma levels of DHEA-S and cortisol before and after treating ADHD patients with one of two medications: methylphenidate (n = 12) or bupropion (n = 10). Boys with ADHD (combined type) were evaluated with the Korean ADHD rating scale (K-ARS) and the computerized ADHD diagnostic system (ADS). All assessments were measured at baseline…

Adverse drug reaction labelling for atomoxetine, methylphenidate and modafinil

DEFF Research Database (Denmark)

Aagaard, Lise; Hansen, Ebba Holme

2013-01-01

Medical product information contains information about efficacy and safety for marketed pharmaceuticals. Three studies have compared safety labelling for different therapeutic categories in different countries and detected large variations in a number of reported adverse drug reactions (ADRs......). The rapid increase in use of medications for treatment of ADHD symptoms has created concern due to lack of information about effects from long-term use. The aim of this study was to compare ADR information in product information (PI)/summary of product characteristics (SPC) for oral formulations...... of atomoxetine, methylphenidate and modafinil marketed by the same pharmaceutical companies in Australia, Denmark and the United States. Discrepancies in listed ADRs were defined as types of ADRs (system organ class) not listed in all countries. For ADRs where discrepancies were detected, we extracted...

Low dopamine transporter occupancy by methylphenidate as a possible reason for reduced treatment effectiveness in ADHD patients with cocaine dependence

NARCIS (Netherlands)

Crunelle, Cleo L.; van den Brink, Wim; Veltman, Dick J.; van Emmerik-van Oortmerssen, Katelijne; Dom, Geert; Schoevers, Robert A.; Booij, Jan

2013-01-01

Methylphenidate (MPH) occupies brain striatal dopamine transporters (DATs) and is an effective treatment for attention deficit hyperactivity disorder (ADHD). However, patients with ADHD and comorbid cocaine dependence do not benefit significantly from treatment with MPH. To better understand the

Methylphenidate effects in the young brain: friend or foe?

Science.gov (United States)

Loureiro-Vieira, Sara; Costa, Vera Marisa; de Lourdes Bastos, Maria; Carvalho, Félix; Capela, João Paulo

2017-08-01

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent neuropsychiatry disorders in children and adolescents, and methylphenidate (MPH) is a first-line stimulant drug available worldwide for its treatment. Despite the proven therapeutic efficacy, concerns have been raised regarding the possible consequences of chronic MPH exposure during childhood and adolescence. Disturbances in the neurodevelopment at these crucial stages are major concerns given the unknown future life consequences. This review is focused on the long-term adverse effects of MPH to the brain biochemistry. Reports conducted with young and/or adolescent animals and studies with humans are reviewed in the context of long-term consequences after early life-exposure. MPH pharmacokinetics is also reviewed as there are differences among laboratory animals and humans that may be relevant to extrapolate the findings. Studies reveal that exposure to MPH in laboratory animals during young and/or adolescent ages can impact the brain, but the outcomes are dependent on MPH dose, treatment period, and animal's age. Importantly, the female sex is largely overlooked in both animal and human studies. Unfortunately, human reports that evaluate adults following adolescent or child exposure to MPH are very scarce. In general, human data indicates that MPH is generally safe, although it can promote several brain changes in early ages. Even so, there is a lack of long course patient evaluation to clearly establish whether MPH-induced changes are friendly or foe to the brain and more human studies are needed to assess the adult brain changes that arise from early MPH treatment. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Response to methylphenidate by adult and pediatric patients with attention-deficit/hyperactivity disorder: the Spanish multicenter DIHANA study

Directory of Open Access Journals (Sweden)

Valdizán-Usón JR

2013-02-01

Full Text Available JR Valdizán-Usón,1 A Cánovas-Martínez,2 MT De Lucas-Taracena,3 F Díaz-Atienza,4 LS Eddy-Ives,5 A Fernández-Jaén,6 M Fernández-Pérez,7 M García-Giral,8 P García-Magán,9 M Garraus-Oneca,10 MA Idiazábal-Alecha,11 M López-Benito,12 G Lorenzo-Sanz,13 J Martínez-Antón,14 MA Martínez-Granero,15 F Montañés-Rada,16 F Mulas-Delgado,17 G Ochando-Perales,18 E Ortega-García,19 A Pelaz-Antolín,20 JA Ramos-Quiroga,21 FC Ruiz-Sanz,22 J Vaquerizo-Madrid,23 A Yusta-Izquierdo241Unidad Trastornos Neurofuncionales, Clínica Montpellier, Zaragoza, 2Hospital Dr Peset, Valencia, 3Hospital 12 de Octubre, Madrid, 4Hospital Virgen de las Nieves, Granada, 5Centre Mèdic Sant Ramon, Santa Coloma de Gramenet, Barcelona, 6Hospital Universitario Quirón, Madrid, 7Centro de Salud La Felguera, Langreo, Asturias, 8Hospital Clínic, Barcelona, 9Unidad Salud Mental, Talavera de la Reina, 10Clínica Universitaria de Navarra, Pamplona, 11Hospital Ntra. Sra. del Pilar, Barcelona, 12Centro Salud Contrueces, Gijón, 13Hospital Ramón y Cajal, Madrid, 14Complejo Hospitalario Carlos Haya, Málaga, 15Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, 16Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, 17Hospital Universitario La Fe, Valencia, 18Hospital Universitario La Fe, Valencia, 19Complejo Asistencial Universitario de León, 20Centro Salud Mental, Alcalá de Henares, 21Hospital Universitari Vall d'Hebron. CIBERSAM. Department of Psychiatry and Legal Medicine. Universitat Autònoma de Barcelona, 22Hospital General Rio Carrión, Palencia, 23Hospital Materno-Infantil, Badajoz, 24Hospital Universitario, Guadalajara, SpainBackground: The purpose of this multicenter Spanish study was to evaluate the response to immediate-release methylphenidate by children and adults diagnosed with attention-deficit/hyperactivity disorder (ADHD, as well as to obtain information on current therapy patterns and safety characteristics.Methods: This multicenter

Dopaminergic dysfunction in abstinent dexamphetamine users: results from a pharmacological fMRI study using a reward anticipation task and a methylphenidate challenge.

Science.gov (United States)

Schouw, M L J; De Ruiter, M B; Kaag, A M; van den Brink, W; Lindauer, R J L; Reneman, L

2013-06-01

Dopamine (DA) is involved in systems governing motor actions, motivational processes and cognitive functions. Preclinical studies have shown that even relatively low doses of d-amphetamine (dAMPH) (equivalent to doses used in clinical Practice) can lead to DA neurotoxicity in rodents and non-human primates (Ricaurte et al., 2005). Therefore, we investigated the DAergic function in eight male recreational users of dAMPH and eight male healthy controls using functional magnetic resonance imaging (fMRI). We compared brain activation between both groups during a monetary incentive delay task (Knutson et al., 2001) with and without an oral methylphenidate (MPH) challenge. All subjects were abstinent for at least 2 weeks during the baseline scan. The second scan was performed on the same day 1.5 h after receiving an oral dose of 35 mg MPH (approximately 0.5 mg/kg) when peak MPH binding was assumed. When anticipating reward, dAMPH users showed lower striatal activation in comparison to control subjects. In addition, MPH induced a reduction in the striatal activation during reward anticipation in healthy controls, whereas no such effect was observed in dAMPH users. The combination of these findings provides further evidence for frontostriatal DAergic dysfunction in recreational dAMPH users and is consistent with preclinical data suggesting neurotoxic effects of chronic dAMPH use. The findings of this explorative study could have important implications for humans in need for treatment with dAMPH, such as patients suffering from ADHD and therefore this study needs replication in a larger sample. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Atomoxetine could improve intra-individual variability in drug-naïve adults with attention-deficit/hyperactivity disorder comparably with methylphenidate: A head-to-head randomized clinical trial.

Science.gov (United States)

Ni, Hsing-Chang; Hwang Gu, Shoou-Lian; Lin, Hsiang-Yuan; Lin, Yu-Ju; Yang, Li-Kuang; Huang, Hui-Chun; Gau, Susan Shur-Fen

2016-05-01

Intra-individual variability in reaction time (IIV-RT) is common in individuals with attention-deficit/hyperactivity disorder (ADHD). It can be improved by stimulants. However, the effects of atomoxetine on IIV-RT are inconclusive. We aimed to investigate the effects of atomoxetine on IIV-RT, and directly compared its efficacy with methylphenidate in adults with ADHD. An 8-10 week, open-label, head-to-head, randomized clinical trial was conducted in 52 drug-naïve adults with ADHD, who were randomly assigned to two treatment groups: immediate-release methylphenidate (n=26) thrice daily (10-20 mg per dose) and atomoxetine once daily (n=26) (0.5-1.2 mg/kg/day). IIV-RT, derived from the Conners' continuous performance test (CCPT), was represented by the Gaussian (reaction time standard error, RTSE) and ex-Gaussian models (sigma and tau). Other neuropsychological functions, including response errors and mean of reaction time, were also measured. Participants received CCPT assessments at baseline and week 8-10 (60.4±6.3 days). We found comparable improvements in performances of CCPT between the immediate-release methylphenidate- and atomoxetine-treated groups. Both medications significantly improved IIV-RT in terms of reducing tau values with comparable efficacy. In addition, both medications significantly improved inhibitory control by reducing commission errors. Our results provide evidence to support that atomoxetine could improve IIV-RT and inhibitory control, of comparable efficacy with immediate-release methylphenidate, in drug-naïve adults with ADHD. Shared and unique mechanisms underpinning these medication effects on IIV-RT awaits further investigation. © The Author(s) 2016.

The age-dependent effects of a single-dose methylphenidate challenge on cerebral perfusion in patients with attention-deficit/hyperactivity disorder

NARCIS (Netherlands)

Schrantee, A.; Mutsaerts, H.J.M.M.; Bouziane, C.; Tamminga, H.G.H.; Bottelier, M.A.; Reneman, L.

2017-01-01

Methylphenidate (MPH) is a stimulant drug and an effective treatment for attention-deficit/hyperactivity disorder (ADHD) in both children and adults. Pre-clinical studies suggest that the response to stimulants is dependent on age, which may reflect the ontogeny of the dopamine (DA) system, which

Methylphenidate misuse in adult patients and the impact of therapeutic use

DEFF Research Database (Denmark)

Jensen, L S; Pagsberg, Anne Katrine; Dalhoff, Kim

2015-01-01

OBJECTIVE: Methylphenidate (MPH) prescription rates for adults increase, but the extent of a parallel rise in toxic exposures and their causes and distribution between different MPH trade names are unexplored. METHOD: We retrospectively analyzed adult MPH exposures reported to the Danish Poison...... Information Centre from January 2006 to July 2012 and the association with MPH sales and the number of patients prescribed MPH. RESULTS: Of the 394 exposures (57% males, median age 27 years) reported, MPH status was available in 249 of whom 65.5% were prescribed MPH. Exposure was in 54% motivated by suicidal...... (particularly Ritalin(®)/Ritalin(®) Uno). Most exposures were intentional and motivated by suicide attempts or recreational use....

High sibling correlation on methylphenidate response but no association with DAT1-10R homozygosity in Dutch sibpairs with ADHD

NARCIS (Netherlands)

van der Meulen, Emma M; Bakker, Steven C; Pauls, David L; Oteman, Nicole; Kruitwagen, Cas L J J; Pearson, Peter L; Sinke, Richard J; Buitelaar, Jan K

2005-01-01

BACKGROUND: A minority of patients with attention-deficit hyperactivity disorder (ADHD) do not respond favorably to methylphenidate. This has been partially associated with homozygosity for the Dopamine transporter (DAT1) 10-repeat allele and the presence of one or two Dopamine D4 receptor (DRD4)

High sibling correlation on methylphenidate response but no association with DAT1-10R homozygosity in Dutch sibpairs with ADHD.

NARCIS (Netherlands)

Meulen, E.M. van der; Bakker, S.C.; Pauls, D.L.; Oteman, N.; Kruitwagen, C.L.J.J.; Pearson, P.L.; Sinke, R.J.; Buitelaar, J.K.

2005-01-01

BACKGROUND: A minority of patients with attention-deficit hyperactivity disorder (ADHD) do not respond favorably to methylphenidate. This has been partially associated with homozygosity for the Dopamine transporter (DAT1) 10-repeat allele and the presence of one or two Dopamine D4 receptor (DRD4)

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity

Directory of Open Access Journals (Sweden)

Huss M

2017-07-01

Full Text Available Michael Huss,1 Praveen Duhan,2 Preetam Gandhi,3 Chien-Wei Chen,4 Carsten Spannhuth,3 Vinod Kumar5 1Child and Adolescent Psychiatry, University Medicine, Mainz, Germany; 2Global Medical Affairs, Novartis Healthcare Pvt. Ltd., Hyderabad, India; 3Development Franchise, Established Medicine Neuroscience, Novartis Pharma AG, Basel, Switzerland; 4Biostatistics Cardio-Metabolic & Established Medicine, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 5Established Medicines, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Abstract: Attention-deficit/hyperactivity disorder (ADHD is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH, a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD. Keywords: methylphenidate, dose optimization, attention-deficit/hyperactivity disorder, ADHD

Use of partial AUC (PAUC) to evaluate bioequivalence--a case study with complex absorption: methylphenidate.

Science.gov (United States)

Fourie Zirkelbach, Jeanne; Jackson, Andre J; Wang, Yaning; Schuirmann, Donald J

2013-01-01

Methylphenidate modified-release products produce early and late peak concentrations critical for treatment of morning and afternoon symptoms of attention deficit hyperactivity disorder (ADHD). Standard bioequivalence (BE) criteria cannot be applied to these products. The performance of partial area under the drug concentration-time curve (PAUC), Cmax and AUCINF to assess BE were independently evaluated for two products. A two-stage analysis was performed on plasma data for two methylphenidate modified-release products (Product 1 and 2). Simulations using the fitted parameters determined how changes in fast absorption rate constant (K0Fast) and fraction available (F1) affected curve shape and BE determination using Cmax, AUCINF and PAUC. The sensitivity of the mean PAUC(test)/PAUC(reference) ratios to changes in K0Fast(test) are product dependent. Product 1 mean PAUC(test)/PAUC(reference) ratios for PAUC0-4h are more responsive to both decreases and increases in K0Fast(test) than Product 2. Product 2 showed a greater response in the mean PAUC(test)/PAUC(reference) ratio for PAUC0-4h when the K0Fast(test) is decreased and less response as the value is increased. PAUC estimated curve shape is sensitive to changes in absorption and are product specific, and may require a new PAUC metric for each drug. A non-product specific metric to assess curve shape is warranted.

Effect of Food Intake on the Pharmacokinetics of a Novel Methylphenidate Extended-Release Oral Suspension for Attention Deficit Hyperactivity Disorder.

Science.gov (United States)

Sallee, Floyd R; Palumbo, Donna R; Abbas, Richat; Berry, Sally A; Puthli, Shivanand P; Kathala, Kalyan K

2017-09-01

We conducted an open-label, single-dose, randomized, crossover study in healthy adults to assess the impact of food on the bioavailability of 60 mg methylphenidate extended-release oral suspension (MEROS; Quillivant XR™)-a long-acting stimulant for the treatment of attention deficit hyperactivity disorder-by comparing the pharmacokinetic parameters under fed and fasting conditions. When MEROS 60 mg was administered under fed conditions compared with fasting conditions, the exposure of methylphenidate (d enantiomer) was higher, with a mean area under the plasma concentration-vs-time curve (AUC) 0-t of 160.2 ng·h/mL vs 140.4 ng·h/mL, and a mean AUC 0-inf of 163.2 ng·h/mL vs 143.7 ng·h/mL, respectively. The ratios of the ln-transformed geometric means for methylphenidate for AUC 0-t and AUC 0-inf were 119.5% (90%CI, 115.7% to 123.5%) and 119.0% (90%CI, 115.2% to 122.8%), respectively, within the standard 80% to 125% bioequivalence acceptance range indicating no food effect on the overall exposure (rate and extent). There was a small increase in the peak plasma concentration (127.6% [90%CI, 119.9% to 135.8%]). However, this effect was small and not likely to be clinically significant. Overall, MEROS 60 mg was safe in both the fed and fasting condition when administered to healthy volunteers in this study. © 2017 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Association of Carboxylesterase 1 Gene (CES1) Polymorphism with Weight loss in Children with Attention Deficit Hyperactivity Disorder during Methylphenidate Treatment

DEFF Research Database (Denmark)

Oxenbøll, Maria; Kaalund-Jørgensen, Kristine; Rasmussen, Simone

2017-01-01

Children with Attention Deficit Hyperactivity Disorder (ADHD) show large variations in response to methylphenidate (MPH) treatment, which may result from genetic factors associated with MPH metabolism. We aimed at investigating a possible link between the -75 T>G polymorphism in the 5’ untranslated...

A randomized, placebo-controlled trial of three fixed dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder.

NARCIS (Netherlands)

Medori, R.; Ramos-Quiroga, J.A.; Casas, M.; Kooij, J.J.S.; Niemela, A.; Trott, G.E.; Lee, E.; Buitelaar, J.K.

2008-01-01

BACKGROUND: There is increasing recognition of attention-deficit/hyperactivity disorder (ADHD) in adults and the need to evaluate efficacy and safety of methylphenidate treatment in these patients. METHODS: In this double-blind trial, 401 adults with ADHD (218 men; 18-63 years) were randomly

The acute effect of methylphenidate on cerebral blood flow in boys with attention-deficit/hyperactivity disorder

International Nuclear Information System (INIS)

Szobot, Claudia M.; Ketzer, Carla; Kapczinski, Flavio; Cunha, Renato D.; Parente, Maria A.; Langleben, Daniel D.; Acton, Paul D.; Rohde, Luis A.P.

2003-01-01

Methylphenidate (MPH) is the most commonly prescribed treatment for attention-deficit/hyperactivity disorder (ADHD). The therapeutic mechanisms of MPH are not, however, fully understood. We studied the effects of MPH on brain activity in male children and adolescents with ADHD, using the blood flow radiotracer technetium-99m ethyl cysteinate dimer ( 99m Tc-ECD) and single-photon emission tomography (SPET). The study was randomized, double blind, and placebo controlled (MPH group, n=19; placebo group, n=17), Radiotracer was administered during the performance of the Continuous Performance Test and before and after 4 days of MPH treatment. Statistical parametric mapping (SPM99) analysis showed a significant reduction in regional cerebral blood flow in the left parietal region in the MPH group compared with the placebo group (P<0.05, corrected for multiple comparisons). Our findings suggest that the posterior attentional system, which includes the parietal cortex, may have a role in the mediation of the therapeutic effects of MPH in ADHD. (orig.)

The acute effect of methylphenidate on cerebral blood flow in boys with attention-deficit/hyperactivity disorder

Energy Technology Data Exchange (ETDEWEB)

Szobot, Claudia M; Ketzer, Carla; Kapczinski, Flavio [Department of Psychiatry, Federal University of Rio Grande do Sul (Brazil); Cunha, Renato D [Service of Nuclear Medicine, Hospital de Clinicas de Porto Alegre (Brazil); Parente, Maria A [Department of Psychology, Federal University of Rio Grande do Sul (Brazil); Langleben, Daniel D [Department of Psychiatry, University of Pennsylvania (United States); Acton, Paul D [Department of Radiology, University of Pennsylvania (United States); Rohde, Luis A.P. [Department of Psychiatry, Federal University of Rio Grande do Sul (Brazil); Servico de Psiquiatria da Infancia e Adolescencia, Hospital de Clinicas de Porto Alegre (HCPA), Rua Ramiro Barcelos 2350, CEP 90035-003, RS Porto Alegre (Brazil)

2003-03-01

Methylphenidate (MPH) is the most commonly prescribed treatment for attention-deficit/hyperactivity disorder (ADHD). The therapeutic mechanisms of MPH are not, however, fully understood. We studied the effects of MPH on brain activity in male children and adolescents with ADHD, using the blood flow radiotracer technetium-99m ethyl cysteinate dimer ({sup 99m}Tc-ECD) and single-photon emission tomography (SPET). The study was randomized, double blind, and placebo controlled (MPH group, n=19; placebo group, n=17), Radiotracer was administered during the performance of the Continuous Performance Test and before and after 4 days of MPH treatment. Statistical parametric mapping (SPM99) analysis showed a significant reduction in regional cerebral blood flow in the left parietal region in the MPH group compared with the placebo group (P<0.05, corrected for multiple comparisons). Our findings suggest that the posterior attentional system, which includes the parietal cortex, may have a role in the mediation of the therapeutic effects of MPH in ADHD. (orig.)

The Influence of Methylphenidate on Hyperactivity and Attention Deficits in Children With ADHD. A Virtual Classroom Test

OpenAIRE

Mühlberger, Andreas; Jekel, K.; Probst, Thomas; Schecklmann, Martin

2016-01-01

Objective: This study compares the performance in a continuous performance test within a virtual reality classroom (CPT-VRC) between medicated children with ADHD, unmedicated children with ADHD, and healthy children. Method: N = 94 children with ADHD (n = 26 of them received methylphenidate and n = 68 were unmedicated) and n = 34 healthy children performed the CPT-VRC. Omission errors, reaction time/variability, commission errors, and body movements were assessed. Furthermore, ADHD...

Age-dependent effects of methylphenidate on the human dopaminergic system in young vs adult patients with attention-deficit/hyperactivity disorder: A randomized clinical trial

NARCIS (Netherlands)

Schrantee, A. (Anouk); Tamminga, H.G.H. (Hyke G. H.); C. Bouziane (Cheima); Bottelier, M.A. (Marco A.); E.E. Bron (Esther); H.J.M.M. Mutsaerts (Henri J. M.); A.H. Zwinderman (Ailko); Groote, I.R. (Inge R.); S.A.R.B. Rombouts (Serge); Lindauer, R.J.L. (Ramon J. L.); S. Klein (Stefan); W.J. Niessen (Wiro); B.C. Opmeer (Brent); Boer, F. (Frits); P.J. Lucassen; Andersen, S.L. (Susan L.); H.M. Geurts (Hilde ); L. Reneman (Liesbeth)

2016-01-01

textabstractIMPORTANCE Although numerous children receivemethylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. OBJECTIVES To determine

Effects of methylphenidate on body index and physical fitness in Korean children with attention deficit hyperactivity disorder.

Science.gov (United States)

Kang, Kyoung Doo; Yun, Sin Weon; Chung, Unsun; Kim, Tae Ho; Park, Jeong Ha; Park, In Hui; Han, Doug Hyun

2016-03-01

The side effects of methylphenidate (MPH) on growth remain a controversial concern. This study aimed to investigate the effect of MPH on clinical symptoms, growth, and physical fitness in Korean children. Fifty male children with attention deficit hyperactivity disorder (ADHD) treated with methylphenidate (MPH-ADHD), 69 MPH-naïve male children with ADHD (Naïve-ADHD), and 60 age-matched and sex-matched healthy control subjects were recruited. Intelligence quotient (IQ), clinical symptoms of ADHD, body index (height, weight, and body mass index [BMI]), and physical fitness (muscular strength, endurance, flexibility, agility, speed, and balance) were assessed. Total IQ and performance IQ scores were significantly different among the three groups, as were mean Korean Attention Deficit Hyperactivity Disorder (K-ARS)-total, K-ARS-inattention, and K-ARS-hyperactivity scores. There was no significant difference in height, weight, or BMI among the three groups. There were significant differences in skill-related fitness scores for balance (healthy controls > MPH-ADHD > Naïve-ADHD) and agility shuttle test time (healthy controls attention, and balance and agility measures of skill-related fitness in Korean children with ADHD. MPH was not associated with growth delays in height, weight, and BMI. Copyright © 2016 John Wiley & Sons, Ltd.

[{sup 11}C]d-threo-Methylphenidate, a new radiotracer for the dopamine transporter. Characterization in baboon and human brain

Energy Technology Data Exchange (ETDEWEB)

Ding, Y.S.; Volkow, N.D.; Fowler, J.S. [Brookhaven National Laboratory, Upton, NY (United States)] [and others

1995-05-01

dl-threo Methylphenidate (MP, Ritalin) is a psychostimulant drug which binds to the dopamine transporter (DAT). We evaluated [{sup 11}C]d-threo-methylphenidate ([{sup 11}C]d-MP), the more active enantiomer, as a radiotracer for the DAT in baboons and human brain. Stereoselectivity, saturability and pharmacological specificity and reproducibility were examined. Stereoselectivity was examined in baboons by comparing [{sup 11C}]d-MP,[{sup 11}C]l-MP and [{sup 11}C]dl-MP. Unlabeled MP was used to assess the reversibility and saturability of the binding. GBR 12909,{beta}-(4-iodophenyl)tropane-2-carboxylic acid methyl ester ({beta}-CIT), tomoxetine and citalopram were used to assess the specificity of the binding. The ratios between the radioactivity in the striatum to that in cerebellum (ST/CB) were 3.3,2.2 and 1.1 for [{sup 11}C]d-MP,[{sup 11}C]dl-MP and [{sup 11}C]l-MP respectively. Most of the striatal binding of [{sup 11}C]d-threo-MP was displaced by injection of nonradioactive MP demonstrating reversibility. Pretreatment with MP (0.5 mg/kg), GBR12909 (1.5 mg/kg) or {beta}-CIT (0.3 mg/kg) reduced ST/CB by about 60% and the ratios of distribution volumes at the steady-state for the triatum to cerebellum (DV{sub st/}DV{sub cb}) by about 50%. Pretreatment with tomoxetine (3.0 mg/kg) or citalopram (2.0 mg/kg), inhibitors of the norepinephrine and serotonin transporter, had no effect. Studies of [{sup 11}C]d-MP in the human brain showed highest uptake in basal ganglia with a half clearance time of about 60 minutes. Repeated studies in 6 normal human subjects showed differences in DV{sub st/}DV{sub cb} between -7% and 8%. MP pretreatment decreased BG but no cortical or cerebellar binding and reduced Bmax/Kd by 91%.

The influence of methylphenidate on the power spectrum of ADHD children – an MEG study

Directory of Open Access Journals (Sweden)

Bauer Susanne

2005-07-01

Full Text Available Abstract Background The present study was dedicated to investigate the influence of Methylphenidate (MPH on cortical processing of children who were diagnosed with different subtypes of Attention Deficit Hyperactivity Disorder (ADHD. As all of the previous studies investigating power differences in different frequency bands have been using EEG, mostly with a relatively small number of electrodes our aim was to obtain new aspects using high density magnetoencephalography (MEG. Methods 35 children (6 female, 29 male participated in this study. Mean age was 11.7 years (± 1.92 years. 17 children were diagnosed of having an Attention-Deficit/Hyperactivity Disorder of the combined type (ADHDcom, DSM IV code 314.01; the other 18 were diagnosed for ADHD of the predominantly inattentive type (ADHDin, DSM IV code 314.0. We measured the MEG during a 5 minute resting period with a 148-channel magnetometer system (MAGNES™ 2500 WH, 4D Neuroimaging, San Diego, USA. Power values were averaged for 5 bands: Delta (D, 1.5–3.5 Hz, Theta (T, 3.5–7.5 Hz, Alpha (A, 7.5–12.5 Hz, Beta (B, 12.5–25 Hz and Global (GL, 1.5–25 Hz.. Additionally, attention was measured behaviourally using the D2 test of attention with and without medication. Results The global power of the frequency band from 1.5 to 25 Hz increased with MPH. Relative Theta was found to be higher in the left hemisphere after administration of MPH than before. A positive correlation was found between D2 test improvement and MPH-induced power changes in the Theta band over the left frontal region. A linear regression was computed and confirmed that the larger the improvement in D2 test performance, the larger the increase in Theta after MPH application. Conclusion Main effects induced by medication were found in frontal regions. Theta band activity increased over the left hemisphere after MPH application. This finding contradicts EEG results of several groups who found lower levels of Theta power

Randomized Controlled Trial of Osmotic-Release Methylphenidate with Cognitive-Behavioral Therapy in Adolescents with Attention-Deficit/Hyperactivity Disorder and Substance Use Disorders

Science.gov (United States)

Riggs, Paula D.; Winhusen, Theresa; Davies, Robert D.; Leimberger, Jeffrey D.; Mikulich-Gilbertson, Susan; Klein, Constance; Macdonald, Marilyn; Lohman, Michelle; Bailey, Genie L.; Haynes, Louise; Jaffee, William B.; Haminton, Nancy; Hodgkins, Candace; Whitmore, Elizabeth; Trello-Rishel, Kathlene; Tamm, Leanne; Acosta, Michelle C.; Royer-Malvestuto, Charlotte; Subramaniam, Geetha; Fishman, Marc; Holmes, Beverly W.; Kaye, Mary Elyse; Vargo, Mark A.; Woody, George E.; Nunes, Edward V.; Liu, David

2011-01-01

Objective: To evaluate the efficacy and safety of osmotic-release methylphenidate (OROS-MPH) compared with placebo for attention-deficit/hyperactivity disorder (ADHD), and the impact on substance treatment outcomes in adolescents concurrently receiving cognitive-behavioral therapy (CBT) for substance use disorders (SUD). Method: This was a…

Disagreements with implications: diverging discourses on the ethics of non-medical use of methylphenidate for performance enhancement

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Forlini, Cynthia; Racine, Eric

2009-01-01

Abstract Background There is substantial evidence that methylphenidate (MPH; Ritalin), is being used by healthy university students for non-medical motives such as the improvement of concentration, alertness, and academic performance. The scope and potential consequences of the non-medical use of MPH upon healthcare and society bring about many points of view. Methods To gain insight into key ethical and social issues on the non-medical use of MPH, we examined discourses in the print media, b...

Effects of 7-day continuous D-amphetamine, methylphenidate, and cocaine treatment on choice between methamphetamine and food in male rhesus monkeys.

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Schwienteck, Kathryn L; Banks, Matthew L

2015-10-01

Methamphetamine addiction is a significant public health problem for which no Food and Drug Administration-approved pharmacotherapies exist. Preclinical drug vs. food choice procedures have been predictive of clinical medication efficacy in the treatment of opioid and cocaine addiction. Whether preclinical choice procedures are predictive of candidate medication effects for other abused drugs, such as methamphetamine, remains unclear. The present study aim was to determine continuous 7-day treatment effects with the monoamine releaser d-amphetamine and the monoamine uptake inhibitor methylphenidate on methamphetamine vs. food choice. In addition, 7-day cocaine treatment effects were also examined. Behavior was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and methamphetamine injections (0-0.32mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=4). Methamphetamine choice dose-effect functions were determined daily before and during 7-day periods of continuous intravenous treatment with d-amphetamine (0.01-0.1mg/kg/h), methylphenidate (0.032-0.32mg/kg/h), or cocaine (0.1-0.32mg/kg/h). During saline treatment, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Continuous 7-day treatments with d-amphetamine, methylphenidate or cocaine did not significantly attenuate methamphetamine vs. food choice up to doses that decreased rates of operant responding. However, 0.1mg/kg/h d-amphetamine did eliminate methamphetamine choice in two monkeys. The present subchronic treatment results support the utility of preclinical methamphetamine choice to evaluate candidate medications for methamphetamine addiction. Furthermore, these results confirm and extend previous results demonstrating differential pharmacological mechanisms between cocaine choice and methamphetamine choice. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effectiveness of atomoxetine and methylphenidate for problematic online gaming in adolescents with attention deficit hyperactivity disorder.

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Park, Jeong Ha; Lee, Young Sik; Sohn, Ji Hyun; Han, Doug Hyun

2016-11-01

There is a high prevalence of problematic online gaming in adolescents with attention deficit hyperactivity disorder (ADHD). In the current study, we compared the effectiveness of atomoxetine (ATM) and methylphenidate (MPH) on problematic online gaming in adolescents with ADHD. We recruited 86 adolescents diagnosed with ADHD together with Internet gaming disorder. These participants were divided into two treatment groups: 44 participants were treated with MPH for 12 weeks, and 42 participants were treated with ATM for 12 weeks. During the 3-month study period, the MPH group showed greater improvement in Korean ADHD rating scale scores than the ATM group. The ATM group showed greater improvement in Child Depression Inventory scores than the MPH group. However, Young Internet Addiction Scale and Behavioral Inhibition & Activation Scales score changes did not differ significantly between the MPH and ATM groups. In both groups, changes in Young Internet Addiction Scale scores were positively correlated with the changes in Behavioral Inhibition & Activation Scales scores. Both MPH and ATM reduced the severity of Internet gaming disorder symptoms, and this reduction was correlated with impulsivity reduction, which also resulted from both ADHD medications. These findings suggest impulsivity plays a critical role in the development of problematic online gaming. Copyright © 2016 John Wiley & Sons, Ltd.

The effect of methylphenidate on sustained attention among adolescents with attention-deficit hyperactivity disorder.

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Lufi, Dubi; Bassin-Savion, Shiry; Rubel, Lilach

2015-01-01

Twenty-seven adolescents diagnosed as having attention-deficit hyperactivity disorder (ADHD) were tested twice with a computerized MATH-CPT (mathematics continuous performance test). In one administration, the participants took medication (methylphenidate, MPH) 1.5 hr before being tested. In another administration, the MATH-CPT was administered without the medication. Treatment with MPH improved the "overall attention level" and in measures of "reaction time" and "impulsivity." MPH did not improve the performance in the four measures of sustained attention. Knowing that treatment with MPH does not improve sustained attention can be helpful in reaching a decision of whether or not a child should be treated with MPH.

Novelty-seeking trait predicts the effect of methylphenidate on creativity.

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Gvirts, Hila Z; Mayseless, Naama; Segev, Aviv; Lewis, D Yael; Feffer, Kfir; Barnea, Yael; Bloch, Yuval; Shamay-Tsoory, Simon G

2017-05-01

In recent years the use of psychostimulants for cognitive enhancement in healthy individuals with no psychiatric disorders has been on the rise. However, it is still unclear whether psychostimulants improve certain cognitive functions at the cost of others, and how these psychostimulants interact with individual personality differences. In the current study, we investigated whether the effect of one common stimulant, methylphenidate (MPH), on creativity is associated with novelty seeking. Thirty-six healthy adults, without attention-deficit hyperactivity disorder (ADHD) symptomology, were assigned randomly in a double-blind fashion to receive MPH or placebo. We found that the effect of MPH on creativity was dependent on novelty-seeking (NS) personality characteristics of the participants. MPH increased creativity in individuals with lower NS, while it reduced creativity levels in individuals with high NS. These findings highlight the role of the dopaminergic system in creativity, and indicate that among healthy individuals NS can be seen as a predictor of the effect of MPH on creativity.

The impact of methylphenidate and its enantiomers on dopamine synthesis and metabolism in vitro.

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Bartl, Jasmin; Palazzesi, Ferruccio; Parrinello, Michele; Hommers, Leif; Riederer, Peter; Walitza, Susanne; Grünblatt, Edna

2017-10-03

Methylphenidate (MPH), a psychostimulant, is an effective first-line treatment for the symptoms associated with Attention-Deficit/Hyperactivity Disorder (ADHD). Although most MPH formulations are composed of the racemic 1:1 mixture of the two enantiomers (d- and l-threo), converging lines of evidence indicate that d-threo MPH seems to be superior to the l-isomer. We aimed to investigate whether MPH racemic mixture or pure enantiomers influence the enzyme activity of tyrosine hydroxylase (TH), monoamine oxidase B (MAO-B), catechol-O-methyltransferase (COMT), and aldehyde dehydrogenase (ALDH) in vitro in homogenates of rat PC12 cells incubated with racemic, d- and l-threo MPH (1nM up to 100μM), or a vehicle for control. We could observe dose dependent enhancement of TH activity with d-threo MPH, probably due to its higher affinity to the enzyme, which we could confirm for d-threo versus l-threo MPH via docking and molecular dynamic simulations analysis. MAO-B enzyme activity was found to be enhanced when incubated with both d- and l-isomers but not with the racemic mixture. This conflicting result was hypothesized to be due to possible aggregation of the two enantiomers or other molecular conformations. Such a possible interaction was observed indirectly, when TH was incubated with constant d-threo MPH while increasing l-isomer (increasing total MPH concentrations). Hence, TH activity was slightly decreased with increased l-isomer. In conclusion, the current in vitro investigation points to the stereoselectivity of the investigated enzymes and pharmacological effects of MPH enantiomers. Copyright © 2017 Elsevier Inc. All rights reserved.

Chronic exposure to MDMA (Ecstasy elicits behavioral sensitization in rats but fails to induce cross-sensitization to other psychostimulants

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Swann Alan C

2006-01-01

Full Text Available Abstract Background The recreational use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy among adolescents and young adults has become increasingly prevalent in recent years. While evidence suggests that the long-term consequences of MDMA use include neurodegeneration to serotonergic and, possibly, dopaminergic pathways, little is known about susceptibility, such as behavioral sensitization, to MDMA. Methods The objectives of this study were to examine the dose-response characteristics of acute and chronic MDMA administration in rats and to determine whether MDMA elicits behavioral sensitization and whether it cross-sensitizes with amphetamine and methylphenidate. Adult male Sprague-Dawley rats were randomly divided into three MDMA dosage groups (2.5 mg/kg, 5.0 mg/kg, and 10.0 mg/kg and a saline control group (N = 9/group. All three MDMA groups were treated for six consecutive days, followed by a 5-day washout, and subsequently re-challenged with their respective doses of MDMA (day 13. Rats were then given an additional 25-day washout period, and re-challenged (day 38 with similar MDMA doses as before followed by either 0.6 mg/kg amphetamine or 2.5 mg/kg methylphenidate on the next day (day 39. Open-field locomotor activity was recorded using a computerized automated activity monitoring system. Results Acute injection of 2.5 mg/kg MDMA showed no significant difference in locomotor activity from rats given saline (control group, while animals receiving acute 5.0 mg/kg or 10.0 mg/kg MDMA showed significant increases in locomotor activity. Rats treated chronically with 5.0 mg/kg and 10.0 mg/kg MDMA doses exhibited an augmented response, i.e., behavioral sensitization, on experimental day 13 in at least one locomotor index. On experimental day 38, all three MDMA groups demonstrated sensitization to MDMA in at least one locomotor index. Amphetamine and methylphenidate administration to MDMA-sensitized animals did not elicit any significant change

An Analysis of Patient Adherence to Treatment during a 1-Year, Open-Label Study of OROS[R] Methylphenidate in Children with ADHD

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Faraone, Stephen V.; Biederman, Joseph; Zimmerman, Brenda

2007-01-01

Objective: Treatment adherence is an important aspect of ADHD symptom management, but there are many factors that may influence adherence. Method: This analysis assessed adherence to OROS methylphenidate during a 1-year, open-label study in children. Adherence was defined as the number of days medication was taken divided by the number of days in…

Effect of Osmotic-Release Oral System Methylphenidate on Different Domains of Attention and Executive Functioning in Children with Attention-Deficit-Hyperactivity Disorder

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Blum, Nathan J.; Jawad, Abbas F.; Clarke, Angela T.; Power, Thomas J.

2011-01-01

Aim: This study investigated whether components of attention and executive functioning improve when children with attention-deficit-hyperactivity disorder (ADHD) are treated with osmotic-release oral system (OROS) methylphenidate. Method: Thirty children (24 males, six females; mean age 8y 6mo, SD 1y 11mo; range 6y 5mo-12y 6mo) with ADHD combined…

Methylphenidate does not improve interference control during a working memory task in young patients with attention-deficit hyperactivity disorder.

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Prehn-Kristensen, Alexander; Krauel, Kerstin; Hinrichs, Hermann; Fischer, Jochen; Malecki, Ulrike; Schuetze, Hartmut; Wolff, Stephan; Jansen, Olav; Duezel, Emrah; Baving, Lioba

2011-05-04

Patients with attention-deficit/hyperactivity disorder (ADHD) show deficits in working memory (WM) which may be related to prefrontal dysfunction. Methylphenidate (MPH) can restore WM deficits in ADHD by enhancing prefrontal activity. At the same time, changes in striatal activation could cause ADHD patients to be more interference-sensitive during working memory tasks. However, it is unclear whether MPH reduces WM distractibility in ADHD. In this fMRI study, 12 ADHD patients and 12 healthy controls participated on two separate days in a delayed-match-to-sample test. During the delay interval, a distractor stimulus was presented in half of the trials. Children and adolescents with ADHD received MPH only on one of the two sessions. Behavioral data analyses revealed that MPH normalized WM in ADHD. However, MPH did not improve WM performance when a distractor was presented during the delay interval. Functional images showed that MPH enhanced prefrontal activity during the delay in ADHD patients when no distractor was present. If the delay was interrupted by a distractor, only healthy controls showed activation of the caudate. In patients with ADHD, however, in line with behavioral data, MPH did not enhance caudate activity. In healthy youth, caudate activity is involved in interference control allowing the successful maintenance of information in working memory even in the presence of distraction. Our findings suggest that interference control, linked to caudate activity, is not adequately enhanced by MPH in ADHD. Copyright © 2011 Elsevier B.V. All rights reserved.

Methylphenidate and Atomoxetine-Responsive Prefrontal Cortical Genetic Overlaps in "Impulsive" SHR/NCrl and Wistar Rats.

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Dela Peña, Ike; Dela Peña, Irene Joy; de la Peña, June Bryan; Kim, Hee Jin; Shin, Chan Young; Han, Doug Hyun; Kim, Bung-Nyun; Ryu, Jong Hoon; Cheong, Jae Hoon

2017-09-01

Impulsivity, the predisposition to act prematurely without foresight, is associated with a number of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Identifying genetic underpinnings of impulsive behavior may help decipher the complex etiology and neurobiological factors of disorders marked by impulsivity. To identify potential genetic factors of impulsivity, we examined common differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of adolescent SHR/NCrl and Wistar rats, which showed marked decrease in preference for the large but delayed reward, compared with WKY/NCrl rats, in the delay discounting task. Of these DEGs, we examined drug-responsive transcripts whose mRNA levels were altered following treatment (in SHR/NCrl and Wistar rats) with drugs that alleviate impulsivity, namely, the ADHD medications methylphenidate and atomoxetine. Prefrontal cortical genetic overlaps between SHR/NCrl and Wistar rats in comparison with WKY/NCrl included genes associated with transcription (e.g., Btg2, Fos, Nr4a2), synaptic plasticity (e.g., Arc, Homer2), and neuron apoptosis (Grik2, Nmnat1). Treatment with methylphenidate and/or atomoxetine increased choice of the large, delayed reward in SHR/NCrl and Wistar rats and changed, in varying degrees, mRNA levels of Nr4a2, Btg2, and Homer2, genes with previously described roles in neuropsychiatric disorders characterized by impulsivity. While further studies are required, we dissected potential genetic factors that may influence impulsivity by identifying genetic overlaps in the PFC of "impulsive" SHR/NCrl and Wistar rats. Notably, these are also drug-responsive transcripts which may be studied further as biomarkers to predict response to ADHD drugs, and as potential targets for the development of treatments to improve impulsivity.

The effect of methylphenidate on Internet video game play in children with attention-deficit/hyperactivity disorder.

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Han, Doug Hyun; Lee, Young Sik; Na, Churl; Ahn, Jee Young; Chung, Un Sun; Daniels, Melissa A; Haws, Charlotte A; Renshaw, Perry F

2009-01-01

A number of studies about attention-deficit/hyperactivity disorder (ADHD) and Internet video game play have examined the prefrontal cortex and dopaminergic system. Stimulants such as methylphenidate (MPH), given to treat ADHD, and video game play have been found to increase synaptic dopamine. We hypothesized that MPH treatment would reduce Internet use in subjects with co-occurring ADHD and Internet video game addictions. Sixty-two children (52 males and 10 females), drug-naive, diagnosed with ADHD, and Internet video game players, participated in this study. At the beginning of the study and after 8 weeks of treatment with Concerta (OROS methylphenidate HCl, Seoul, Korea), participants were assessed with Young's Internet Addiction Scale, Korean version (YIAS-K), Korean DuPaul's ADHD Rating Scale, and the Visual Continuous Performance Test. Their Internet usage time was also recorded. After 8 weeks of treatment, the YIAS-K scores and Internet usage times were significantly reduced. The changes in the YIAS-K scores between the baseline and 8-week assessments were positively correlated with the changes in total and inattention scores from the Korean DuPaul's ADHD Rating Scale, as well as omission errors from the Visual Continuous Performance Test. There was also a significant difference in the number of omission errors among non-Internet-addicted, mildly Internet addicted, and severely Internet addicted participants. We suggest that Internet video game playing might be a means of self-medication for children with ADHD. In addition, we cautiously suggest that MPH might be evaluated as a potential treatment of Internet addiction.

Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate

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Michaelides, M.; Wang, G.; Michaelides, M.; Pascau, J.; Gispert, J.-D.; Delis, F.; Grandy, D.K.; Wang, G.-J.; Desco, M.; Rubinstein, M.; Volkow, N.D.; Thanos, P.K.

2010-07-16

Methylphenidate (MP) is widely used to treat attention deficit hyperactivity disorder (ADHD). Variable number of tandem repeats polymorphisms in the dopamine D4 receptor (D{sub 4}) gene have been implicated in vulnerability to ADHD and the response to MP. Here we examined the contribution of dopamine D4 receptors (D4Rs) to baseline brain glucose metabolism and to the regional metabolic responses to MP. We compared brain glucose metabolism (measured with micro-positron emission tomography and [{sup 18}F]2-fluoro-2-deoxy-D-glucose) at baseline and after MP (10 mg/kg, i.p.) administration in mice with genetic deletion of the D{sub 4}. Images were analyzed using a novel automated image registration procedure. Baseline D{sub 4}{sup -/-} mice had lower metabolism in the prefrontal cortex (PFC) and greater metabolism in the cerebellar vermis (CBV) than D{sub 4}{sup +/+} and D{sub 4}{sup +/-} mice; when given MP, D{sub 4}{sup -/-} mice increased metabolism in the PFC and decreased it in the CBV, whereas in D{sub 4}{sup +/+} and D{sub 4}{sup +/-} mice, MP decreased metabolism in the PFC and increased it in the CBV. These findings provide evidence that D4Rs modulate not only the PFC, which may reflect the activation by dopamine of D4Rs located in this region, but also the CBV, which may reflect an indirect modulation as D4Rs are minimally expressed in this region. As individuals with ADHD show structural and/or functional abnormalities in these brain regions, the association of ADHD with D4Rs may reflect its modulation of these brain regions. The differential response to MP as a function of genotype could explain differences in brain functional responses to MP between patients with ADHD and healthy controls and between patients with ADHD with different D{sub 4} polymorphisms.

Effectiveness of parental training, methylphenidate treatment, and their combination on academic achievements and behavior at school of children with attention-deficit hyperactivity disorder.

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Golubchik, Pavel; Hamerman, Hagar; Manor, Iris; Peskin, Miriam; Weizman, Abraham

2018-03-30

This study aimed to compare the effectiveness of parental training (PT), methylphenidate treatment (MPH), and the combination of PT and MPH treatment (PT/MPH) on school achievements in children with attention-deficit hyperactivity disorder (ADHD). Twenty eight ADHD patients (age: 10.1±1.11 years) were divided into three groups: (a) PT (N=10), (b) PT/MPH (N=8), and (c) MPH alone (N=10). Their grades in academics and conduct, from their school reports before and after treatment (6 months), were coded as achievement scores. No significant differences in baseline academic and conduct scores were found between the groups (F=0.033, d.f.=2, P=0.97 and F=0.024, d.f.=2, P=0.98, respectively). No significant changes before versus after treatment were detected in academic (3.83±0.93 vs. 3.85±0.88, paired t=0.086, d.f.=9, P=0.93, NS) or conduct (3.90±1.10 vs. 4.10±1.00, paired t=1.50, d.f.=9, P=0.17, NS) scores in the PT group. The same was true for the PT/MPH group (academic scores: 3.75±0.98 vs. 4.05±0.83, d.f.=7, t=0.927, P=0.38; conduct scores: 3.85±0.83 vs. 4.12±0.83, d.f.=7, t=0.79, P=0.45). Only the MPH group showed significant improvements in those scores (academic scores: 3/73±0.85 vs. 4/44±0.48, d.f.=9, t=3.33, P=0.0088; conduct scores: 3.80±0.70 vs. 4.60±0.70, d.f.=9, t=3.2, P=0.011). Methylphenidate alone is superior to either parental training or parental training/methylphenidate in improving academics and conduct at school.

Questões atuais no tratamento farmacológico do TDAH em adultos com metilfenidato Actual issues in the pharmacological treatment of ADHD in adults with methylphenidate

Directory of Open Access Journals (Sweden)

Mario R. Louzã

2007-01-01

Full Text Available O tratamento farmacológico do transtorno do déficit de atenção com hiperatividade (TDAH em adultos inclui o uso de psicoestimulantes, antidepressivos e atomoxetina, sendo o primeiro considerado a indicação de primeira escolha. A eficácia do metilfenidato foi demonstrada em adultos quando se empregavam doses maiores, proporcionalmente similares àquelas usadas em estudos em crianças. O perfil de eventos adversos do metilfenidato, incluindo aqueles relativos ao sistema cardiovascular, parece bastante seguro.Pharmacotherapy of attention-deficit/hyperactivity disorder in adulthood includes psychostimulants, antidepressants and atomoxetine, the first of them being considered the first choice. Methylphenidate efficacy has been demonstrated in adults when higher doses were used, in a proportionate similar way to what has been described in children. Methylphenidate profile of adverse events, including cardiovascular ones, seems to be safe.

Increase or Decrease of fMRI Activity in Adult Attention Deficit/ Hyperactivity Disorder: Does It Depend on Task Difficulty?

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Biehl, Stefanie C; Merz, Christian J; Dresler, Thomas; Heupel, Julia; Reichert, Susanne; Jacob, Christian P; Deckert, Jürgen; Herrmann, Martin J

2016-05-27

Attention deficit/hyperactivity disorder has been shown to affect working memory, and fMRI studies in children and adolescents with attention deficit/hyperactivity disorder report hypoactivation in task-related attentional networks. However, studies with adult attention deficit/hyperactivity disorder patients addressing this issue as well as the effects of clinically valid methylphenidate treatment are scarce. This study contributes to closing this gap. Thirty-five adult patients were randomized to 6 weeks of double-blind placebo or methylphenidate treatment. Patients completed an fMRI n-back working memory task both before and after the assigned treatment, and matched healthy controls were tested and compared to the untreated patients. There were no whole-brain differences between any of the groups. However, when specified regions of interest were investigated, the patient group showed enhanced BOLD responses in dorsal and ventral areas before treatment. This increase was correlated with performance across all participants and with attention deficit/hyperactivity disorder symptoms in the patient group. Furthermore, we found an effect of treatment in the right superior frontal gyrus, with methylphenidate-treated patients exhibiting increased activation, which was absent in the placebo-treated patients. Our results indicate distinct activation differences between untreated adult attention deficit/hyperactivity disorder patients and matched healthy controls during a working memory task. These differences might reflect compensatory efforts by the patients, who are performing at the same level as the healthy controls. We furthermore found a positive effect of methylphenidate on the activation of a frontal region of interest. These observations contribute to a more thorough understanding of adult attention deficit/hyperactivity disorder and provide impulses for the evaluation of therapy-related changes. © The Author 2016. Published by Oxford University Press on behalf

The effect of methylphenidate on very low frequency electroencephalography oscillations in adult ADHD.

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Cooper, Ruth E; Skirrow, Caroline; Tye, Charlotte; McLoughlin, Grainne; Rijsdijk, Fruhling; Banaschweski, Tobias; Brandeis, Daniel; Kuntsi, Jonna; Asherson, Philip

2014-04-01

Altered very low-frequency electroencephalographic (VLF-EEG) activity is an endophenotype of ADHD in children and adolescents. We investigated VLF-EEG case-control differences in adult samples and the effects of methylphenidate (MPH). A longitudinal case-control study was conducted examining the effects of MPH on VLF-EEG (.02-0.2Hz) during a cued continuous performance task. 41 untreated adults with ADHD and 47 controls were assessed, and 21 cases followed up after MPH treatment, with a similar follow-up for 38 controls (mean follow-up=9.4months). Cases had enhanced frontal and parietal VLF-EEG and increased omission errors. In the whole sample, increased parietal VLF-EEG correlated with increased omission errors. After controlling for subthreshold comorbid symptoms, VLF-EEG case-control differences and treatment effects remained. Post-treatment, a time by group interaction emerged; VLF-EEG and omission errors reduced to the same level as controls, with decreased inattentive symptoms in cases. Reduced VLF-EEG following MPH treatment provides preliminary evidence that changes in VLF-EEG may relate to MPH treatment effects on ADHD symptoms; and that VLF-EEG may be an intermediate phenotype of ADHD. Further studies of the treatment effect of MPH in larger controlled studies are required to formally evaluate any causal link between MPH, VLF-EEG and ADHD symptoms. Copyright © 2014 Elsevier Inc. All rights reserved.

Serum brain-derived neurotrophic factor levels in treatment-naïve boys with attention-deficit/hyperactivity disorder treated with methylphenidate: an 8-week, observational pretest-posttest study.

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Akay, Aynur Pekcanlar; Resmi, Halil; Güney, Sevay Alsen; Erkuran, Handan Özek; Özyurt, Gonca; Sargin, Enis; Topuzoglu, Ahmet; Tufan, Ali Evren

2018-01-01

Brain-derived neurotrophic factor (BDNF) is an important neurotrophin in the brain that modulates dopaminergic neurons. In this study, we aimed to investigate the changes in serum BDNF levels of children with attention-deficit/hyperactivity disorder (ADHD) in response to OROS methylphenidate treatment. We also aimed to determine whether there were any pre-post-differences between ADHD subtypes and comorbid psychiatric disorders in serum BDNF levels. Fifty male children with ADHD and 50 male healthy controls within the age range of 6-12 years were recruited to the study. The psychiatric diagnoses were determined by applying a structured interview with Kiddie schedule for affective disorders and schizophrenia for school-age children-present and lifetime version. The symptom severity of ADHD was measured using the Clinical Global Impression ADHD Severity Scale (CGI-S). Physicians completed Du Paul ADHD questionnaires. The levels of serum BDNF were assessed before and after 8 weeks of treatment with effective dosages of OROS methylphenidate. In the present study, the mean serum BDNF levels of boys with ADHD and of the healthy controls were 2626.33 ± 1528.05 and 2989.11 ± 1420.08 pg/mL, respectively. Although there were no statistically significant difference between the ADHD group and healthy controls at baseline (p = 0.22), the increase of serum BDNF was statistically significant from baseline to endpoint in the ADHD group (p = 0.04). The mean serum BDNF levels at baseline and endpoint of the ADHD group were 2626.33 ± 1528.05 and 3255.80 ± 1908.79 pg/mL, respectively. The serum BDNF levels of ADHD-inattentive subtype were significantly lower at baseline (p = 0.02), whereas BDNF levels post-treatment showed no significant difference. The increase of serum BDNF levels with methylphenidate treatment after 8 weeks was significantly higher in the inattentive group (p = 0.005). The increase of serum BDNF levels with methylphenidate treatment after 8

Association Between 5-HTTLPR Polymorphism and Tics after Treatment with Methylphenidate in Korean Children with Attention-Deficit/Hyperactivity Disorder.

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Park, Seo Yeon; Kim, Eun Joo; Cheon, Keun-Ah

2015-10-01

The purpose of this study is to examine the relationship between 5-HTTLPR polymorphism (44-bp insertion/deletion polymorphism of serotonin transporter gene) and methylphenidate (MPH) treatment response, as well as the association between the adverse events of MPH treatment and 5-HTTLPR polymorphism in children with attention-deficit/hyperactivity disorder (ADHD). A total of 114 children with ADHD (mean age 9.08 ± 1.94 years) were recruited from the child psychiatric clinic in a hospital in South Korea. We have extracted the genomic DNA of the subjects from their blood lymphocytes and analyzed 5-HTTLPR polymorphism of the SLC6A4 gene. All children were treated with MPH for 8 weeks, with clinicians monitoring both the improvement of ADHD symptoms and the side effects. We compared the response to MPH treatment and adverse events among those with the genotype of 5-HRRLPR polymorphism. There was no significant association between the 5-HTTLPR genotype and the response to MPH treatment in children with ADHD. Subjects with the S/L+L/L genotype tended to have tics and nail biting (respectively, p tics and nail-biting as an adverse event of methylphenidate. This may aid in our understanding of the genetic contribution and genetic susceptibility of a particular allele in those ADHD patients with tics or nail biting.

Effects of Methylphenidate and Behavior Modification on the Social and Academic Behavior of Children with Disruptive Behavior Disorders: The Moderating Role of Callous/Unemotional Traits

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Waschbusch, Daniel A.; Carrey, Normand J.; Willoughby, Michael T.; King, Sara; Andrade, Brendan F.

2007-01-01

This study examined whether response to behavior modification with and without methylphenidate differed for children with attention-deficit/hyperactivity disorder (ADHD) and conduct problems (CP) depending on the presence of callous/unemotional (CU) traits. Participants were 37 children ages 7 to 12, including 19 with ADHD/CP-only and 18 with…

Extinction memory is facilitated by methylphenidate and regulated by dopamine and noradrenaline receptors.

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Furini, Cristiane R G; Behling, Jonny A K; Zinn, Carolina G; Zanini, Mara Lise; Assis Brasil, Eduardo; Pereira, Luiza Doro; Izquierdo, Ivan; de Carvalho Myskiw, Jociane

2017-05-30

Extinction is defined as the learned inhibition of retrieval and is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear disorders. The psychostimulant, methylphenidate (MPH) is known to increase extracellular levels of noradrenaline and dopamine by blocking their reuptake and studies have demonstrated that MPH can modulate hippocampal physiology and/or functions including long-term potentiation (LTP), learning and memory. However, the influence of MPH on fear extinction memory has been insufficiently studied. Here we investigate the effect of MPH infused into the CA1 region of the hippocampus on extinction memory in animals normally incapable of showing contextual fear conditioning (CFC) extinction because of weak training, and the possible mechanisms through which it acts during this process. For this, male Wistar rats with infusion cannulae stereotaxically implanted in the CA1 region were submitted to a weak extinction protocol in a CFC apparatus. Animals that received intra-CA1 infusion of MPH (12.5μg/side) 20min before the extinction training (Ext Tr) expressed less freezing behavior than Veh-treated animals during both Ext Tr and extinction retention Test (Ext Test). Additionally, the administration of MPH+Timolol (1μg/side) or MPH+SCH23390 (1.5μg/side) intra-CA1 20min before the Ext Tr blocked the enhancing effect of the MPH on extinction learning. These results suggest that MPH in the CA1 region of the hippocampus is able to induce the consolidation of extinction memory and this process occurs through both β-adrenergic and D1/D5 dopaminergic receptors. Copyright © 2017 Elsevier B.V. All rights reserved.

Adverse pregnancy outcomes after exposure to methylphenidate or atomoxetine during pregnancy

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Bro SP

2015-01-01

Full Text Available Søren Pauli Bro,1 Maiken Ina Siegismund Kjaersgaard,2 Erik Thorlund Parner,2 Merete Juul Sørensen,3 Jørn Olsen,4 Bodil Hammer Bech,4 Lars Henning Pedersen,4,5 Jakob Christensen,6,7 Mogens Vestergaard11Research Unit and Section for General Practice, Department of Public Health, 2Section for Biostatistics, Department of Public Health, Aarhus University, 3Regional Center for Child and Adolescent Psychiatry, Aarhus University Hospital, 4Section for Epidemiology, Department of Public Health, 5Department of Clinical Medicine – Obstetrics and Gynecology, Aarhus University, 6Department of Clinical Pharmacology, 7Department of Neurology, Aarhus University Hospital, Aarhus, DenmarkObjective: To determine if prenatal exposure to methylphenidate (MPH or atomoxetine (ATX increases the risk of adverse pregnancy outcomes in women with attention deficit/hyperactivity disorder (ADHD.Materials and methods: This was a population-based cohort study of all pregnancies in Denmark from 1997 to 2008. Information on use of ADHD medication, ADHD diagnosis, and pregnancy outcomes was obtained from nationwide registers.Results: We identified 989,932 pregnancies, in which 186 (0.02% women used MPH/ATX and 275 (0.03% women had been diagnosed with ADHD but who did not take MPH/ATX. Our reference pregnancies had no exposure to MPH/ATX and no ADHD diagnosis. Exposure to MPH/ATX was associated with an increased risk of spontaneous abortion (SA; ie, death of an embryo or fetus in the first 22 weeks of gestation (adjusted relative risk [aRR] 1.55, 95% confidence interval [CI] 1.03–2.36. The risk of SA was also increased in pregnancies where the mother had ADHD but did not use MPH/ATX (aRR 1.56, 95% CI 1.11–2.20. The aRR of Apgar scores <10 was increased among exposed women (aRR 2.06, 95% CI 1.11–3.82 but not among unexposed women with ADHD (aRR 0.99, 95% CI 0.48–2.05.Conclusion: MPH/ATX was associated with a higher risk of SA, but our study indicated that it may at

Electrical Stimulation of the Ventral Tegmental Area Induces Reanimation from General Anesthesia

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Solt, Ken; Van Dort, Christa J.; Chemali, Jessica J.; Taylor, Norman E.; Kenny, Jonathan D.; Brown, Emery N.

2014-01-01

BACKGROUND Methylphenidate or a D1 dopamine receptor agonist induce reanimation (active emergence) from general anesthesia. We tested whether electrical stimulation of dopaminergic nuclei also induces reanimation from general anesthesia. METHODS In adult rats, a bipolar insulated stainless steel electrode was placed in the ventral tegmental area (VTA, n = 5) or substantia nigra (SN, n = 5). After a minimum 7-day recovery period, the isoflurane dose sufficient to maintain loss of righting was established. Electrical stimulation was initiated and increased in intensity every 3 min to a maximum of 120μA. If stimulation restored the righting reflex, an additional experiment was performed at least 3 days later during continuous propofol anesthesia. Histological analysis was conducted to identify the location of the electrode tip. In separate experiments, stimulation was performed in the prone position during general anesthesia with isoflurane or propofol, and the electroencephalogram was recorded. RESULTS To maintain loss of righting, the dose of isoflurane was 0.9% ± 0.1 vol%, and the target plasma dose of propofol was 4.4 μg/ml ± 1.1 μg/ml (mean ± SD). In all rats with VTA electrodes, electrical stimulation induced a graded arousal response including righting that increased with current intensity. VTA stimulation induced a shift in electroencephalogram peak power from δ (anesthesia with isoflurane or propofol. These results are consistent with the hypothesis that dopamine release by VTA, but not SN, neurons induces reanimation from general anesthesia. PMID:24398816

Pro-inflammatory activated Kupffer cells by lipids induce hepatic NKT cells deficiency through activation-induced cell death.

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Tongfang Tang

Full Text Available BACKGROUND: Dietary lipids play an important role in the progression of non-alcoholic fatty liver disease (NAFLD through alternation of liver innate immune response. AIMS: The present study was to investigate the effect of lipid on Kupffer cells phenotype and function in vivo and in vitro. And further to investigate the impact of lipid on ability of Kupffer cell lipid antigen presentation to activate NKT cells. METHODS: Wild type male C57BL/6 mice were fed either normal or high-fat diet. Hepatic steatosis, Kupffer cell abundance, NKT cell number and cytokine gene expression were evaluated. Antigen presentation assay was performed with Kupffer cells treated with certain fatty acids in vitro and co-cultured with NKT cells. RESULTS: High-fat diet induced hepatosteatosis, significantly increased Kupffer cells and decreased hepatic NKT cells. Lipid treatment in vivo or in vitro induced increase of pro-inflammatory cytokines gene expression and toll-like receptor 4 (TLR4 expression in Kupffer cells. Kupffer cells expressed high levels of CD1d on cell surface and only presented exogenous lipid antigen to activate NKT cells. Ability of Kupffer cells to present antigen and activate NKT cells was enhanced after lipid treatment. In addition, pro-inflammatory activated Kupffer cells by lipid treatment induced hepatic NKT cells activation-induced apoptosis and necrosis. CONCLUSION: High-fat diet increase Kupffer cells number and induce their pro-inflammatory status. Pro-inflammatory activated Kupfffer cells by lipid promote hepatic NKT cell over-activation and cell death, which lead to further hepatic NKT cell deficiency in the development of NAFLD.

Pro-inflammatory activated Kupffer cells by lipids induce hepatic NKT cells deficiency through activation-induced cell death.

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Tang, Tongfang; Sui, Yongheng; Lian, Min; Li, Zhiping; Hua, Jing

2013-01-01

Dietary lipids play an important role in the progression of non-alcoholic fatty liver disease (NAFLD) through alternation of liver innate immune response. The present study was to investigate the effect of lipid on Kupffer cells phenotype and function in vivo and in vitro. And further to investigate the impact of lipid on ability of Kupffer cell lipid antigen presentation to activate NKT cells. Wild type male C57BL/6 mice were fed either normal or high-fat diet. Hepatic steatosis, Kupffer cell abundance, NKT cell number and cytokine gene expression were evaluated. Antigen presentation assay was performed with Kupffer cells treated with certain fatty acids in vitro and co-cultured with NKT cells. High-fat diet induced hepatosteatosis, significantly increased Kupffer cells and decreased hepatic NKT cells. Lipid treatment in vivo or in vitro induced increase of pro-inflammatory cytokines gene expression and toll-like receptor 4 (TLR4) expression in Kupffer cells. Kupffer cells expressed high levels of CD1d on cell surface and only presented exogenous lipid antigen to activate NKT cells. Ability of Kupffer cells to present antigen and activate NKT cells was enhanced after lipid treatment. In addition, pro-inflammatory activated Kupffer cells by lipid treatment induced hepatic NKT cells activation-induced apoptosis and necrosis. High-fat diet increase Kupffer cells number and induce their pro-inflammatory status. Pro-inflammatory activated Kupfffer cells by lipid promote hepatic NKT cell over-activation and cell death, which lead to further hepatic NKT cell deficiency in the development of NAFLD.

Does switching from oral extended-release methylphenidate to the methylphenidate transdermal system affect health-related quality-of-life and medication satisfaction for children with attention-deficit/hyperactivity disorder?

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Landgraf Jeanne M

2009-12-01

Full Text Available Abstract Background To evaluate health-related quality of life (HRQL and medication satisfaction after switching from a stable dose of oral extended-release methylphenidate (ER-MPH to methylphenidate transdermal system (MTS via a dose-transition schedule in children with attention-deficit/hyperactivity disorder (ADHD. Methods In a 4-week, multisite, open-label study, 171 children (164 in the intent-to-treat [ITT] population aged 6-12 years diagnosed with ADHD abruptly switched from a stable dose of oral ER-MPH to MTS nominal dosages of 10, 15, 20, and 30 mg using a predefined dose-transition schedule. Subjects remained on the scheduled dose for the first week, after which the dose was then titrated to an optimal effect. The ADHD Impact Module-Children (AIM-C, a disease-specific validated HRQL survey instrument measuring child and family impact, was used to assess the impact of ADHD symptoms on the lives of children and their families at baseline and study endpoint. Satisfaction with MTS use was assessed via a Medication Satisfaction Survey (MSS at study endpoint. Both the AIM-C and MSS were completed by a caregiver (parent/legally authorized representative. Tolerability was monitored by spontaneous adverse event (AE reporting. Results AIM-C child and family HRQL mean scores were above the median possible score at baseline and were further improved at endpoint across all MTS doses. Similar improvements were noted for behavior, missed doses, worry, and economic impact AIM-C item scores. Overall, 93.8% of caregivers indicated a high level of satisfaction with their child's use of the study medication. The majority of treatment-emergent AEs (> 98% were mild to moderate in intensity, and the most commonly reported AEs included headache, decreased appetite, insomnia, and abdominal pain. Seven subjects discontinued the study due to intolerable AEs (n = 3 and application site reactions (n = 4. Conclusion This study demonstrates that MTS, when carefully

Ventricular fibrillation cardiac arrest produces a chronic striatal hyperdopaminergic state that is worsened by methylphenidate treatment.

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Nora, Gerald J; Harun, Rashed; Fine, David F; Hutchison, Daniel; Grobart, Adam C; Stezoski, Jason P; Munoz, Miranda J; Kochanek, Patrick M; Leak, Rehana K; Drabek, Tomas; Wagner, Amy K

2017-07-01

Cardiac arrest survival rates have improved with modern resuscitation techniques, but many survivors experience impairments associated with hypoxic-ischemic brain injury (HIBI). Currently, little is understood about chronic changes in striatal dopamine (DA) systems after HIBI. Given the common empiric clinical use of DA enhancing agents in neurorehabilitation, investigation evaluating dopaminergic alterations after cardiac arrest (CA) is necessary to optimize rehabilitation approaches. We hypothesized that striatal DA neurotransmission would be altered chronically after ventricular fibrillation cardiac arrest (VF-CA). Fast-scan cyclic voltammetry was used with median forebrain bundle (MFB) maximal electrical stimulations (60Hz, 10s) in rats to characterize presynaptic components of DA neurotransmission in the dorsal striatum (D-Str) and nucleus accumbens 14 days after a 5-min VF-CA when compared to Sham or Naïve. VF-CA increased D-Str-evoked overflow [DA], total [DA] released, and initial DA release rate versus controls, despite also increasing maximal velocity of DA reuptake (V max ). Methylphenidate (10 mg/kg), a DA transporter inhibitor, was administered to VF-CA and Shams after establishing a baseline, pre-drug 60 Hz, 5 s stimulation response. Methylphenidate increased initial evoked overflow [DA] more-so in VF-CA versus Sham and reduced D-Str V max in VF-CA but not Shams; these findings are consistent with upregulated striatal DA transporter in VF-CA versus Sham. Our work demonstrates that 5-min VF-CA increases electrically stimulated DA release with concomitant upregulation of DA reuptake 2 weeks after brief VF-CA insult. Future work should elucidate how CA insult duration, time after insult, and insult type influence striatal DA neurotransmission and related cognitive and motor functions. © 2017 International Society for Neurochemistry.

Effect of methylphenidate on the quality of life in children with epilepsy and attention deficit hyperactivity disorder: and open-label study using an osmotic-controlled release oral delivery system.

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Yoo, Hanik K; Park, Subin; Wang, Hee-Ryung; Lee, Joong Sun; Kim, Kunwoo; Paik, Kyoung-Won; Yum, Mi Sun; Ko, Tae-Sung

2009-12-01

This open study explored whether methylphenidate could be tolerated and effective in improving the quality of life (QOL) and attention deficit hyperactivity disorder (ADHD) symptoms of children with epilepsy and ADHD. Twenty-five subjects (aged 10.1 +/- 3.0 years) with ADHD and epilepsy were recruited at an outpatient clinic in Seoul, Korea. We used the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE), ADHD rating scale (ARS) and clinical global impression (CGI) in this study. Osmotic-controlled release oral delivery system (OROS) methylphenidate, 1.0 +/- 0.4 mg/kg/day, was administered for 55.2 +/- 7.5 days. The QOL subscales including physical restriction (p = 0.005), self-esteem (p = 0.002), memory (p < 0.001), language (p = 0.005), other cognition (p < 0.001), social interaction (p = 0.002), behaviour (p < 0.001), general health (p = 0.002) and QOL (p < 0.001) were significantly increased and the ARS (p < 0.001) and CGI-Severity of illness scores (p < 0.001) were significantly reduced after medication. Although 60% of subjects had experienced adverse effects, most were tolerable and only two subjects withdrew from the study owing to unbearable adverse effects (anorexia and insomnia). Two subjects had seizure attacks during the study period without having to discontinue the trial drug. Despite limitations related to the small sample size and the open design of the present pilot study, our results suggest that OROS methylphenidate may be well tolerated and effective in reducing ADHD symptoms and improving QOL in this patient population.

Distribution of induced activity in tungsten targets

International Nuclear Information System (INIS)

Donahue, R.J.; Nelson, W.R.

1988-09-01

Estimates are made of the induced activity created during high-energy electron showers in tungsten, using the EGS4 code. Photon track lengths, neutron yields and spatial profiles of the induced activity are presented. 8 refs., 9 figs., 1 tab

Changes of Heart Rate Variability during Methylphenidate Treatment in Attention-Deficit Hyperactivity Disorder Children: A 12-Week Prospective Study.

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Kim, Hayeon Jennifer; Yang, Jaewon; Lee, Moon Soo

2015-09-01

The aim of this study was to clarify the relationship between the autonomic nervous system and attention deficit hyperactivity disorder (ADHD) rating scales and to evaluate the usefulness of heart rate variability (HRV) as a psychophysiological biomarker for ADHD. Subjects were recruited from outpatients in the Department of Child and Adolescent Psychiatry at the Korea University Medical Center from August 2007 to December 2010. Subjects received methylphenidate. Time- and frequency-domain analyses of HRV, the Korean ADHD rating scale (K-ARS), and computerized ADHD diagnostic system were evaluated before treatment. After a 12-week period of medication administration, we repeated the HRV measurements and K-ARS rating. Eighty-six subjects were initially enrolled and 37 participants completed the 12-week treatment and HRV measurements subsequent to the treatment. Significant correlations were found between the K-ARS inattention score and some HRV parameters. All of the HRV parameters, except the standard deviations of the normal-to-normal interval, very low frequency, and low frequency to high frequency, showed a significant positive correlation between baseline and endpoint measures in completers. High frequency (HF) and the square root of the mean squared differences of successive normal-to-normal intervals (RMSSD), which are related to parasympathetic vagal tone, showed significant decreases from baseline to endpoint. The HRV test was shown to be reproducible. The decrease in HF and RMSSD suggests that parasympathetic dominance in ADHD can be altered by methylphenidate treatment. It also shows the possibility that HRV parameters can be used as psychophysiological markers in the treatment of ADHD.

Norepinephrine genes predict response time variability and methylphenidate-induced changes in neuropsychological function in attention deficit hyperactivity disorder.

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Kim, Bung-Nyun; Kim, Jae-Won; Cummins, Tarrant D R; Bellgrove, Mark A; Hawi, Ziarih; Hong, Soon-Beom; Yang, Young-Hui; Kim, Hyo-Jin; Shin, Min-Sup; Cho, Soo-Churl; Kim, Ji-Hoon; Son, Jung-Woo; Shin, Yun-Mi; Chung, Un-Sun; Han, Doug-Hyun

2013-06-01

Noradrenergic dysfunction may be associated with cognitive impairments in attention-deficit/hyperactivity disorder (ADHD), including increased response time variability, which has been proposed as a leading endophenotype for ADHD. The aim of this study was to examine the relationship between polymorphisms in the α-2A-adrenergic receptor (ADRA2A) and norepinephrine transporter (SLC6A2) genes and attentional performance in ADHD children before and after pharmacological treatment.One hundred one medication-naive ADHD children were included. All subjects were administered methylphenidate (MPH)-OROS for 12 weeks. The subjects underwent a computerized comprehensive attention test to measure the response time variability at baseline before MPH treatment and after 12 weeks. Additive regression analyses controlling for ADHD symptom severity, age, sex, IQ, and final dose of MPH examined the association between response time variability on the comprehensive attention test measures and allelic variations in single-nucleotide polymorphisms of the ADRA2A and SLC6A2 before and after MPH treatment.Increasing possession of an A allele at the G1287A polymorphism of SLC6A2 was significantly related to heightened response time variability at baseline in the sustained (P = 2.0 × 10) and auditory selective attention (P = 1.0 × 10) tasks. Response time variability at baseline increased additively with possession of the T allele at the DraI polymorphism of the ADRA2A gene in the auditory selective attention task (P = 2.0 × 10). After medication, increasing possession of a G allele at the MspI polymorphism of the ADRA2A gene was associated with increased MPH-related change in response time variability in the flanker task (P = 1.0 × 10).Our study suggested an association between norepinephrine gene variants and response time variability measured at baseline and after MPH treatment in children with ADHD. Our results add to a growing body of evidence, suggesting that response time

Age-dependent effects of acute methylphenidate on amygdala reactivity in stimulant treatment-naive patients with Attention Deficit/Hyperactivity Disorder.

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Bottelier, Marco A; Schrantee, Anouk; Ferguson, Bart; Tamminga, Hyke G H; Bouziane, Cheima; Kooij, J J Sandra; de Ruiter, Michiel B; Reneman, Liesbeth

2017-11-30

In the present study, we investigate whether methylphenidate (MPH) affects emotional processing and whether this effect is modulated by age. We measured amygdala reactivity with functional Magnetic Resonance Imaging (fMRI) during processing of angry and fearful facial expressions in male stimulant treatment-naive patients with ADHD (N = 35 boys; N = 46 men) and 23 healthy control subjects (N = 11 boys; N = 12 men). In ADHD patients, we also measured amygdala reactivity 90min after an acute oral challenge with MPH (0.5mg/kg). Mean amygdala reactivity was analyzed for all subjects using a repeated measures analysis of variance (ANOVA). Whole-brain maps were analyzed for the patients only. At baseline, we found a age*diagnosis effect approaching significance (p = 0.05) in the right amygdala due to lower reactivity in children with Attention Deficit/Hyperactivity Disorder (ADHD) vs. controls (-31%), but higher reactivity in adults with ADHD vs. controls (+31%). MPH significantly reduced right amygdala reactivity in all patients, resulting in further reductions in children. In the left amygdala, reduction of amygdala reactivity was confined to adult ADHD patients whereas there was no change in children with ADHD. MPH-induced decrease of amygdala reactivity in adults might be a promising avenue for managing emotional dysregulation when replicated for chronic MPH treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Additional biological therapies for attention-deficit hyperactivity disorder: repetitive transcranical magnetic stimulation of 1 Hz helps to reduce methylphenidate

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Helmut Niederhofer

2011-12-01

Full Text Available Excessive hyperactivity, impulsiveness and attentional difficulties characterize attentiondeficit hyperactivity disorder (ADHD. The aim of this case report is to signal the possible therapeutic effectiveness of the repetitive transcranial magnetic stimulation (rTMS. Low frequency (1Hz, 1200 stim/die for five days was applied on the impending scalp in the motor additional area of a patient suffering from combined type ADHD who received methylphenidate (MPH. We saw a significant improvement, especially according to criteria associated with hyperactivity. The improvement lasted for at least three weeks and suggested the final reduction in dosage of MPH.to 10 mg.

Enhanced stimulus-induced gamma activity in humans during propofol-induced sedation.

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Neeraj Saxena

Full Text Available Stimulus-induced gamma oscillations in the 30-80 Hz range have been implicated in a wide number of functions including visual processing, memory and attention. While occipital gamma-band oscillations can be pharmacologically modified in animal preparations, pharmacological modulation of stimulus-induced visual gamma oscillations has yet to be demonstrated in non-invasive human recordings. Here, in fifteen healthy humans volunteers, we probed the effects of the GABAA agonist and sedative propofol on stimulus-related gamma activity recorded with magnetoencephalography, using a simple visual grating stimulus designed to elicit gamma oscillations in the primary visual cortex. During propofol sedation as compared to the normal awake state, a significant 60% increase in stimulus-induced gamma amplitude was seen together with a 94% enhancement of stimulus-induced alpha suppression and a simultaneous reduction in the amplitude of the pattern-onset evoked response. These data demonstrate, that propofol-induced sedation is accompanied by increased stimulus-induced gamma activity providing a potential window into mechanisms of gamma-oscillation generation in humans.

Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

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Meng, Zhen [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China)

2015-05-01

Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.

Distúrbio do déficit de atenção: tratamento com metilfenidato Attention deficit disorder: treatment with methylphenidate

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Marilisa M. Guerreiro

1996-03-01

Full Text Available Os autores apresentam os resultados do tratamento com metilfenidato usado em 24 crianças com diagnóstico de distúrbio do déficit de atenção realizado com base nos critérios expostos no DSM-III. A dose utilizada foi de 5 a 10 mg ao dia, dividida em uma ou duas tomadas. Resposta satisfatória ao tratamento foi encontrada em 79,1% dos pacientes e insatisfatória em 16,6%. Em um caso o resultado não pode ser avaliado pela necessidade de interrupção precoce do tratamento. Efeitos colaterais ocorreram em duas crianças (cefaléia e/ou náusea. Os resultados terapêuticos e os efeitos colaterais indesejáveis são comparados com os da literatura, ressaltando-se a eficácia e a segurança do tratamento com metilfenidato .The authors present the results of the treatment with methylphenidate in 24 children with attention deficit disorder based on DSM-III. The prescribed dose was 5 to 10 mg per day, once or twice a day. The results were good in 79.1% of the patients and poor in 16.6%. The drug was withdrawn in one patient because of side effects and the evaluation of efficacy was not possible. Side effects occurred in 2 children (headache and/or nausea. The therapeutic response and the side effects are compared with the literature. The authors claim attention to the efficacy and safety of the treatment with methylphenidate.

Activating AMP-activated protein kinase by an α1 selective activator compound 13 attenuates dexamethasone-induced osteoblast cell death

International Nuclear Information System (INIS)

Guo, Shiguang; Mao, Li; Ji, Feng; Wang, Shouguo; Xie, Yue; Fei, Haodong; Wang, Xiao-dong

2016-01-01

Excessive glucocorticoid (GC) usage may lead to non-traumatic femoral head osteonecrosis. Dexamethasone (Dex) exerts cytotoxic effect to cultured osteoblasts. Here, we investigated the potential activity of Compound 13 (C13), a novel α1 selective AMP-activated protein kinase (AMPK) activator, against the process. Our data revealed that C13 pretreatment significantly attenuated Dex-induced apoptosis and necrosis in both osteoblastic-like MC3T3-E1 cells and primary murine osteoblasts. AMPK activation mediated C13′ cytoprotective effect in osteoblasts. The AMPK inhibitor Compound C, shRNA-mediated knockdown of AMPKα1, or dominant negative mutation of AMPKα1 (T172A) almost abolished C13-induced AMPK activation and its pro-survival effect in osteoblasts. On the other hand, forced AMPK activation by adding AMPK activator A-769662 or exogenous expression a constitutively-active (ca) AMPKα1 (T172D) mimicked C13's actions and inhibited Dex-induced osteoblast cell death. Meanwhile, A-769662 or ca-AMPKα1 almost nullified C13's activity in osteoblast. Further studies showed that C13 activated AMPK-dependent nicotinamide adenine dinucleotide phosphate (NADPH) pathway to inhibit Dex-induced reactive oxygen species (ROS) production in MC3T3-E1 cells and primary murine osteoblasts. Such effects by C13 were almost reversed by Compound C or AMPKα1 depletion/mutation. Together, these results suggest that C13 alleviates Dex-induced osteoblast cell death via activating AMPK signaling pathway. - Highlights: • Compound 13 (C13) attenuates dexamethasone (Dex)-induced osteoblast cell death. • C13-induced cytoprotective effect against Dex in osteoblasts requires AMPK activation. • Forced AMPK activation protects osteoblasts from Dex, nullifying C13's activities. • C13 increases NADPH activity and inhibits Dex-induced oxidative stress in osteoblasts.

Activating AMP-activated protein kinase by an α1 selective activator compound 13 attenuates dexamethasone-induced osteoblast cell death

Energy Technology Data Exchange (ETDEWEB)

Guo, Shiguang [Department of Intensive Care Unit, Huai' an First People' s Hospital, Nanjing Medical University, Huai' an (China); Mao, Li [Department of Endocrinology, Huai' an First People' s Hospital, Nanjing Medical University, Huai' an (China); Ji, Feng, E-mail: huaiaifengjidr@163.com [Department of Orthopedics, Huai' an First People' s Hospital, Nanjing Medical University, Huai' an (China); Wang, Shouguo; Xie, Yue; Fei, Haodong [Department of Orthopedics, Huai' an First People' s Hospital, Nanjing Medical University, Huai' an (China); Wang, Xiao-dong, E-mail: xiaodongwangsz@163.com [The Center of Diagnosis and Treatment for Children' s Bone Diseases, The Children' s Hospital Affiliated to Soochow University, Suzhou (China)

2016-03-18

Excessive glucocorticoid (GC) usage may lead to non-traumatic femoral head osteonecrosis. Dexamethasone (Dex) exerts cytotoxic effect to cultured osteoblasts. Here, we investigated the potential activity of Compound 13 (C13), a novel α1 selective AMP-activated protein kinase (AMPK) activator, against the process. Our data revealed that C13 pretreatment significantly attenuated Dex-induced apoptosis and necrosis in both osteoblastic-like MC3T3-E1 cells and primary murine osteoblasts. AMPK activation mediated C13′ cytoprotective effect in osteoblasts. The AMPK inhibitor Compound C, shRNA-mediated knockdown of AMPKα1, or dominant negative mutation of AMPKα1 (T172A) almost abolished C13-induced AMPK activation and its pro-survival effect in osteoblasts. On the other hand, forced AMPK activation by adding AMPK activator A-769662 or exogenous expression a constitutively-active (ca) AMPKα1 (T172D) mimicked C13's actions and inhibited Dex-induced osteoblast cell death. Meanwhile, A-769662 or ca-AMPKα1 almost nullified C13's activity in osteoblast. Further studies showed that C13 activated AMPK-dependent nicotinamide adenine dinucleotide phosphate (NADPH) pathway to inhibit Dex-induced reactive oxygen species (ROS) production in MC3T3-E1 cells and primary murine osteoblasts. Such effects by C13 were almost reversed by Compound C or AMPKα1 depletion/mutation. Together, these results suggest that C13 alleviates Dex-induced osteoblast cell death via activating AMPK signaling pathway. - Highlights: • Compound 13 (C13) attenuates dexamethasone (Dex)-induced osteoblast cell death. • C13-induced cytoprotective effect against Dex in osteoblasts requires AMPK activation. • Forced AMPK activation protects osteoblasts from Dex, nullifying C13's activities. • C13 increases NADPH activity and inhibits Dex-induced oxidative stress in osteoblasts.

Population pharmacokinetics of methylphenidate hydrochloride extended-release multiple-layer beads in pediatric subjects with attention deficit hyperactivity disorder

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Teuscher NS

2015-05-01

Full Text Available Nathan S Teuscher,1 Akwete Adjei,2 Robert L Findling,3,4 Laurence L Greenhill,5 Robert J Kupper,2 Sharon Wigal6 1PK/PD Associates, Trophy Club, TX, 2Rhodes Pharmaceuticals L.P., Coventry, RI, 3Department of Psychiatric Services and Research, Kennedy Krieger Institute, Baltimore, MD, 4Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, 5Department of Psychiatry, Division of Child and Adolescent Psychiatry, New York State Psychiatric Institute, Columbia University, New York, NY, 6AVIDA Inc., Newport Beach, CA, USA Abstract: A new multilayer-bead formulation of extended-release methylphenidate hydrochloride (MPH-MLR has been evaluated in pharmacokinetic studies in healthy adults and in Phase III efficacy/safety studies in children and adolescents with attention deficit hyperactivity disorder (ADHD. Using available data in healthy adults, a two-input, one-compartment, first-order elimination population pharmacokinetic model was developed using nonlinear mixed-effect modeling. The model was then extended to pediatric subjects, and was found to adequately describe plasma concentration–time data for this population. A pharmacokinetic/pharmacodynamic model was also developed using change from baseline in the ADHD Rating Scale (ADHD-RS-IV total scores from a pediatric Phase III trial and simulated plasma concentration–time data. During simulations for each MPH-MLR dose level (10–80 mg, increased body weight resulted in decreased maximum concentration. Additionally, as maximum concentration increased, ADHD-RS-IV total score improved (decreased. Knowledge of the relationship between dose, body weight, and clinical response following the administration of MPH-MLR in children and adolescents may be useful for clinicians selecting initial dosing of MPH-MLR. Additional study is needed to confirm these results. Keywords: population pharmacokinetics, Aptensio XR™, MPH-MLR, methylphenidate

A multicenter, open-label trial to evaluate the quality of life in adults with ADHD treated with long-acting methylphenidate (OROS MPH): Concerta Quality of Life (CONQoL) study.

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Mattos, Paulo; Louzã, Mário Rodrigues; Palmini, André Luís Fernandes; de Oliveira, Irismar Reis; Rocha, Fábio Lopes

2013-07-01

The available literature provides few studies on the effectiveness of methylphenidate in improving quality of life in individuals with ADHD. To assess the effectiveness of methylphenidate OROS formulation (OROS MPH) through QoL in adults with ADHD. A 12-week, multicenter, open-label trial involving 60 patients was used. The measures used were Adult Self-Rating Scale, Adult ADHD Quality of Life Scale (AAQoL), State and Trait Anxiety Inventory (STAI), Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression (CGI), and safety measures. A significance statistic level of 5% was adopted. Analyses included 60 patients (66.7% male; M age = 31.1 years) for safety and 58 patients for effectiveness. All AAQoL subscales improved from baseline to Week 12 (p < .0001), as well as the Total AAQoL (p < .0001). A significant reduction on Clinical Global Impression-Improvement (CGI-I), HAM-D, STAI, and ASRS scores was observed (p < .0001). No serious adverse event was reported. Treatment of adult ADHD patients with OROS MPH improves QoL.

Effects of scallop shell extract on scopolamine-induced memory impairment and MK801-induced locomotor activity.

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Hasegawa, Yasushi; Inoue, Tatsuro; Kawaminami, Satoshi; Fujita, Miho

2016-07-01

To evaluate the neuroprotective effects of the organic components of scallop shells (scallop shell extract) on memory impairment and locomotor activity induced by scopolamine or 5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine (MK801). Effect of the scallop shell extract on memory impairment and locomotor activity was investigated using the Y-maze test, the Morris water maze test, and the open field test. Scallop shell extract significantly reduced scopolamine-induced short-term memory impairment and partially reduced scopolamine-induced spatial memory impairment in the Morris water maze test. Scallop shell extract suppressed scopolamine-induced elevation of acetylcholine esterase activity in the cerebral cortex. Treatment with scallop shell extract reversed the increase in locomotor activity induced by scopolamine. Scallop shell extract also suppressed the increase in locomotor activity induced by MK801. Our results provide initial evidence that scallop shell extract reduces scopolamine-induced memory impairment and suppresses MK-801-induced hyperlocomotion. Copyright © 2016 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

Transdermal and oral dl-methylphenidate-ethanol interactions in C57BL/6J mice: transesterification to ethylphenidate and elevation of d-methylphenidate concentrations.

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Bell, Guinevere H; Novak, Andrew J; Griffin, William C; Patrick, Kennerly S

2011-07-01

We tested the hypothesis that C57BL/6J mice will model human metabolic interactions between dl-methylphenidate (MPH) and ethanol, placing an emphasis on the MPH transdermal system (MTS). Specifically, we asked: (1) will ethanol increase d-MPH biological concentrations, (2) will MTS facilitate the systemic bioavailability of l-MPH, and (3) will l-MPH enantioselectively interact with ethanol to yield l-ethylphenidate (l-EPH)? Mice were dosed with MTS (¼ of a 12.5 cm(2) patch on shaved skin) or a comparable oral dl-MPH dose (7.5 mg/kg), with or without ethanol (3.0 g/kg), and then placed in metabolic cages for 3 h. MPH and EPH isomer concentrations in blood, brain, and urine were analyzed by gas chromatographic-mass spectrometry monitoring of N-(S)-prolylpiperidyl fragments. As in humans, MTS greatly facilitated the absorption of l-MPH in this mouse strain. Similarly, ethanol led to the enantioselective formation of l-EPH and to an elevation in d-MPH concentrations with both MTS and oral MPH. Although only guarded comparisons between MTS and oral MPH can be made due to route-dependent drug absorption rate differences, MTS was associated with significant MPH-ethanol interactions. Ethanol-mediated increases in circulating concentrations of d-MPH carry toxicological and abuse liability implications should this animal model hold for ethanol-consuming attention-deficit hyperactivity disorder patients or coabusers. Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association

Evidence That Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain

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Volkow, N.D.; Fowler, J.; Volkow, N.D.; Tomasi, D.; Wang, G.-J.; Fowler, J.S.; Logan, J.; Benveniste, H.; Kin, R.; Thanos, P.K.; Sergi, F.

2012-01-01

Dopamine D2 receptors are involved with wakefulness, but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [ 11 C]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([ 11 C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [ 11 C]raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.

Shock-induced electrical activity in polymeric solids. A mechanically induced bond scission model

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Graham, R.A.

1979-01-01

When polymeric solids are subjected to high-pressure shock loading, two anomalous electrical phenomena, shock-induced conduction and shock-induced polarization, are observed. The present paper proposes a model of mechanically induced bond scission within the shock front to account for the effects. An experimental study of shock-induced polarization in poly(pyromellitimide) (Vespel SP-1) is reported for shock compressions from 17 to 23% (pressures from 2.5 to 5.4 GPa). Poly(pyromellitimide) is found to be a strong generator of such polarization and the polarization is found to reflect an irreversible or highly hysteretic process. The present measurements are combined with prior measurements to establish a correlation between monomer structure and strength of shock-induced polarization; feeble signals are observed in the simpler monomer repeat units of poly(tetrafluoroethylene) and polyethylene while the strongest signals are observed in more complex monomers of poly(methyl methacrylate) and poly(pyromellitimide). It is also noted that there is an apparent correlation between shock-induced conduction and shock-induced polarization. Such shock-induced electrical activity is also found to be well correlated with the propensity for mechanical bond scission observed in experiments carried out in conventional mechanochemical studies. The bond scission model can account for characteristics observed for electrical activity in shock-loaded polymers and their correlation to monomer structure. Localization of elastic energy within the monomer repeat unit or along the main chain leads to the different propensities for bond scission and resulting shock-induced electrical activity

Methylphenidate treatment in children with attention deficit hyperactivity disorder and comorbid social phobia.

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Golubchik, Pavel; Sever, Jonathan; Weizman, Abraham

2014-07-01

The aim of this study was to assess the response of social phobia (SP) symptoms to methylphenidate (MPH) treatment in children with attention deficit hyperactivity disorder (ADHD). Twenty-one ADHD patients with SP, aged between 8 and 18 years, received 12 weeks of MPH treatment. The severity of SP symptoms were assessed by the Liebowitz Social Anxiety Scale for Children and Adolescents (LSAS-CA), and the severity of ADHD symptoms was assessed by the ADHD Rating Scale at baseline and at endpoint. MPH treatment was associated with a significant decrease in the ADHD Rating Scale scores (P<0.0001) and in the total LSAS-CA scores (P=0.013), as well as the school-related items of LSAS-CA (P=0.011). A significant correlation was found between the reductions in ADHD score and total LSAS-CA score (P=0.038), especially in school-related SP. The improvement in ADHD symptoms because of MPH treatment correlates with a parallel improvement in SP. MPH treatment appears to be safe and effective in ADHD/SP children.

Prediction of methylphenidate treatment outcome in adults with attention-deficit/hyperactivity disorder (ADHD).

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Retz, Wolfgang; Retz-Junginger, Petra

2014-11-01

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent mental disorder of childhood, which often persists in adulthood. Methylphenidate (MPH) is one of the most effective medications to treat ADHD, but also few adult patients show no sufficient response to this drug. In this paper, we give an overview regarding genetic, neuroimaging, clinical and other studies which have tried to reveal the reasons for non-response in adults with ADHD, based on a systematic literature search. Although MPH is a well-established treatment for adults with ADHD, research regarding the prediction of treatment outcome is still limited and has resulted in inconsistent findings. No reliable neurobiological markers of treatment response have been identified so far. Some findings from clinical studies suggest that comorbidity with substance use disorders and personality disorders has an impact on treatment course and outcome. As MPH is widely used in the treatment of adults with ADHD, much more work is needed regarding positive and negative predictors of long-term treatment outcome in order to optimize the pharmacological treatment of adult ADHD patients.

Social isolation induces deficit of latent learning performance in mice: a putative animal model of attention deficit/hyperactivity disorder.

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Ouchi, Hirofumi; Ono, Kazuya; Murakami, Yukihisa; Matsumoto, Kinzo

2013-02-01

Social isolation of rodents (SI) elicits a variety of stress responses such as increased aggressiveness, hyper-locomotion, and reduced susceptibility to pentobarbital. To obtain a better understanding of the relevance of SI-induced behavioral abnormalities to psychiatric disorders, we examined the effect of SI on latent learning as an index of spatial attention, and discussed the availability of SI as an epigenetic model of attention deficit hyperactivity disorder (ADHD). Except in specially stated cases, 4-week-old male mice were housed in a group or socially isolated for 3-70 days before experiments. The animals socially isolated for 1 week or more exhibited spatial attention deficit in the water-finding test. Re-socialized rearing for 5 weeks after 1-week SI failed to attenuate the spatial attention deficit. The effect of SI on spatial attention showed no gender difference or correlation with increased aggressive behavior. Moreover, SI had no effect on cognitive performance elucidated in a modified Y-maze or an object recognition test, but it significantly impaired contextual and conditional fear memory elucidated in the fear-conditioning test. Drugs used for ADHD therapy, methylphenidate (1-10 mg/kg, i.p.) and caffeine (0.5-1 mg/kg, i.p.), improved SI-induced latent learning deficit in a manner reversible with cholinergic but not dopaminergic antagonists. Considering the behavioral features of SI mice together with their susceptibility to ADHD drugs, the present findings suggest that SI provides an epigenetic animal model of ADHD and that central cholinergic systems play a role in the effect of methylphenidate on SI-induced spatial attention deficit. Copyright © 2012 Elsevier B.V. All rights reserved.

The effects of methylphenidate on cognitive performance of healthy male rats

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Claire Louise Rostron

2013-06-01

Full Text Available We aimed to investigate the effects of methylphenidate (MPH in healthy rats on two distinct radial maze tasks which rely on brain structures and neurotransmitters known to be affected by MPH: the Random Foraging Non-Delay Task (RFNDT and the Delay Spatial Win Shift Task (DSWT. Hooded Lister rats were trained to complete either the RFNDT or the DSWT having received oral treatment of either a vehicle or MPH (3.0 mg/kg and 5.0 mg/kg for RFNDT, 3.0 mg/kg for DSWT. We found no effect of MPH on the RFNDT relative to the control group. However, those treated with 5.0 mg/kg MPH did take significantly longer to reach criterion performance than those treated with the 3.0 mg/kg MPH, suggesting some doses of MPH can have detrimental effects. For the DSWT, if MPH was present in both phases, performance did not differ from when it was absent in both phases. However, when present in only one phase there was an increase in errors made, although this only reached significance for when MPH was present only in the test-phase. These data suggest that MPH may have detrimental effects on task performance and can result in state dependent effects in healthy individuals.

Activation of Nrf2 protects against triptolide-induced hepatotoxicity.

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Jia Li

Full Text Available Triptolide, the major active component of Tripterygium wilfordii Hook f. (TWHF, has a wide range of pharmacological activities. However, the toxicities of triptolide, particularly the hepatotoxicity, limit its clinical application. The hepatotoxicity of triptolide has not been well characterized yet. The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2 in triptolide-induced toxicity and whether activation of Nrf2 could protect against triptolide-induced hepatotoxicity. The results showed that triptolide caused oxidative stress and cell damage in HepG2 cells, and these toxic effects could be aggravated by Nrf2 knockdown or be counteracted by overexpression of Nrf2. Treatment with a typical Nrf2 agonist, sulforaphane (SFN, attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. Moreover, the hepatoprotective effect of SFN on triptolide-induced liver injury was associated with the activation of Nrf2 and its downstream targets. Collectively, these results indicate that Nrf2 activation protects against triptolide-induced hepatotoxicity.

Activation of AMP-activated protein kinase by tributyltin induces neuronal cell death

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Nakatsu, Yusuke; Kotake, Yaichiro; Hino, Atsuko; Ohta, Shigeru

2008-01-01

AMP-activated protein kinase (AMPK), a member of the metabolite-sensing protein kinase family, is activated by energy deficiency and is abundantly expressed in neurons. The environmental pollutant, tributyltin chloride (TBT), is a neurotoxin, and has been reported to decrease cellular ATP in some types of cells. Therefore, we investigated whether TBT activates AMPK, and whether its activation contributes to neuronal cell death, using primary cultures of cortical neurons. Cellular ATP levels were decreased 0.5 h after exposure to 500 nM TBT, and the reduction was time-dependent. It was confirmed that most neurons in our culture system express AMPK, and that TBT induced phosphorylation of AMPK. Compound C, an AMPK inhibitor, reduced the neurotoxicity of TBT, suggesting that AMPK is involved in TBT-induced cell death. Next, the downstream target of AMPK activation was investigated. Nitric oxide synthase, p38 phosphorylation and Akt dephosphorylation were not downstream of TBT-induced AMPK activation because these factors were not affected by compound C, but glutamate release was suggested to be controlled by AMPK. Our results suggest that activation of AMPK by TBT causes neuronal death through mediating glutamate release

EGFR Activation and Ultraviolet Light‐Induced Skin Carcinogenesis

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Taghrid B. El-Abaseri

2007-01-01

Full Text Available The epidermal growth factor receptor (EGFR regulates the proliferation of keratinocytes through multiple mechanisms that differ depending on the localization of the cell within the skin. Ultraviolet (UV irradiation, the main etiologic factor in the development of skin cancer, also activates the receptor. In this review, we discuss how the UV-induced activation of EGFR regulates the response of the skin to UV. UV-induced EGFR activation increases keratinocyte proliferation, suppresses apoptosis, and augments and accelerates epidermal hyperplasia in response to UV. Pharmacological inhibition of the UV-induced activation of EGFR in a genetically initiated mouse skin tumorigenesis model suppresses tumorigenesis and the activation of mitogen-activated protein (MAP kinases and phosphatidyl inositol-3-kinase (PI3K/AKT signaling pathways. EGFR has pleiotropic, complex, and cell-type-specific functions in cutaneous keratinocytes; suggesting that the receptor is an appropriate target for the development of molecularly targeted therapies for skin cancer and other pathologies.

Does Methylphenidate Affect Cystometric Parameters in Spontaneously Hypertensive Rats?

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Khae Hawn Kim

2015-06-01

Full Text Available Purpose: Methylphenidate (MPH is one of the most commonly prescribed psychostimulants for attention deficit hyperactivity disorder (ADHD. However, there is limited research on its effects on lower urinary tract function. This study investigated changes in cystometric parameters after intragastric administration of MPH in conscious spontaneously hypertensive rats (SHRs, an animal model of ADHD. Methods: Fourteen- to 16-week-old male SHRs (n=10, weighing between 280 and 315 g, were used. Three micturition cycles were recorded before administering MPH. One hour after each intragastric MPH injection, three cycles of cystometrogram were obtained in the awake condition. Various cystometric parameters were evaluated, including basal pressure (BP, maximal pressure (MP, threshold pressure (TP, bladder capacity (BC, micturition volume (MV, micturition interval (MI, and residual volume (RV. The data were analyzed using paired Student t-tests. Results: Five SHRs were each administered a dose of 3-mg/kg MPH, and the other five received a dose of 6-mg/kg MPH. BP and MP increased significantly in the rats that received the 3-mg/kg MPH injection, but not in those that received the 6-mg/kg injection. BC, MV, and MI significantly increased in the rats that received the 6-mg/kg MPH injection, but not in those that received the 3-mg/kg injection. There were no significant changes in TP after either injection. Conclusions: Significant increases in BC, MV, and MI after the 6-mg/kg MPH injection suggest that the peripheral and the central nervous systems may play important roles in bladder function in those receiving MPH for ADHD.

Evidence That Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain

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Volkow N. D.; Fowler J.; Volkow, N.D.; Tomasi, D.; Wang, G.-J.; Fowler, J.S.; Logan, J.; Benveniste, H.; Kin, R.; Thanos, P.K.; Sergi F.

2012-03-23

Dopamine D2 receptors are involved with wakefulness, but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [{sup 11}C]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([{sup 11}C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [{sup 11}C]raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.

Predictors of pharmacological treatment outcomes with atomoxetine or methylphenidate in patients with attention-deficit/hyperactivity disorder from China, Egypt, Lebanon, Russian Federation, Taiwan, and United Arab Emirates.

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Treuer, T; Feng, Q; Desaiah, D; Altin, M; Wu, S; El-Shafei, A; Serebryakova, E; Gado, M; Faries, D

2014-09-01

The reduced availability of data from non-Western countries limits our ability to understand attention-deficit/hyperactivity disorder (ADHD) treatment outcomes, specifically, adherence and persistence of ADHD in children and adolescents. This analysis assessed predictors of treatment outcomes in a non-Western cohort of patients with ADHD treated with atomoxetine or methylphenidate. Data from a 12-month, prospective, observational study in outpatients aged 6-17 years treated with atomoxetine (N = 234) or methylphenidate (N = 221) were analysed post hoc to determine potential predictors of treatment outcomes. Participating countries included the Russian Federation, China, Taiwan, Egypt, United Arab Emirates and Lebanon. Factors associated with remission were analysed with stepwise multiple logistic regression and classification and regression trees (CART). Cox proportional hazards models with propensity score adjustment assessed differences in atomoxetine persistence among initial-dose cohorts. In patients treated with atomoxetine who had available dosing information (N = 134), Cox proportional hazards revealed lower (atomoxetine-treated patients were associated with age (older), country (United Arab Emirates) and gender (female) (all p atomoxetine) and prior atomoxetine use were associated with greater remission rates. These findings may help clinicians assess factors upon initiation of ADHD treatment to improve course prediction, proper dosing and treatment adherence and persistence. Observational study, therefore no registration. © 2014 John Wiley & Sons Ltd.

Attention deficit/hyperactivity disorder and interictal epileptiform discharges: it is safe to use methylphenidate?

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Socanski, Dobrinko; Aurlien, Dag; Herigstad, Anita; Thomsen, Per Hove; Larsen, Tor Ketil

2015-02-01

This study investigated whether interictal epileptiform discharges (IED) on a baseline routine EEG in children with ADHD was associated with the occurrence of epileptic seizures (Sz) or influenced the use of methylphenidate (MPH) during 2 years follow-up. A retrospective chart-review of 517 ADHD children with EEG revealed IED in 39 cases. These patients (IED group) were matched on age and gender with 39 patients without IED (non-IED group). We measured at baseline, 1 year and 2 years Sz occurrence, the use of MPH and antiepileptic drug (AED). At baseline, 12 patients in the IED group had active epilepsy and three of them had Sz during the last year. 36 (92.3%) patients were treated with MPH. Initial positive response to MPH was achieved in 83.3% compared with 89.2% in the non-IED group. At 1 and 2 years follow-up, three patients who also had Sz at baseline and difficult to treat epilepsy, had Sz, without changes in seizure frequency. We found no statistically significant differences between the groups with respect to MPH use at 1 year and at 2 years. Ten patients from IED group, who did not have confirmed epilepsy diagnosis, temporarily used AEDs during the first year of follow-up. Despite the occurrence of IED, the use of MPH was safe during 2 years follow-up. IED predict the Sz occurrence in children with previous epilepsy, but does not necessarily suggest an increased seizure risk. A caution is warranted in order not to overestimate the significance of temporarily occurrence of IED. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Methylphenidate improves motor functions in children diagnosed with Hyperkinetic Disorder

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Iversen Synnøve

2009-05-01

Full Text Available Abstract Background A previous study showed that a high percentage of children diagnosed with Hyperkinetic Disorder (HKD displayed a consistent pattern of motor function problems. The purpose of this study was to investigate the effect of methylphenidate (MPH on such motor performance in children with HKD Methods 25 drug-naïve boys, aged 8–12 yr with a HKD-F90.0 diagnosis, were randomly assigned into two groups within a double blind cross-over design, and tested with a motor assessment instrument, during MPH and placebo conditions. Results The percentage of MFNU scores in the sample indicating 'severe motor problems' ranged from 44–84%, typically over 60%. Highly significant improvements in motor performance were observed with MPH compared to baseline ratings on all the 17 subtests of the MFNU 1–2 hr after administration of MPH. There were no significant placebo effects. The motor improvement was consistent with improvement of clinical symptoms. Conclusion The study confirmed our prior clinical observations showing that children with ADHD typically demonstrate marked improvements of motor functions after a single dose of 10 mg MPH. The most pronounced positive MPH response was seen in subtests measuring either neuromotor inhibition, or heightened muscular tone in the gross movement muscles involved in maintaining the alignment and balance of the body. Introduction of MPH generally led to improved balance and a generally more coordinated and controlled body movement.

Methylphenidate and emotional-motivational processing in attention-deficit/hyperactivity disorder.

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Conzelmann, Annette; Woidich, Eva; Mucha, Ronald F; Weyers, Peter; Müller, Mathias; Lesch, Klaus-Peter; Jacob, Christian P; Pauli, Paul

2016-08-01

In line with the assumption that emotional-motivational deficits are one core dysfunction in ADHD, in one of our previous studies we observed a reduced reactivity towards pleasant pictures in adult ADHD patients as compared to controls. This was indicated by a lack of attenuation of the startle reflex specifically during pleasant pictures in ADHD patients. The first choice medical agents in ADHD, methylphenidate (MPH), is discussed to normalize these dysfunctions. However, experimental evidence in the sense of double-blind placebo-controlled study designs is lacking. Therefore, we investigated 61 adult ADHD patients twice, one time with placebo and one time with MPH with the same experimental design as in our study previously and assessed emotion processing during the presentation of pleasant, neutral and unpleasant pictures. We obtained startle reflex data as well as valence and arousal ratings in association with the pictures. As previously shown, ADHD patients showed a diminished startle attenuation during pleasant pictures while startle potentiation during unpleasant pictures was normal. Valence and arousal ratings unsuspiciously increased with increasing pleasantness and arousal of the pictures, respectively. There were no significant influences of MPH. The study replicates that ADHD patients show a reduced reactivity towards pleasant stimuli. MPH did not normalize this dysfunction. Possibly, MPH only influences emotions during more complex behavioural tasks that involve executive functions in adults with ADHD. Our results emphasize the importance for the use of double-blind placebo-controlled designs in psychopharmacological research.

Cold suppresses agonist-induced activation of TRPV1.

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Chung, M-K; Wang, S

2011-09-01

Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death

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Wei, Kuo-Liang; Chen, Fei-Yun; Lin, Chih-Yi; Gao, Guan-Lun; Kao, Wen-Ya; Yeh, Chi-Hui; Chen, Chang-Rong; Huang, Hao-Chun; Tsai, Wei-Ren; Jong, Koa-Jen; Li, Wan-Jung; Su, Jyan-Gwo Joseph

2016-01-01

Carbendazim inhibits microtubule assembly, thus blocking mitosis and inhibiting cancer cell proliferation. Accordingly, carbendazim is being explored as an anticancer drug. Data show that carbendazim increased mRNA and protein expressions and promoter activity of CYP1A1. In addition, carbendazim activated transcriptional activity of the aryl hydrocarbon response element, and induced nuclear translocation of the aryl hydrocarbon receptor (AhR), a sign the AhR is activated. Carbendazim-induced CYP1A1 expression was blocked by AhR antagonists, and was abolished in AhR signal-deficient cells. Results demonstrated that carbendazim activated the AhR, thereby stimulating CYP1A1 expression. In order to understand whether AhR-induced metabolic enzymes turn carbendazim into less-toxic metabolites, Hoechst 33342 staining to reveal carbendazim-induced nuclear changes and flow cytometry to reveal the subG 0 /G 1 population were applied to monitor carbendazim-induced cell apoptosis. Carbendazim induced less apoptosis in Hepa-1c1c7 cells than in AhR signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with β-NF, an AhR agonist that highly induces CYP1A1 expression, decreased carbendazim-induced cell death. In addition, the lower the level of AhR was, the lower the vitality present in carbendazim-treated cells, including hepatoma cells and their derivatives with AhR RNA interference, also embryonic kidney cells, bladder carcinoma cells, and AhR signal-deficient Hepa-1c1c7 cells. In summary, carbendazim is an AhR agonist. The toxicity of carbendazim was lower in cells with the AhR signal. This report provides clues indicating that carbendazim is more potent at inducing cell death in tissues without than in those with the AhR signal, an important reference for applying carbendazim in cancer chemotherapy. - Highlights: • Carbendazim induced transcriptional activity of the aryl hydrocarbon response element. • Carbendazim induced nuclear translocation of the aryl hydrocarbon

Activation of aryl hydrocarbon receptor reduces carbendazim-induced cell death

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Wei, Kuo-Liang [Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan, ROC (China); College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, ROC (China); Chen, Fei-Yun; Lin, Chih-Yi [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Gao, Guan-Lun [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Department of Biological Resources, National Chiayi University, Chiayi, 60004, Taiwan, ROC (China); Kao, Wen-Ya [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Yeh, Chi-Hui [Department of Environmental Engineering, College of Engineering, Da-Yeh University, Dacun, Changhua 51591, Taiwan, ROC (China); Chen, Chang-Rong [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Huang, Hao-Chun [Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan, ROC (China); Tsai, Wei-Ren [Division of Applied Toxicology, Taiwan Agricultural Chemicals and Toxic Substances Research Institute, Council of Agriculture, Executive Yuan, Taichung 41358, Taiwan, ROC (China); Jong, Koa-Jen [Department of Biological Resources, National Chiayi University, Chiayi, 60004, Taiwan, ROC (China); Li, Wan-Jung [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China); Su, Jyan-Gwo Joseph, E-mail: jgjsu@mail.ncyu.edu.tw [Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan, ROC (China)

2016-09-01

Carbendazim inhibits microtubule assembly, thus blocking mitosis and inhibiting cancer cell proliferation. Accordingly, carbendazim is being explored as an anticancer drug. Data show that carbendazim increased mRNA and protein expressions and promoter activity of CYP1A1. In addition, carbendazim activated transcriptional activity of the aryl hydrocarbon response element, and induced nuclear translocation of the aryl hydrocarbon receptor (AhR), a sign the AhR is activated. Carbendazim-induced CYP1A1 expression was blocked by AhR antagonists, and was abolished in AhR signal-deficient cells. Results demonstrated that carbendazim activated the AhR, thereby stimulating CYP1A1 expression. In order to understand whether AhR-induced metabolic enzymes turn carbendazim into less-toxic metabolites, Hoechst 33342 staining to reveal carbendazim-induced nuclear changes and flow cytometry to reveal the subG{sub 0}/G{sub 1} population were applied to monitor carbendazim-induced cell apoptosis. Carbendazim induced less apoptosis in Hepa-1c1c7 cells than in AhR signal-deficient Hepa-1c1c7 mutant cells. Pretreatment with β-NF, an AhR agonist that highly induces CYP1A1 expression, decreased carbendazim-induced cell death. In addition, the lower the level of AhR was, the lower the vitality present in carbendazim-treated cells, including hepatoma cells and their derivatives with AhR RNA interference, also embryonic kidney cells, bladder carcinoma cells, and AhR signal-deficient Hepa-1c1c7 cells. In summary, carbendazim is an AhR agonist. The toxicity of carbendazim was lower in cells with the AhR signal. This report provides clues indicating that carbendazim is more potent at inducing cell death in tissues without than in those with the AhR signal, an important reference for applying carbendazim in cancer chemotherapy. - Highlights: • Carbendazim induced transcriptional activity of the aryl hydrocarbon response element. • Carbendazim induced nuclear translocation of the aryl

GSK621 activates AMPK signaling to inhibit LPS-induced TNFα production

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Wu, Yong-hong; Li, Quan; Li, Ping; Liu, Bei

2016-01-01

LPS stimulation in macrophages/monocytes induces TNFα production. We here tested the potential effect of GSK621, a novel AMP-activated protein kinase (AMPK) activator, against the process. In RAW264.7 macrophages, murine bone marrow-derived macrophages (BMDMs), and chronic obstructive pulmonary disease (COPD) patients' monocytes, GSK621 significantly inhibited LPS-induced TNFα protein secretion and mRNA synthesis. Inhibition of AMPK, through AMPKα shRNA knockdown or dominant negative mutation (T172A), almost abolished GSK621's suppression on TNFα in RAW264.7 cells. Reversely, forced-expression of a constitutively-active AMPKα (T172D) mimicked GSK621 actions and reduced LPS-induced TNFα production. Molecularly, GSK621 suppressed LPS-induced reactive oxygen species (ROS) production and nuclear factor kappa B (NFκB) activation. In vivo, GSK621 oral administration inhibited LPS-induced TNFα production and endotoxin shock in mice. In summary, GSK621 activates AMPK signaling to inhibit LPS-induced TNFα production in macrophages/monocytes. - Highlights: • GSK621 inhibits LPS-induced TNFα production/expression in RAW264.7 cells and BMDMs. • GSK621 inhibits LPS-induced TNFα production/expression in COPD patients' PBMCs. • GSK621's inhibition on TNFα production by LPS requires AMPK activation. • GSK621 inhibits LPS-induced ROS production and NFκB activation, dependent on AMPK. • GSK621 oral administration inhibits LPS-induced TNFα production and endotoxin shock in mice.

Prospective observational study protocol to investigate long-term adverse effects of methylphenidate in children and adolescents with ADHD: the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study.

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Inglis, S K; Carucci, S; Garas, P; Häge, A; Banaschewski, T; Buitelaar, J K; Dittmann, R W; Falissard, B; Hollis, C; Kovshoff, H; Liddle, E; McCarthy, S; Nagy, P; Neubert, A; Rosenthal, E; Sonuga-Barke, E; Wong, I; Zuddas, A; Coghill, D C

2016-04-26

Methylphenidate is the most frequently used medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in Europe. Following concerns about its safety, the European Commission called for research into the long-term effects of methylphenidate on children and adolescents with ADHD. The Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) research programme was designed to address this call. At the heart of this programme is a 2-year longitudinal naturalistic pharmacovigilance study being conducted in 27 European sites. 3 cohorts of children and adolescents (aged 6-17) living in the UK, Germany, Italy and Hungary are being recruited:Group 1 (Medicated ADHD): 800 ADHD medication-naive children and adolescents with a clinical diagnosis of ADHD about to start methylphenidate treatment for the first time.Group 2 (Unmedicated ADHD): 400 children and adolescents with a clinical diagnosis of ADHD who have never been treated with ADHD medication and have no intention of beginning medication.Group 3 (Non-ADHD): 400 children and adolescents without ADHD who are siblings of individuals in either group 1 or 2.All participants will be assessed 5 times during their 2-year follow-up period for growth and development, psychiatric, neurological and cardiovascular health. The primary outcome measure will be the height velocity SD score. Ethical approval for the study has been granted by the East of Scotland Research Ethics Service. Following this approval, patient information leaflets and consent forms were translated as necessary and submissions made by lead sites in each of the other 3 countries to their own ethics committees. Following ethical approval in each country, local ethical permissions at each site were sought and obtained as needed. The study's website (http://www.adhd-adduce.org/page/view/2/Home) provides information for researchers, participants and the general public. NCT01470261. Published by the BMJ Publishing Group Limited

Salicylate-induced abnormal activity in the inferior colliculus of rats.

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Chen, G D; Jastreboff, P J

1995-02-01

The evaluation of the spontaneous activity of 471 units from the external nucleus of the IC revealed that salicylate induces an increase of the spontaneous activity and the emergence of a bursting type of activity longer than 4 spikes. For sharply tuned units, the affected cells were from the frequency range of 10-16 kHz, which corresponds to the behaviorally measured pitch of salicylate-induced tinnitus in rats. An exogenous calcium supplement, provided under the conditions shown to attenuate the behavioral manifestation of salicylate-induced tinnitus, abolished the modification of the spontaneous activity induced by salicylate. Finally, profound changes of activity were observed for cells not responding to contralateral sound. We propose that the observed long bursts of discharges represent tinnitus-related neuronal activity. The results are consistent with the hypothesis that GABA-mediated disinhibition is involved in the processing of tinnitus-related neuronal activity.

Effects of Parecoxib and Fentanyl on nociception-induced cortical activity

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Wang Ying-Wei

2010-01-01

Full Text Available Abstract Background Analgesics, including opioids and non-steroid anti-inflammatory drugs reduce postoperative pain. However, little is known about the quantitative effects of these drugs on cortical activity induced by nociceptive stimulation. The aim of the present study was to determine the neural activity in response to a nociceptive stimulus and to investigate the effects of fentanyl (an opioid agonist and parecoxib (a selective cyclooxygenase-2 inhibitor on this nociception-induced cortical activity evoked by tail pinch. Extracellular recordings (electroencephalogram and multi-unit signals were performed in the area of the anterior cingulate cortex while intracellular recordings were made in the primary somatosensory cortex. The effects of parecoxib and fentanyl on induced cortical activity were compared. Results Peripheral nociceptive stimulation in anesthetized rats produced an immediate electroencephalogram (EEG desynchronization resembling the cortical arousal (low-amplitude, fast-wave activity, while the membrane potential switched into a persistent depolarization state. The induced cortical activity was abolished by fentanyl, and the fentanyl's effect was reversed by the opioid receptor antagonist, naloxone. Parecoxib, on the other hand, did not significantly affect the neural activity. Conclusion Cortical activity was modulated by nociceptive stimulation in anesthetized rats. Fentanyl showed a strong inhibitory effect on the nociceptive-stimulus induced cortical activity while parecoxib had no significant effect.

Effects of methylphenidate on acute math performance in children with attention-deficit hyperactivity disorder.

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Grizenko, Natalie; Cai, Emmy; Jolicoeur, Claude; Ter-Stepanian, Mariam; Joober, Ridha

2013-11-01

Examine the short-term (acute) effects of methylphenidate (MPH) on math performance in children with attention-deficit hyperactivity disorder (ADHD) and what factors predict improvement in math performance. One hundred ninety-eight children with ADHD participated in a double-blind, placebo-controlled, randomized crossover MPH trial. Math response to MPH was determined through administration of math problems adjusted to their academic level during the Restricted Academic Situation Scale (RASS). Student t tests were conducted to assess change in math performance with psychostimulants. Correlation between change on the RASS and change on the math performance was also examined. Linear regression was performed to determine predictor variables. Children with ADHD improved significantly in their math with MPH (P math performance on MPH was highly correlated. A child's age at baseline and Wechsler Individual Achievement Test (WIAT)-Numerical Operations standard scores at baseline accounted for 15% of variances for acute math improvement. MPH improves acute math performance in children with ADHD. Younger children with lower math scores (as assessed by the WIAT) improved most on math scores when given psychostimulants. NCT00483106.

A prenatal nicotine exposure mouse model of methylphenidate responsive ADHD-associated cognitive phenotypes.

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Zhu, Jinmin; Fan, Fangfang; McCarthy, Deirdre M; Zhang, Lin; Cannon, Elisa N; Spencer, Thomas J; Biederman, Joseph; Bhide, Pradeep G

2017-05-01

Prenatal exposure to nicotine via cigarette smoke or other forms of tobacco use is a significant environmental risk factor for attention deficit hyperactivity disorder (ADHD). The neurobiological mechanisms underlying the link between prenatal nicotine exposure (PNE) and ADHD are not well understood. Animal models, especially rodent models, are beginning to bridge this gap in knowledge. Although ADHD is characterized by hyperactivity, inattention, impulsivity and working memory deficits, the majority of the animal models are based on only one or two ADHD associated phenotypes, in particular, hyperactivity or inattention. We report a PNE mouse model that displays the full range of ADHD associated behavioral phenotypes including working memory deficit, attention deficit and impulsive-like behavior. All of the ADHD-associated phenotypes respond to a single administration of a therapeutic equivalent dose of methylphenidate. In an earlier study, we showed that PNE produces hyperactivity, frontal cortical hypodopaminergic state and thinning of the cingulate cortex. Collectively, these data suggest that the PNE mouse model recapitulates key features of ADHD and may be a suitable preclinical model for ADHD research. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Methylphenidate-risperidone combination in child psychiatry: A retrospective analysis of 44 cases.

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Javelot, H; Glay-Ribau, C; Ligier, F; Weiner, L; Didelot, N; Messaoudi, M; Socha, M; Body-Lawson, F; Kabuth, B

2014-05-01

Psychotimulant-antipyschotic combinations are frequently used in child psychiatry, but have been rarely described in the literature. We propose here a retrospective study of 44 children who received the combination methylphenidate (MPH)-risperidone (RIS). The sample is composed of children who received either MPH (n=28) or RIS (n=16) as primary treatment. A vast majority of the children had a comorbid attention deficit hyperactivity disorder (ADHD) diagnosis. For over 60% of patients, regardless of their initial monotherapy, bitherapy decreased the symptoms of ADHD and conduct disorder, sleep disorders and anxiety. Concerning the safety of the bitherapy, a compensation effect on weight gain and appetite was respectively observed in 70% and 50% of patients. Even though iatrogenic tachycardia can be encountered with both drugs, it has never been reported when they are associated and we have reported a total of 3 cases in our study. We have also observed a case of dyskinesia resolved with the discontinuation of the treatment. MPH-RIS bitherapy appears to be particularly effective in ADHD with conduct disorder symptoms. Although tolerance may limit its use, the benefit/risk ratio seems favourable for a number of children. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Stress-Induced In Vivo Recruitment of Human Cytotoxic Natural Killer Cells Favors Subsets with Distinct Receptor Profiles and Associates with Increased Epinephrine Levels.

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Marc B Bigler

Full Text Available Acute stress drives a 'high-alert' response in the immune system. Psychoactive drugs induce distinct stress hormone profiles, offering a sought-after opportunity to dissect the in vivo immunological effects of acute stress in humans.3,4-methylenedioxymethamphetamine (MDMA, methylphenidate (MPH, or both, were administered to healthy volunteers in a randomized, double-blind, placebo-controlled crossover-study. Lymphocyte subset frequencies, natural killer (NK cell immune-phenotypes, and changes in effector function were assessed, and linked to stress hormone levels and expression of CD62L, CX3CR1, CD18, and stress hormone receptors on NK cells.MDMA/MPH > MDMA > MPH robustly induced an epinephrine-dominant stress response. Immunologically, rapid redistribution of peripheral blood lymphocyte-subsets towards phenotypically mature NK cells occurred. NK cytotoxicity was unaltered, but they expressed slightly reduced levels of the activating receptor NKG2D. Preferential circulation of mature NK cells was associated with high epinephrine receptor expression among this subset, as well as expression of integrin ligands previously linked to epinephrine-induced endothelial detachment.The acute epinephrine-induced stress response was characterized by rapid accumulation of mature and functional NK cells in the peripheral circulation. This is in line with studies using other acute stressors and supports the role of the acute stress response in rapidly mobilizing the innate immune system to counteract incoming threats.

Ethanol-Induced Neurodegeneration and Glial Activation in the Developing Brain

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Mariko Saito

2016-08-01

Full Text Available Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD. While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy. Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7 mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain.

Six months methylphenidate treatment improves emotion dysregulation in adolescents with attention deficit/hyperactivity disorder: a prospective study

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Suzer Gamli I

2018-05-01

Full Text Available Ipek Suzer Gamli,1 Aysegul Yolga Tahiroglu2 1Sanliurfa Education and Research Hospital, Eyyubiye, Sanliurfa, Turkey; 2Child and Adolescent Psychiatry Department, Cukurova University School of Medicine, Saricam, Adana, Turkey Purpose: Individuals with attention deficit/hyperactivity disorder (ADHD may suffer from emotional dysregulation (ED, although this symptom is not listed among the diagnostic criteria. Methylphenidate (MPH is useful in reducing emotional symptoms in ADHD. The aim of the present study was to determine both psychosocial risk factors and presence of ED in adolescents with ADHD before and after MPH treatment. Participants and methods: Eighty-two patients aged 12–18 years with ADHD were included as participants. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime, the Difficulties in Emotion Regulation Scale (DERS, sociodemographic form, and the Inventory of Statements About Self-Injury were administered. Results were compared before and after 6 months MPH treatment. Results: A significant improvement was detected on DERS for impulsivity (15.9±6.8 initial vs 14.2±6.5 final test, p<0.01 and total score (88.4±23.3 initial vs 82.4±2.7 final test, p<0.05 across all patients taking MPH regardless of subtype and sex. Despite treatment, a significant difference remained for impulsivity, strategies, and total score in patients with comorbid oppositional defiant disorder (ODD compared with those without ODD, but no difference was detected for conduct disorder comorbidity. In patients who self-harm, scores for goals, impulsivity, strategies, clarity, and total score were higher before treatment: furthermore, impulsivity and total score remained high after treatment. In maltreated patients, goals, impulsivity, strategies, and total scores were significantly higher before treatment; however, their symptoms were ameliorated after treatment with MPH. Conclusion: Individuals with

Adolescent Exposure to Methylphenidate Increases Impulsive Choice Later in Life

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Zarish Abbas

2017-10-01

Full Text Available Background: The psychostimulant methylphenidate (MPH is known to temporarily reduce impulsive choice and promote self-control. What is not sufficiently understood is how repeated treatment with MPH affects impulsive choice in the long run, and whether any such effect is contingent on exposure at certain developmental stages.Methods: Using an animal model for impulsive choice, we examined first whether giving MPH through early adolescence alters delay discounting, an operational measure of impulsive choice, later in adulthood. We then tested whether equivalent long-term effects are observed if exposure to the drug occurred during adulthood. Starting on postnatal day 25 or postnatal day 60, male rats received one of a range of doses of MPH for 10 consecutive days. Twenty-six days later, all rats were trained to choose between a lever that produced a small immediate reward and a lever that produced a large reward after a range of delays.Results: Rats showed a long-term decrease in the selection of the delayed larger reward when treated with moderate doses of MPH during early adolescence, but not when treated with the lower or higher doses. In contrast, no differences were observed in the selection of the delayed larger reward in animals that were treated with various doses of MPH during adulthood.Conclusions: Our findings suggest effects of MPH on impulsive choice that are contingent on dosage and on the developmental period of exposure. When administered during adolescence, moderate doses of MPH increase impulsive choice long after the end of treatment, whereas these same doses administered during adulthood were without effect

Factors Associated With Adherence to Methylphenidate Treatment in Adult Patients With Attention-Deficit/Hyperactivity Disorder and Substance Use Disorders.

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Skoglund, Charlotte; Brandt, Lena; Almqvist, Catarina; DʼOnofrio, Brian M; Konstenius, Maija; Franck, Johan; Larsson, Henrik

2016-06-01

Adherence to treatment is one of the most consistent factors associated with a favorable addiction treatment outcome. Little is known about factors associated with treatment adherence in individuals affected with comorbid attention-deficit/hyperactivity disorder and substance use disorders (SUD). This study aimed to explore whether treatment-associated factors, such as the prescribing physician's (sub)specialty and methylphenidate (MPH) dose, or patient-related factors, such as sex, age, SUD subtype, and psychiatric comorbidity, were associated with adherence to MPH treatment. Swedish national registers were used to identify adult individuals with prescriptions of MPH and medications specifically used in the treatment of SUD or a diagnosis of SUD and/or coexisting psychiatric diagnoses. Primary outcome measure was days in active MPH treatment in stratified dose groups (≤36 mg, ≥37 mg to ≤54 mg, ≥55 mg to ≤72 mg, ≥73 mg to ≤90 mg, ≥91 mg to ≤108 mg, and ≥109 mg). Lower MPH doses (ie, ≤36 mg day 100) were associated with treatment discontinuation between days 101 and 830 (HR≤36 mg, 1.67; HR37-54mg, 1.37; HR55-72mg, 1.36; HR73-90mg, 1.19; HR≥108mg, 1.09). The results showed a linear trend (P attention-deficit/hyperactivity disorder and SUD.

Ethylphenidate as a selective dopaminergic agonist and methylphenidate-ethanol transesterification biomarker.

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Patrick, Kennerly S; Corbin, Timothy R; Murphy, Cristina E

2014-12-01

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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation.

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Rocha, Sandra M; Saraiva, Tatiana; Cristóvão, Ana C; Ferreira, Raquel; Santos, Tiago; Esteves, Marta; Saraiva, Cláudia; Je, Goun; Cortes, Luísa; Valero, Jorge; Alves, Gilberto; Klibanov, Alexander; Kim, Yoon-Seong; Bernardino, Liliana

2016-06-04

Histamine is an amine widely known as a peripheral inflammatory mediator and as a neurotransmitter in the central nervous system. Recently, it has been suggested that histamine acts as an innate modulator of microglial activity. Herein, we aimed to disclose the role of histamine in microglial phagocytic activity and reactive oxygen species (ROS) production and to explore the consequences of histamine-induced neuroinflammation in dopaminergic (DA) neuronal survival. The effect of histamine on phagocytosis was assessed both in vitro by using a murine N9 microglial cell line and primary microglial cell cultures and in vivo. Cells were exposed to IgG-opsonized latex beads or phosphatidylserine (PS) liposomes to evaluate Fcγ or PS receptor-mediated microglial phagocytosis, respectively. ROS production and protein levels of NADPH oxidases and Rac1 were assessed as a measure of oxidative stress. DA neuronal survival was evaluated in vivo by counting the number of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) of mice. We found that histamine triggers microglial phagocytosis via histamine receptor 1 (H1R) activation and ROS production via H1R and H4R activation. By using apocynin, a broad NADPH oxidase (Nox) inhibitor, and Nox1 knockout mice, we found that the Nox1 signaling pathway is involved in both phagocytosis and ROS production induced by histamine in vitro. Interestingly, both apocynin and annexin V (used as inhibitor of PS-induced phagocytosis) fully abolished the DA neurotoxicity induced by the injection of histamine in the SN of adult mice in vivo. Blockade of H1R protected against histamine-induced Nox1 expression and death of DA neurons in vivo. Overall, our results highlight the relevance of histamine in the modulation of microglial activity that ultimately may interfere with neuronal survival in the context of Parkinson's disease (PD) and, eventually, other neurodegenerative diseases which are accompanied by microglia-induced

Misconceptions about mirror-induced motor cortex activation.

NARCIS (Netherlands)

Praamstra, P.; Torney, L.; Rawle, C.J.; Miall, R.C.

2011-01-01

Observation of self-produced hand movements through a mirror, creating an illusion of the opposite hand moving, was recently reported to induce ipsilateral motor cortex activation, that is, motor cortex activation for the hand in rest. The reported work goes far beyond earlier work on motor cortex

Gastroprotective activity of polysaccharide from Hericium erinaceus against ethanol-induced gastric mucosal lesion and pylorus ligation-induced gastric ulcer, and its antioxidant activities.

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Wang, Xiao-Yin; Yin, Jun-Yi; Zhao, Ming-Ming; Liu, Shi-Yu; Nie, Shao-Ping; Xie, Ming-Yong

2018-04-15

The gastroprotective activity of Hericium erinaceus polysaccharide was investigated in rats. The antioxidant activities were also evaluated. Pre-treatment of polysaccharide could reduce ethanol-induced gastric mucosal lesion and pylorus ligation-induced gastric ulcer. The polysaccharide exhibited scavenging activities of 1, 1-diphenyl-2-picryl-hydrozyl and hydroxyl radicals, and ferrous ion-chelating ability. In the pylorus ligation-induced model, gastric secretions (volume of gastric juice, gastric acid, pepsin and mucus) of ulcer rats administrated with polysaccharide were regulated. Levels of tumor necrosis factor-α and interleukins-1β in serum, and myeloperoxidase activity of gastric tissue were reduced, while antioxidant status of gastric tissue was improved. Defensive factors (nitric oxide, prostaglandin E2, epidermal growth factor) in gastric tissue were increased. These results indicate that Hericium erinaceus polysaccharide possess gastroprotective activity, and the possible mechanisms are related to its regulations of gastric secretions, improvements of anti-inflammatory and antioxidant status, as well as increments of defensive factors releases. Copyright © 2018 Elsevier Ltd. All rights reserved.

Activity deprivation induces neuronal cell death: mediation by tissue-type plasminogen activator.

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Eldi Schonfeld-Dado

Full Text Available Spontaneous activity is an essential attribute of neuronal networks and plays a critical role in their development and maintenance. Upon blockade of activity with tetrodotoxin (TTX, neurons degenerate slowly and die in a manner resembling neurodegenerative diseases-induced neuronal cell death. The molecular cascade leading to this type of slow cell death is not entirely clear. Primary post-natal cortical neurons were exposed to TTX for up to two weeks, followed by molecular, biochemical and immunefluorescence analysis. The expression of the neuronal marker, neuron specific enolase (NSE, was down-regulated, as expected, but surprisingly, there was a concomitant and striking elevation in expression of tissue-type plasminogen activator (tPA. Immunofluorescence analysis indicated that tPA was highly elevated inside affected neurons. Transfection of an endogenous tPA inhibitor, plasminogen activator inhibitor-1 (PAI-1, protected the TTX-exposed neurons from dying. These results indicate that tPA is a pivotal player in slowly progressing activity deprivation-induced neurodegeneration.

Influence of Methylphenidate on the Frequency of Stuttering: A Randomized Controlled Trial.

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Rabaeys, Henk; Bijleveld, Henny-Annie; Devroey, Dirk

2015-10-01

Recently, a case report described a decrease in frequency of stuttering after intake of methylphenidate (MPH). This study was undertaken to investigate if this effect could again be reproduced in a population of young healthy male adult persons with developmental stuttering. A double-blind randomized crossover trial, with a 2-week washout period, including 15 Dutch-speaking young healthy persons with developmental stuttering, assessed the effects of a single dose of 20 mg MPH compared with placebo on stuttering. Dependent and 1-sample t tests were used to detect significant differences. The end point was the number of stutter moments and self-perceived improvement. MPH yielded a significant decrease in the number of stutter moments when reading and speaking (P = 0.002), which was not the case with placebo (P = 0.090). There was a significant improvement from baseline after intake of MPH as compared with placebo (P = 0.003). Self-perceived improvement with MPH was not significantly better as compared with placebo (P = 0.28). This study showed that the participants had an objective statistically significant decrease in the frequency of stuttering with MPH, and this was not the case with placebo. This was also the case for a reduction in stutter moments when reading out loud and speaking spontaneously. However, this result was not subjectively perceived by the participants. © The Author(s) 2015.

Methylphenidate does not enhance visual working memory but benefits motivation in macaque monkeys.

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Oemisch, Mariann; Johnston, Kevin; Paré, Martin

2016-10-01

Working memory is a limited-capacity cognitive process that retains relevant information temporarily to guide thoughts and behavior. A large body of work has suggested that catecholamines exert a major modulatory influence on cognition, but there is only equivocal evidence of a direct influence on working memory ability, which would be reflected in a dependence on working memory load. Here we tested the contribution of catecholamines to working memory by administering a wide range of acute oral doses of the dopamine and norepinephrine reuptake inhibitor methylphenidate (MPH, 0.1-9 mg/kg) to three female macaque monkeys (Macaca mulatta), whose working memory ability was measured from their performance in a visual sequential comparison task. This task allows the systematic manipulation of working memory load, and we therefore tested the specific hypothesis that MPH modulates performance in a manner that depends on both dose and memory load. We found no evidence of a dose- or memory load-dependent effect of MPH on performance. In contrast, significant effects on measures of motivation were observed. These findings suggest that an acute increase in catecholamines does not seem to affect the retention of visual information per se. As such, these results help delimit the effects of MPH on cognition. Copyright © 2016 Elsevier Ltd. All rights reserved.

Tics and other stereotyped movements as side effects of pharmacological treatment.

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Madruga-Garrido, Marcos; Mir, Pablo

2013-01-01

Tics and other stereotyped abnormal movements can be seen as adverse effects of some pharmacologic drugs. Among these drugs, antipsychotics may provoke tardive syndromes after a chronic exposure, primarily in the case of typical antipsychotics. These syndromes include tardive tics, tardive dyskinesia, or tardive akathisia, which present with tics or stereotyped movements as a clinical phenomenon. Psychostimulants (mainly methylphenidate) have traditionally been associated with the appearance of tics due to the increased dopamine activity caused by stimulants. Nevertheless, in recent years, several studies have concluded not only that methylphenidate does not exacerbate or reactivate tics but also that tics can improve with its use in patients with associated attention deficit and hyperactivity disorder and tic disorder. Antiepileptic drugs, although infrequently, can also induce tics, with carbamazepine and lamotrigine described as tic inducers. Other antiepileptics, including levetiracetam and topiramate, have been proposed as a potential treatment for tic disorders due to a positive effect on tics, especially in those with associated epileptic disorder. Clinical and therapeutic approaches to tics and stereotyped movements after exposure to antipsychotics, stimulants, and antiepileptic drugs will be reviewed in this chapter. © 2013 Elsevier Inc. All rights reserved.

NOX2-Induced Activation of Arginase and Diabetes-Induced Retinal Endothelial Cell Senescence

Directory of Open Access Journals (Sweden)

Modesto Rojas

2017-06-01

Full Text Available Increases in reactive oxygen species (ROS and decreases in nitric oxide (NO have been linked to vascular dysfunction during diabetic retinopathy (DR. Diabetes can reduce NO by increasing ROS and by increasing activity of arginase, which competes with nitric oxide synthase (NOS for their commons substrate l-arginine. Increased ROS and decreased NO can cause premature endothelial cell (EC senescence leading to defective vascular repair. We have previously demonstrated the involvement of NADPH oxidase 2 (NOX2-derived ROS, decreased NO and overactive arginase in DR. Here, we investigated their impact on diabetes-induced EC senescence. Studies using diabetic mice and retinal ECs treated with high glucose or H2O2 showed that increases in ROS formation, elevated arginase expression and activity, and decreased NO formation led to premature EC senescence. NOX2 blockade or arginase inhibition prevented these effects. EC senescence was also increased by inhibition of NOS activity and this was prevented by treatment with a NO donor. These results indicate that diabetes/high glucose-induced activation of arginase and decreases in NO bioavailability accelerate EC senescence. NOX2-generated ROS contribute importantly to this process. Blockade of NOX2 or arginase represents a strategy to prevent diabetes-induced premature EC senescence by preserving NO bioavailability.

The Influence of Methylphenidate on Hyperactivity and Attention Deficits in Children With ADHD: A Virtual Classroom Test.

Science.gov (United States)

Mühlberger, A; Jekel, K; Probst, T; Schecklmann, M; Conzelmann, A; Andreatta, M; Rizzo, A A; Pauli, P; Romanos, M

2016-05-13

This study compares the performance in a continuous performance test within a virtual reality classroom (CPT-VRC) between medicated children with ADHD, unmedicated children with ADHD, and healthy children. N = 94 children with ADHD (n = 26 of them received methylphenidate and n = 68 were unmedicated) and n = 34 healthy children performed the CPT-VRC. Omission errors, reaction time/variability, commission errors, and body movements were assessed. Furthermore, ADHD questionnaires were administered and compared with the CPT-VRC measures. The unmedicated ADHD group exhibited more omission errors and showed slower reaction times than the healthy group. Reaction time variability was higher in the unmedicated ADHD group compared with both the healthy and the medicated ADHD group. Omission errors and reaction time variability were associated with inattentiveness ratings of experimenters. Head movements were correlated with hyperactivity ratings of parents and experimenters. Virtual reality is a promising technology to assess ADHD symptoms in an ecologically valid environment. © The Author(s) 2016.

Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig Loci in activated B cells

NARCIS (Netherlands)

Staszewski, Ori; Baker, Richard E.; Ucher, Anna J.; Martier, Raygene; Stavnezer, Janet; Guikema, Jeroen E. J.

2011-01-01

After immunization or infection, activation-induced cytidine deaminase (AID) initiates diversification of immunoglobulin (Ig) genes in B cells, introducing mutations within the antigen-binding V regions (somatic hypermutation, SHM) and double-strand DNA breaks (DSBs) into switch (S) regions, leading

Sphingosine-1-phosphate mediates epidermal growth factor-induced muscle satellite cell activation

Energy Technology Data Exchange (ETDEWEB)

Nagata, Yosuke, E-mail: cynagata@mail.ecc.u-tokyo.ac.jp; Ohashi, Kazuya; Wada, Eiji; Yuasa, Yuki; Shiozuka, Masataka; Nonomura, Yoshiaki; Matsuda, Ryoichi

2014-08-01

Skeletal muscle can regenerate repeatedly due to the presence of resident stem cells, called satellite cells. Because satellite cells are usually quiescent, they must be activated before participating in muscle regeneration in response to stimuli such as injury, overloading, and stretch. Although satellite cell activation is a crucial step in muscle regeneration, little is known of the molecular mechanisms controlling this process. Recent work showed that the bioactive lipid sphingosine-1-phosphate (S1P) plays crucial roles in the activation, proliferation, and differentiation of muscle satellite cells. We investigated the role of growth factors in S1P-mediated satellite cell activation. We found that epidermal growth factor (EGF) in combination with insulin induced proliferation of quiescent undifferentiated mouse myoblast C2C12 cells, which are also known as reserve cells, in serum-free conditions. Sphingosine kinase activity increased when reserve cells were stimulated with EGF. Treatment of reserve cells with the D-erythro-N,N-dimethylsphingosine, Sphingosine Kinase Inhibitor, or siRNA duplexes specific for sphingosine kinase 1, suppressed EGF-induced C2C12 activation. We also present the evidence showing the S1P receptor S1P2 is involved in EGF-induced reserve cell activation. Moreover, we demonstrated a combination of insulin and EGF promoted activation of satellite cells on single myofibers in a manner dependent on SPHK and S1P2. Taken together, our observations show that EGF-induced satellite cell activation is mediated by S1P and its receptor. - Highlights: • EGF in combination with insulin induces proliferation of quiescent C2C12 cells. • Sphingosine kinase activity increases when reserve cells are stimulated with EGF. • EGF-induced activation of reserve cells is dependent on sphingosine kinase and ERK. • The S1P receptor S1P2 is involved in EGF-induced reserve cell activation. • EGF-induced reserve cell activation is mediated by S1P and its

Sphingosine-1-phosphate mediates epidermal growth factor-induced muscle satellite cell activation

International Nuclear Information System (INIS)

Nagata, Yosuke; Ohashi, Kazuya; Wada, Eiji; Yuasa, Yuki; Shiozuka, Masataka; Nonomura, Yoshiaki; Matsuda, Ryoichi

2014-01-01

Skeletal muscle can regenerate repeatedly due to the presence of resident stem cells, called satellite cells. Because satellite cells are usually quiescent, they must be activated before participating in muscle regeneration in response to stimuli such as injury, overloading, and stretch. Although satellite cell activation is a crucial step in muscle regeneration, little is known of the molecular mechanisms controlling this process. Recent work showed that the bioactive lipid sphingosine-1-phosphate (S1P) plays crucial roles in the activation, proliferation, and differentiation of muscle satellite cells. We investigated the role of growth factors in S1P-mediated satellite cell activation. We found that epidermal growth factor (EGF) in combination with insulin induced proliferation of quiescent undifferentiated mouse myoblast C2C12 cells, which are also known as reserve cells, in serum-free conditions. Sphingosine kinase activity increased when reserve cells were stimulated with EGF. Treatment of reserve cells with the D-erythro-N,N-dimethylsphingosine, Sphingosine Kinase Inhibitor, or siRNA duplexes specific for sphingosine kinase 1, suppressed EGF-induced C2C12 activation. We also present the evidence showing the S1P receptor S1P2 is involved in EGF-induced reserve cell activation. Moreover, we demonstrated a combination of insulin and EGF promoted activation of satellite cells on single myofibers in a manner dependent on SPHK and S1P2. Taken together, our observations show that EGF-induced satellite cell activation is mediated by S1P and its receptor. - Highlights: • EGF in combination with insulin induces proliferation of quiescent C2C12 cells. • Sphingosine kinase activity increases when reserve cells are stimulated with EGF. • EGF-induced activation of reserve cells is dependent on sphingosine kinase and ERK. • The S1P receptor S1P2 is involved in EGF-induced reserve cell activation. • EGF-induced reserve cell activation is mediated by S1P and its

Obesity-induced vascular inflammation involves elevated arginase activity.

Science.gov (United States)

Yao, Lin; Bhatta, Anil; Xu, Zhimin; Chen, Jijun; Toque, Haroldo A; Chen, Yongjun; Xu, Yimin; Bagi, Zsolt; Lucas, Rudolf; Huo, Yuqing; Caldwell, Ruth B; Caldwell, R William

2017-11-01

Obesity-induced vascular dysfunction involves pathological remodeling of the visceral adipose tissue (VAT) and increased inflammation. Our previous studies showed that arginase 1 (A1) in endothelial cells (ECs) is critically involved in obesity-induced vascular dysfunction. We tested the hypothesis that EC-A1 activity also drives obesity-related VAT remodeling and inflammation. Our studies utilized wild-type and EC-A1 knockout (KO) mice made obese by high-fat/high-sucrose (HFHS) diet. HFHS diet induced increases in body weight, fasting blood glucose, and VAT expansion. This was accompanied by increased arginase activity and A1 expression in vascular ECs and increased expression of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-10 (IL-10), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) mRNA and protein in both VAT and ECs. HFHS also markedly increased circulating inflammatory monocytes and VAT infiltration by inflammatory macrophages, while reducing reparative macrophages. Additionally, adipocyte size and fibrosis increased and capillary density decreased in VAT. These effects of HFHS, except for weight gain and hyperglycemia, were prevented or reduced in mice lacking EC-A1 or treated with the arginase inhibitor 2-( S )-amino-6-boronohexanoic acid (ABH). In mouse aortic ECs, exposure to high glucose (25 mM) and Na palmitate (200 μM) reduced nitric oxide production and increased A1, TNF-α, VCAM-1, ICAM-1, and MCP-1 mRNA, and monocyte adhesion. Knockout of EC-A1 or ABH prevented these effects. HFHS diet-induced VAT inflammation is mediated by EC-A1 expression/activity. Limiting arginase activity is a possible therapeutic means of controlling obesity-induced vascular and VAT inflammation.

Dose-response characteristics of methylphenidate on locomotor behavior and on sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats

Directory of Open Access Journals (Sweden)

Swann Alan C

2006-01-01

Full Text Available Abstract Background Methylphenidate (MPD is a psychostimulant commonly prescribed for attention deficit/hyperactivity disorder. The mode of action of the brain circuitry responsible for initiating the animals' behavior in response to psychostimulants is not well understood. There is some evidence that psychostimulants activate the ventral tegmental area (VTA, nucleus accumbens (NAc, and prefrontal cortex (PFC. Methods The present study was designed to investigate the acute dose-response of MPD (0.6, 2.5, and 10.0 mg/kg on locomotor behavior and sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats previously implanted with permanent electrodes. For locomotor behavior, adult male Wistar-Kyoto (WKY; n = 39 rats were given saline on experimental day 1 and either saline or an acute injection of MPD (0.6, 2.5, or 10.0 mg/kg, i.p. on experimental day 2. Locomotor activity was recorded for 2-h post injection on both days using an automated, computerized activity monitoring system. Electrophysiological recordings were also performed in the adult male WKY rats (n = 10. Five to seven days after the rats had recovered from the implantation of electrodes, each rat was placed in a sound-insulated, electrophysiological test chamber where its sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10.0 mg/kg MPD injection. Time interval between injections was 90 min. Results Results showed an increase in locomotion with dose-response characteristics, while a dose-response decrease in amplitude of the components of sensory evoked field responses of the VTA, NAc, and PFC neurons. For example, the P3 component of the sensory evoked field response of the VTA decreased by 19.8% ± 7.4% from baseline after treatment of 0.6 mg/kg MPD, 37.8% ± 5.9% after 2.5 mg/kg MPD, and 56.5% ± 3.9% after 10 mg/kg MPD. Greater attenuation from baseline was observed in the NAc and PFC. Differences in the intensity of

Dihydrotestosterone Potentiates EGF-Induced ERK Activation by Inducing SRC in Fetal Lung Fibroblasts

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Smith, Susan M.; Murray, Sandy; Pham, Lucia D.; Minoo, Parviz; Nielsen, Heber C.

2014-01-01

Lung maturation is regulated by interactions between mesenchymal and epithelial cells, and is delayed by androgens. Fibroblast–Type II cell communications are dependent on extracellular signal-regulated kinases (ERK) 1/2 activation by the ErbB receptor ligands epidermal growth factor (EGF), transforming growth factor (TGF)-α, and neuregulin (Nrg). In other tissues, dihydrotestosterone (DHT) has been shown to activate SRC by a novel nontranscriptional mechanism, which phosphorylates EGF receptors to potentiate EGF-induced ERK1/2 activation. This study sought to determine if DHT potentiates EGFR signaling by a nontranscriptional mechanism. Embryonic day (E)17 fetal lung cells were isolated from dams treated with or without DHT since E12. Cells were exposed to 30 ng/ml DHT for periods of 30 minutes to 3 days before being stimulated with 100 ng/ml EGF, TGF-α, or Nrg for up to 30 minutes. Lysates were immunoblotted for ErbB and SRC pathway signaling intermediates. DHT increased ERK1/2 activation by EGF, TGF-α, and Nrg in fibroblasts and Type II cells. Characterization in fibroblasts showed that potentiation of the EGF pathway was significant after 60 minutes of DHT exposure and persisted in the presence of the translational inhibitor cycloheximide. SRC and EGF receptor phosphorylation was increased by DHT, as was EGF-induced SHC1 phosphorylation and subsequent association with GRB2. Finally, SRC silencing, SRC inhibition with PP2, and overexpression of a dominant-negative SRC each prevented DHT from increasing EGF-induced ERK1/2 phosphorylation. These results suggest that DHT activates SRC to potentiate the signaling pathway leading from the EGF receptor to ERK activation in primary fetal lung fibroblasts. PMID:24484548

Epstein-Barr Virus Lytic Reactivation Activates B Cells Polyclonally and Induces Activation-Induced Cytidine Deaminase Expression: A Mechanism Underlying Autoimmunity and Its Contribution to Graves' Disease.

Science.gov (United States)

Nagata, Keiko; Kumata, Keisuke; Nakayama, Yuji; Satoh, Yukio; Sugihara, Hirotsugu; Hara, Sayuri; Matsushita, Michiko; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Hayashi, Kazuhiko

2017-04-01

Graves' disease is an autoimmune disease that results in and is the most common cause of hyperthyroidism, and the reactivation of persisting Epstein-Barr virus (EBV) in B lymphocytes induces the differentiation of host B cells into plasma cells. We previously reported that some EBV-infected B cells had thyrotropin receptor antibodies (TRAbs) as surface immunoglobulins (Igs), and EBV reactivation induced these TRAb+EBV+ cells to produce TRAbs. EBV reactivation induces Ig production from host B cells. The purpose of the present study was to examine total Ig productions from B cell culture fluids and to detect activation-induced cytidine deaminase (AID), nuclear factor kappa B (NF-κB), and EBV latent membrane protein (LMP) 1 in culture B cells during EBV reactivation induction and then we discussed the mechanisms of EBV reactivation-induced Ig production in relation to autoimmunity. We showed that the EBV reactivation induces the production of every isotype of Ig and suggested that the Ig production was catalyzed by AID through LMP1 and NF-κB. The results that the amount of IgM was significantly larger compared with IgG suggested the polyclonal B cell activation due to LMP1. We proposed the pathway of EBV reactivation induced Ig production; B cells newly infected with EBV are activated by polyclonal B cell activation and produce Igs through plasma cell differentiation induced by EBV reactivation. LMP1-induced AID enabled B cells to undergo class-switch recombination to produce every isotype of Ig. According to this mechanism, EBV rescues autoreactive B cells to produce autoantibodies, which contribute to the development and exacerbation of autoimmune diseases.

Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta

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He, Rui-Qing; Tang, Xiao-Feng; Zhang, Bao-Li [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Shanghai Institute of Hypertension, Shanghai (China); Li, Xiao-Dong [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China); Hong, Mo-Na [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Shanghai Institute of Hypertension, Shanghai (China); Chen, Qi-Zhi [Shanghai Institute of Hypertension, Shanghai (China); Han, Wei-Qing, E-mail: whan020@gmail.com [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China); Gao, Ping-Jin, E-mail: gaopingjin@sibs.ac.cn [State Key Laboratory of Medical Genetics, Shanghai Key Laboratory of Hypertension and Department of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (China); Laboratory of Vascular Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Shanghai Institute of Hypertension, Shanghai (China)

2016-04-29

Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-β and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes. - Highlights: • Direct activation of PAR1 and PAR2 led to adventitial fibroblast (AF) activation. • PAR1 and PAR2 antagonists attenuated Ang II-induced AF activation. • Ang II induced the upregulation and transactivation of PAR1/PAR2 in AFs.

Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta

International Nuclear Information System (INIS)

He, Rui-Qing; Tang, Xiao-Feng; Zhang, Bao-Li; Li, Xiao-Dong; Hong, Mo-Na; Chen, Qi-Zhi; Han, Wei-Qing; Gao, Ping-Jin

2016-01-01

Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-β and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes. - Highlights: • Direct activation of PAR1 and PAR2 led to adventitial fibroblast (AF) activation. • PAR1 and PAR2 antagonists attenuated Ang II-induced AF activation. • Ang II induced the upregulation and transactivation of PAR1/PAR2 in AFs.

Methylphenidate disintegration from oral formulations for intravenous use by experienced substance users.

Science.gov (United States)

Bjarnadottir, G D; Johannsson, M; Magnusson, A; Rafnar, B O; Sigurdsson, E; Steingrimsson, S; Asgrimsson, V; Snorradottir, I; Bragadottir, H; Haraldsson, H M

2017-09-01

Methylphenidate (MPH) is a prescription stimulant used to treat attention-deficit hyperactivity disorder. MPH is currently the preferred substance among most intravenous (i.v.) substance users in Iceland. Four types of MPH preparations were available in Iceland at the time of study: Immediate-release (IR), sustained-release (SR), osmotic controlled-release oral delivery (OROS) tablet and osmotic-controlled release (OCR). MPH OROS has previously been rated the least desirable by i.v. users and we hypothesized that this was associated with difficulty of disintegrating MPH from OROS formulation. The aim of the study was to measure the amount of MPH and the viscosity of the disintegrated solutions that were made from the four MPH formulations by four i.v.-users and non-users. A convenience sample of four i.v. substance users and 12 non-users. Non-users imitated the methods applied by experienced i.v. substance users for disintegrated MPH formulations. Both groups managed to disintegrate over 50% of MPH from IR and SR formulations but only 20% from OROS (pusers and non-users. To our knowledge, this is the first investigation of viscosity and the amount of disintegrated MPH from prescription drugs for i.v. use. The results indicate that the ease of disintegration, amount of MPH and viscosity may explain the difference in popularity for i.v. use between different MPH formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Acupuncture inhibits cue-induced heroin craving and brain activation.

Science.gov (United States)

Cai, Xinghui; Song, Xiaoge; Li, Chuanfu; Xu, Chunsheng; Li, Xiliang; Lu, Qi

2012-11-25

Previous research using functional MRI has shown that specific brain regions associated with drug dependence and cue-elicited heroin craving are activated by environmental cues. Craving is an important trigger of heroin relapse, and acupuncture may inhibit craving. In this study, we performed functional MRI in heroin addicts and control subjects. We compared differences in brain activation between the two groups during heroin cue exposure, heroin cue exposure plus acupuncture at the Zusanli point (ST36) without twirling of the needle, and heroin cue exposure plus acupuncture at the Zusanli point with twirling of the needle. Heroin cue exposure elicited significant activation in craving-related brain regions mainly in the frontal lobes and callosal gyri. Acupuncture without twirling did not significantly affect the range of brain activation induced by heroin cue exposure, but significantly changed the extent of the activation in the heroin addicts group. Acupuncture at the Zusanli point with twirling of the needle significantly decreased both the range and extent of activation induced by heroin cue exposure compared with heroin cue exposure plus acupuncture without twirling of the needle. These experimental findings indicate that presentation of heroin cues can induce activation in craving-related brain regions, which are involved in reward, learning and memory, cognition and emotion. Acupuncture at the Zusanli point can rapidly suppress the activation of specific brain regions related to craving, supporting its potential as an intervention for drug craving.

Prospective, naturalistic study of open-label OROS methylphenidate treatment in Chinese school-aged children with attention-deficit/hyperactivity disorder

Institute of Scientific and Technical Information of China (English)

ZHENG Yi; GONG Mei-en; YIN Qing-yun; MAI Jian-ning; JING Jin; LUO Xiang-yang; MA Hong-wei; LI Hai-bo; XIE Ling; LI Yan; Kuang Gui-fang; WANG Yu-feng; YI Ming-ji; WANG Feng; ZHU Xiao-hua; YAO Yah-bin; QIN Jiong; WANG Li-wen; ZOU Li-ping; JIN Xing-ming; XU Tong; WANG Yi; QI Yuan-li

2011-01-01

Background Attention deficit hyperactivity disorder (ADHD) is one of the most common mental disorders during childhood,characterized by the core symptoms of hyperactivity,impulsivity and inattention and puts great burden on children themselves,their families and the society.Osmotic release oral system methylphenidate (OROS-MPH) is a once-daily controlled-release formulation developed to overcome some of the limitations associated with immediate-release methylphenidate (IR-MPH).It has been marketed in China since 2005 but still lacks data from large-sample clinical trials on efficacy and safety profiles.The aim of this study was to evaluate the effectiveness and safety of OROS-MPH in children aged 6 to 16 years with ADHD under naturalistic clinical setting.Methods This 6-week,multi-center,prospective,open-label study enrolled 1447 ADHD children to once-daily OROS-MPH (18 mg,36 mg or 54 mg) treatment.The effectiveness measures were parent-rated Inattention and Overactivity With Aggression (IOWA) Conners I/O and O/D subscales,physician-rated CGI-I and parent-rated global efficacy assessment scale.Blood pressure,pulse rate measurement,adverse events (AEs) and concomitant medications and treatment review were conducted by the investigator and were served as safety measures.Results A total of 1447 children with ADHD (mean age (9.52±2.36) years) were enrolled in this trial.Totally 96.8％children received an OROS-MPH modal dose of 18 mg,3.1％ with 36 mg and 0.1％ with 54 mg at the endpoint of study.The parent IOWA Conners I/O score at the end of week 2 showed statistically significant (P ＜0.001) improvement with OROS-MPH (mean:6.95±2.71) versus the score at baseline (10.45±2.72).The change in the parent IOWA Conners O/D subscale,CGI-I and parent-rated global efficacy assessment scale also supported the superior efficacy for OROS-MPH treatment.Fewer than half of 1447 patients (511 (35.3％)) reported AEs,and the majority of the events reported were mild (68.2�

Prior methylphenidate self-administration alters the subsequent reinforcing effects of methamphetamine in rats.

Science.gov (United States)

Baladi, Michelle G; Nielsen, Shannon M; Umpierre, Anthony; Hanson, Glen R; Fleckenstein, Annette E

2014-12-01

Methylphenidate (MPD) is clinically effective in treating the symptoms of attention-deficit hyperactivity disorder; however, its relatively widespread availability has raised public health concerns on nonmedical use of MPD among certain adult populations. Most preclinical studies investigate whether presumed therapeutically relevant doses of MPD alter sensitivity to the reinforcing effects of other drugs, but it remains unclear whether doses of MPD likely exceeding therapeutic relevance impact the subsequent reinforcing effects of drugs. To begin to address this question, the effect of prior MPD self-administration (0.56 mg/kg/infusion) on the subsequent reinforcing effects of methamphetamine (METH, 0.032 or 0.1 mg/kg/infusion) was investigated in male Sprague-Dawley rats. For comparison, it was also determined whether prior experimenter-administered MPD, injected daily at a presumed therapeutically relevant dose (2 mg/kg), altered the subsequent reinforcing effects of METH. Results indicated that, under the current conditions, only a history of MPD self-administration increased sensitivity to the subsequent reinforcing effects of METH. Furthermore, MPD did not impact food-maintained responding, suggesting that the effect of MPD might be specific to drug reinforcers. These data suggest that short-term, nonmedical use of MPD might alter the positive reinforcing effects of METH in a manner relevant to vulnerability to drug use in humans.

Chronophin activation is necessary in Doxorubicin-induced actin cytoskeleton alteration.

Science.gov (United States)

Lee, Su Jin; Park, Jeen Woo; Kang, Beom Sik; Lee, Dong-Seok; Lee, Hyun-Shik; Choi, Sooyoung; Kwon, Oh-Shin

2017-06-01

Although doxorubicin (Dox)-induced oxidative stress is known to be associated with cytotoxicity, the precise mechanism remains unclear. Genotoxic stress not only generates free radicals, but also affects actin cytoskeleton stability. We showed that Dox-induced RhoA signaling stimulated actin cytoskeleton alterations, resulting in central stress fiber disruption at early time points and cell periphery cortical actin formation at a later stage, in HeLa cells. Interestingly, activation of a cofilin phosphatase, chronophin (CIN), was initially evoked by Dox-induced RhoA signaling, resulting in a rapid phosphorylated cofilin turnover leading to actin cytoskeleton remodeling. In addition, a novel interaction between CIN and 14-3-3ζ was detected in the absence of Dox treatment. We demonstrated that CIN activity is quite contrary to 14-3-3ζ binding, and the interaction leads to enhanced phosphorylated cofilin levels. Therefore, initial CIN activation regulation could be critical in Dox-induced actin cytoskeleton remodeling through RhoA/cofilin signaling. [BMB Reports 2017; 50(6): 335-340].

HTLV-1 Tax-induced NFκB activation is independent of Lys-63-linked-type polyubiquitination

International Nuclear Information System (INIS)

Gohda, Jin; Irisawa, Masato; Tanaka, Yuetsu; Sato, Shintaro; Ohtani, Kiyoshi; Fujisawa, Jun-ichi; Inoue, Jun-ichiro

2007-01-01

Human T-cell leukemia virus type 1 (HTLV-1) Tax-induced activation of nuclear factor-κB (NFκB) is thought to play a critical role in T-cell transformation and onset of adult T-cell leukemia. However, the molecular mechanism of the Tax-induced NFκB activation remains unknown. One of the mitogen-activated protein kinase kinase kinses (MAP3Ks) members, TAK1, plays a critical role in cytokine-induced activation of NFκB, which involves lysine 63-linked (K63) polyubiquitination of NEMO, a noncatalytic subunit of the IκB kinase complex. Here we show that Tax induces K63 polyubiquitination of NEMO. However, TAK1 is dispensable for Tax-induced NFκB activation, and deubiquitination of the K63 polyubiquitin chain failed to block Tax-induced NFκB activation. In addition, silencing of other MAP3Ks, including MEKK1, MEKK3, NIK, and TPL-2, did not affect Tax-induced NFκB activation. These results strongly suggest that unlike cytokine signaling, Tax-induced NFκB activation does not involve K63 polyubiquitination-mediated MAP3K activation

Fructokinase activity mediates dehydration-induced renal injury.

Science.gov (United States)

Roncal Jimenez, Carlos A; Ishimoto, Takuji; Lanaspa, Miguel A; Rivard, Christopher J; Nakagawa, Takahiko; Ejaz, A Ahsan; Cicerchi, Christina; Inaba, Shinichiro; Le, MyPhuong; Miyazaki, Makoto; Glaser, Jason; Correa-Rotter, Ricardo; González, Marvin A; Aragón, Aurora; Wesseling, Catharina; Sánchez-Lozada, Laura G; Johnson, Richard J

2014-08-01

The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24 h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy.

Neuropharmacology of light-induced locomotor activation.

Science.gov (United States)

Amato, Davide; Pum, Martin E; Groos, Dominik; Lauber, Andrea C; Huston, Joseph P; Carey, Robert J; de Souza Silva, Maria A; Müller, Christian P

2015-08-01

Presentation of non-aversive light stimuli for several seconds was found to reliably induce locomotor activation and exploratory-like activity. Light-induced locomotor activity (LIA) can be considered a convenient simple model to study sensory-motor activation. LIA was previously shown to coincide with serotonergic and dopaminergic activation in specific cortical areas in freely moving and anesthetized animals. In the present study we explore the neuropharmacology of LIA using a receptor antagonist/agonist approach in rats. The non-selective 5-HT2-receptor antagonist ritanserin (1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. Selective antagonism of either the 5-HT2A-receptor by MDL 11,939 (0.1-0.4 mg/kg, i.p.), or the 5-HT2C-receptor by SDZ SER 082 (0.125-0.5 mg/kg, i.p.), alone or in combination, had no significant influence on LIA. Also the selective 5-HT1A-receptor antagonist, WAY 100635 (0.4 mg/kg, i.p.) did not affect LIA. Neither did the preferential dopamine D2-receptor antagonist, haloperidol (0.025-0.1 mg/kg, i.p.) nor the D2/D3-receptor agonist, quinpirole (0.025-0.5 mg/kg, i.p.) affect the expression of LIA. However, blocking the glutamatergic NMDA-receptor with phencyclidine (PCP, 1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. This effect was also observed with ketamine (10 mg/kg, i.p.). These findings suggest that serotonin and dopamine receptors abundantly expressed in the cortex do not mediate light-stimulus triggered locomotor activity. PCP and ketamine effects, however, suggest an important role of NMDA receptors in LIA. Copyright © 2015 Elsevier Ltd. All rights reserved.

Remission in children and adolescents diagnosed with attention-deficit/hyperactivity disorder via an effective and tolerable titration scheme for osmotic release oral system methylphenidate.

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Chou, Wen-Jiun; Chen, Shin-Jaw; Chen, Ying-Sheue; Liang, Hsin-Yi; Lin, Chih-Chien; Tang, Ching-Shu; Huang, Yu-Shu; Yeh, Chin-Bin; Chou, Miao-Chun; Lin, Dai-Yueh; Hou, Po-Hsun; Wu, Yu-Yu; Liu, Hung-Jen; Huang, Ya-Fen; Hwang, Kai-Ling; Chan, Chin-Hong; Pan, Chia-Ho; Chang, Hsueh-Ling; Huang, Chi-Fen; Hsu, Ju-Wei

2012-06-01

The purpose of this study was to identify the optimal dose of osmotic release oral system methylphenidate (OROS-MPH) using a dosage forced-titration scheme to achieve symptomatic remission in children with attention- deficit/hyperactivity disorder (ADHD). We also evaluated the efficacy and safety of, and patient and parent satisfaction with, the change in therapy from immediate-release methylphenidate (IR-MPH) to OROS-MPH over 10 weeks. We recruited 521 children and adolescents aged 6-18 years with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnosis of ADHD, who had received IR-MPH treatments (titration phase of OROS-MPH to achieve symptomatic remission (defined as a score of 0 or 1 for each of the first 18 ADHD items in the Chinese version of the Swanson, Nolan, and Pelham, Version IV [SNAP-IV]), followed by a 4-week maintenance phase. The global ADHD severity and drug side effects of the participants were evaluated. Parents completed the ratings scales for the ADHD-related symptoms. Patient and parent satisfaction for the OROS-MPH treatment was also assessed. Among the 439 participants with ADHD who completed the trial, 290 participants (66.1%) achieved symptomatic remission. The mean dose of OROS-MPH among participants in remission was 36.7 mg (1.08 mg/kg) per day. Increased efficacy, superior satisfaction, and safety equivalent to that of IR-MPH were demonstrated in intra-individual comparisons from the baseline to the end of study. Determinants for remission included less severe ADHD symptoms (SNAP-IV score history of ADHD, and an appropriate dosage of medication according to the patient's weight. The findings suggest remission as a treatment goal for ADHD therapy by providing an optimal dosage of medication for children and adolescents with ADHD through using an effective and tolerable forced-titration scheme.

Pharmacological Management of Treatment-Induced Insomnia in ADHD

Science.gov (United States)

Kratochvil, Christopher J.; Lake, Marybeth; Pliszka, Steven R.; Walkup, John T.

2005-01-01

A 7-year-old girl with attention-deficit/hyperactivity disorder (ADHD), combined subtype, and oppositional defiant disorder presents with a complaint of marked insomnia. Her parents describe 60 to 90 minutes of nightly initial insomnia that began with the initiation of 36 mg OROS methylphenidate (Concerta) 2 months ago. Behavioral interventions…

Autophagy activation, not peroxisome proliferator-activated receptor γ coactivator 1α, may mediate exercise-induced improvements in glucose handling during diet-induced obesity.

Science.gov (United States)

Rosa-Caldwell, Megan E; Brown, Jacob L; Lee, David E; Blackwell, Thomas A; Turner, Kyle W; Brown, Lemuel A; Perry, Richard A; Haynie, Wesley S; Washington, Tyrone A; Greene, Nicholas P

2017-09-01

What is the central question of this study? What are the individual and combined effects of muscle-specific peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) overexpression and physical activity during high-fat feeding on glucose and exercise tolerance? What is the main finding and its importance? Our main finding is that muscle-specific PGC-1α overexpression provides no protection against lipid-overload pathologies nor does it enhance exercise adaptations. Instead, physical activity, regardless of PGC-1α content, protects against high-fat diet-induced detriments. Activation of muscle autophagy was correlated with exercise protection, suggesting that autophagy might be a mediating factor for exercise-induced protection from lipid overload. The prevalence of glucose intolerance is alarmingly high. Efforts to promote mitochondrial biogenesis through peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) to mitigate glucose intolerance have been controversial. However, physical activity remains a primary means to alleviate the condition. The aim of this study was to determine the combined effects of muscle-specific overexpression of PGC-1α and physical activity on glucose handling during diet-induced obesity. Wild-type (WT, ∼20) and PGC-1α muscle transgenic (MCK-PGC-1α, ∼20) mice were given a Western diet (WD) at 8 weeks age and allowed to consume food ab libitum throughout the study. At 12 weeks of age, all animals were divided into sedentary (SED) or voluntary wheel running (VWR) interventions. At 7, 11 and 15 weeks of age, animals underwent glucose tolerance tests (GTT) and graded exercise tests (GXT). At 16 weeks of age, tissues were collected. At 11 weeks, the MCK-PGC-1α animals had 50% greater glucose tolerance integrated area under the curve compared with WT. However, at 15 weeks, SED animals also had greater GTT integrated area under the curve compared with VWR, regardless of genotype; furthermore, SED

Methylphenidate enhances cognitive performance in adults with poor baseline capacities regardless of attention-deficit/hyperactivity disorder diagnosis.

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Agay, Nirit; Yechiam, Eldad; Carmel, Ziv; Levkovitz, Yechiel

2014-04-01

We compare the view that the effect of methylphenidate (MPH) is selective to individuals with attention-deficit/hyperactivity disorder (ADHD) with an alternative approach suggesting that its effect is more prominent for individuals with weak baseline capacities in relevant cognitive tasks. To evaluate theses 2 approaches, we administered sustained attention, working memory, and decision-making tasks to 20 ADHD adults and 19 control subjects, using a within-subject placebo-controlled design. The results demonstrated no main effects of MPH in the decision-making tasks. In the sustained attention and working-memory tasks, MPH enhanced performance of both ADHD and non-ADHD adults to a similar extent compared with placebo. Hence, the effect of MPH was not selective to ADHD adults. In addition, those benefitting most from MPH in all 3 task domains tended to be individuals with poor task performance. However, in most tasks, individuals whose performance was impaired by MPH were not necessarily better (or worse) performers. The findings suggest that the administration of MPH to adults with ADHD should consider not only clinical diagnosis but also their functional (performance-based) profile.

Activation of peroxisome proliferator-activated receptor-γ (PPARγ) induces cell death through MAPK-dependent mechanism in osteoblastic cells

International Nuclear Information System (INIS)

Kim, Sung Hun; Yoo, Chong Il; Kim, Hui Taek; Park, Ji Yeon; Kwon, Chae Hwa; Keun Kim, Yong

2006-01-01

The present study was undertaken to determine the role of the mitogen-activated protein kinase (MAPK) subfamilies in cell death induced by PPARγ agonists in osteoblastic cells. Ciglitazone and troglitazone, PPARγ agonists, resulted in a concentration- and time-dependent cell death, which was largely attributed to apoptosis. But a PPARα agonist ciprofibrate did not affect the cell death. Ciglitazone caused reactive oxygen species (ROS) generation and ciglitazone-induced cell death was prevented by antioxidants, suggesting an important role of ROS generation in the ciglitazone-induced cell death. ROS generation and cell death induced by ciglitazone were inhibited by the PPARγ antagonist GW9662. Ciglitazone treatment caused activation of extracellular signal-regulated kinase (ERK) and p38. Activation of ERK was dependent on epidermal growth factor receptor (EGFR) and that of p38 was independent. Ciglitazone-induced cell death was significantly prevented by PD98059, an inhibitor of ERK upstream kinase MEK1/2, and SB203580, a p38 inhibitor. Ciglitazone treatment increased Bax expression and caused a loss of mitochondrial membrane potential, and its effect was prevented by N-acetylcysteine, PD98059, and SB203580. Ciglitazone induced caspase activation, which was prevented by PD98059 and SB203580. The general caspase inhibitor z-DEVD-FMK and the specific inhibitor of caspases-3 DEVD-CHO exerted the protective effect against the ciglitazone-induced cell death. The EGFR inhibitors AG1478 and suramin protected against the ciglitazone-induced cell death. Taken together, these findings suggest that the MAPK signaling pathways play an active role in mediating the ciglitazone-induced cell death of osteoblasts and function upstream of a mitochondria-dependent mechanism. These data may provide a novel insight into potential therapeutic strategies for treatment of osteoporosis

Kupffer cells activation promoted binge drinking-induced fatty liver by activating lipolysis in white adipose tissues.

Science.gov (United States)

Zhao, Yu-Ying; Yang, Rui; Xiao, Mo; Guan, Min-Jie; Zhao, Ning; Zeng, Tao

2017-09-01

Kupffer cells (KCs) have been suggested to play critical roles in chronic ethanol induced early liver injury, but the role of KCs in binge drinking-induced hepatic steatosis remains unclear. This study was designed to investigate the roles of KCs inhibitor (GdCl 3 ) and TNF-α antagonist (etanercept) on binge drinking-induced liver steatosis and to explore the underlying mechanisms. C57BL/6 mice were exposed to three doses of ethanol (6g/kg body weight) to mimic binge drinking-induced fatty liver. The results showed that both GdCl 3 and etanercept partially but significantly alleviated binge drinking-induced increase of hepatic triglyceride (TG) level, and reduced fat droplets accumulation in mice liver. GdCl 3 but not etanercept significantly blocked binge drinking-induced activation of KCs. However, neither GdCl 3 nor etanercept could affect binge drinking-induced decrease of PPAR-α, ACOX, FAS, ACC and SCD protein levels, or increase of the LC3 II/LC3 I ratio and p62 protein level. Interestingly, both GdCl 3 and etanercept significantly suppressed binge drinking-induced phosphorylation of HSL in epididymal adipose tissues. Results of in vitro studies with cultured epididymal adipose tissues showed that TNF-α could increase the phosphorylation of HSL in adipose tissues and upgrade the secretion of free fatty acid (FFA) in the culture medium. Taken together, KCs inhibitor and TNF-α antagonist could partially attenuate binge drinking-induced liver steatosis, which might be attributed to the suppression of mobilization of white adipose tissues. These results suggest that KCs activation may promote binge drinking-induced fatty liver by TNF-α mediated activation of lipolysis in white adipose tissues. Copyright © 2017 Elsevier B.V. All rights reserved.

Human retinal pigment epithelial cell-induced apoptosis in activated T cells

DEFF Research Database (Denmark)

Jørgensen, A; Wiencke, A K; la Cour, M

1998-01-01

human retinal pigment epithelial (RPE) cells can induce apoptosis in activated T cells. METHODS: Fas ligand (FasL) expression was detected by flow cytometry and immunohistochemistry. Cultured RPE cells were cocultured with T-cell lines and peripheral blood lymphocytes for 6 hours to 2 days. Induction...... of apoptosis was detected by 7-amino-actinomycin D and annexin V staining. RESULTS: Retinal pigment epithelial cells expressed FasL and induced apoptosis in activated Fas+ T cells. Blocking of Fas-FasL interaction with antibody strongly inhibited RPE-mediated T-cell apoptosis. Retinal pigment epithelial cells...... induced apoptosis in several activated T-cell populations and T-cell lines, including T-cell antigen receptor (TCR)-CD3-negative T-cell lines. In contrast, RPE cells induced little or no apoptosis in resting peripheral T cells. Major histocompatibility complex (MHC) class II monoclonal antibodies, which...

Nrf2 activation prevents cadmium-induced acute liver injury

International Nuclear Information System (INIS)

Wu, Kai C.; Liu, Jie J.; Klaassen, Curtis D.

2012-01-01

Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H 2 DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1-HKO mice were

Nrf2 activation prevents cadmium-induced acute liver injury

Energy Technology Data Exchange (ETDEWEB)

Wu, Kai C. [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Liu, Jie J. [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Klaassen, Curtis D., E-mail: cklaasse@kumc.edu [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States)

2012-08-15

Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H{sub 2}DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1-HKO mice

Laser Induced Selective Activation For Subsequent Autocatalytic Electroless Plating

DEFF Research Database (Denmark)

Zhang, Yang

. The third hypothesis is that the activation and rinsing process can be described by diffusion. This hypothesis is proved using Fick’s diffusion laws combined with the short-time-plating experiment. The influence of laser parameters on the surface structure is investigated for Nd:YAG, UV, and fiber lasers......The subject of this PhD thesis is “Laser induced selective activation for subsequent autocatalytic electroless plating.” The objective of the project is to investigate the process chains for micro structuring of polymer surfaces for selective micro metallization. Laser induced selective activation...... (LISA) is introduced and studied as a new technique for producing 3D moulded interconnect devices (3D-MIDs). This technique enables the metallization of polymer surface modified by laser and subsequently activated by a PdCl2/SnCl2 system. Various technologies exist on an industrial level...

Kefiran suppresses antigen-induced mast cell activation.

Science.gov (United States)

Furuno, Tadahide; Nakanishi, Mamoru

2012-01-01

Kefir is a traditional fermented milk beverage produced by kefir grains in the Caucasian countries. Kefiran produced by Lactobacillus kefiranofaciens in kefir grains is an exopolysaccharide having a repeating structure with glucose and galactose residues in the chain sequence and has been suggested to exert many health-promoting effects such as immunomodulatory, hypotensive, hypocholesterolemic activities. Here we investigated the effects of kefiran on mast cell activation induced by antigen. Pretreatment with kefiran significantly inhibited antigen-induced Ca(2+) mobilization, degranulation, and tumor necrosis factor-α production in bone marrow-derived mast cells (BMMCs) in a dose-dependent manner. The phosphorylation of Akt, glycogen synthase kinase 3β, and extracellular signal-regulated kinases (ERKs) after antigen stimulation was also suppressed by pretreatment of BMMCs with kefiran. These findings indicate that kefiran suppresses mast cell degranulation and cytokine production by inhibiting the Akt and ERKs pathways, suggesting an anti-inflammatory effect for kefiran.

Minocycline attenuates sevoflurane-induced cell injury via activation of Nrf2

Science.gov (United States)

Tian, Yue; Wu, Xiuying; Guo, Shanbin; Ma, Ling; Huang, Wei; Zhao, Xiaochun

2017-01-01

Minocycline has been demonstrated to exert neuroprotective effects in various experimental models. In the present study, we investigated the mechanisms underlying the protective effects of minocycline on cell injury induced by the inhalation of the anesthetic, sevoflurane. In our in vivo experiments using rats, minocycline attenuated sevoflurane-induced neuronal degeneration and apoptosis in the rat hippocampus, and this effect was associated with the minocycline-mediated suppression of oxidative stress in the hippocampus. In in vitro experiments, minocycline inhibited sevoflurane-induced apoptosis and the production of reactive oxygen species (ROS) in H4 human neuroglioma cells. In addition, minocycline suppressed the sevoflurane-induced upregulation of interleukin (IL)-6 and the activation of the nuclear factor-κB (NF-κB) signaling pathway in H4 cells. Furthermore, we found that nuclear factor E2-related factor 2 (Nrf2), an activator of the stress response, was upregulated and activated upon sevoflurane treatment both in the rat hippocampus and in H4 cells. In addition, minocycline further augmented the upregulation and activation of Nrf2 when used in conjunction with sevoflurane. Moreover, the knockdown of Nrf2 in H4 cells by small interfering RNA (siRNA) diminished the cytoprotective effect of minocycline, and attenuated the inhibitory effect of minocycline on ROS production, IL-6 upregulation and the activation of the NF-κB signaling pathway. On the whole, our findings indicate that minocycline may exert protective effects against sevoflurane-induced cell injury via the Nrf2-modulated antioxidant response and the inhibition of the activation of the NF-κB signaling pathway. PMID:28260081

mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity.

Science.gov (United States)

Jin, Zhe-Zhu; Wang, Wei; Fang, Di-Long; Jin, Yong-Jun

2016-09-30

We here tested the anti-colorectal cancer (CRC) activity by a first-in-class small molecule TRAIL inducer ONC201. The potential effect of mTOR on ONC201's actions was also examined. ONC201 induced moderate cytotoxicity against CRC cell lines (HT-29, HCT-116 and DLD-1) and primary human CRC cells. Significantly, AZD-8055, a mTOR kinase inhibitor, sensitized ONC201-induced cytotoxicity in CRC cells. Meanwhile, ONC201-induced TRAIL/death receptor-5 (DR-5) expression, caspase-8 activation and CRC cell apoptosis were also potentiated with AZD-8055 co-treatment. Reversely, TRAIL sequestering antibody RIK-2 or the caspase-8 specific inhibitor z-IETD-fmk attenuated AZD-8055 plus ONC201-induced CRC cell death. Further, mTOR kinase-dead mutation (Asp-2338-Ala) or shRNA knockdown significantly sensitized ONC201's activity in CRC cells, leading to profound cell death and apoptosis. On the other hand, expression of a constitutively-active S6K1 (T389E) attenuated ONC201-induced CRC cell apoptosis. For the mechanism study, we showed that ONC201 blocked Akt, but only slightly inhibited mTOR in CRC cells. Co-treatment with AZD-8055 also concurrently blocked mTOR activation. These results suggest that mTOR could be a primary resistance factor of ONC201 in CRC cells. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of Active Mastication on Chronic Stress-Induced Bone Loss in Mice.

Science.gov (United States)

Azuma, Kagaku; Furuzawa, Manabu; Fujiwara, Shu; Yamada, Kumiko; Kubo, Kin-ya

2015-01-01

Chronic psychologic stress increases corticosterone levels, which decreases bone density. Active mastication or chewing attenuates stress-induced increases in corticosterone. We evaluated whether active mastication attenuates chronic stress-induced bone loss in mice. Male C57BL/6 (B6) mice were randomly divided into control, stress, and stress/chewing groups. Stress was induced by placing mice in a ventilated restraint tube (60 min, 2x/day, 4 weeks). The stress/chewing group was given a wooden stick to chew during the experimental period. Quantitative micro-computed tomography, histologic analysis, and biochemical markers were used to evaluate the bone response. The stress/chewing group exhibited significantly attenuated stress-induced increases in serum corticosterone levels, suppressed bone formation, enhanced bone resorption, and decreased trabecular bone mass in the vertebrae and distal femurs, compared with mice in the stress group. Active mastication during exposure to chronic stress alleviated chronic stress-induced bone density loss in B6 mice. Active mastication during chronic psychologic stress may thus be an effective strategy to prevent and/or treat chronic stress-related osteopenia.

Clinical significance of plasminogen activator inhibitor activity in patients with exercise-induced ischemia

International Nuclear Information System (INIS)

Sakata, K.; Kurata, C.; Taguchi, T.; Suzuki, S.; Kobayashi, A.; Yamazaki, N.; Rydzewski, A.; Takada, Y.; Takada, A.

1990-01-01

To assess the fibrinolytic system in patients with exercise-induced ischemia and its relation to ischemia and severity of coronary artery disease (CAD), 47 patients with CAD confirmed by results of coronary angiography underwent symptom-limited multistage exercise thallium-201 emission computed tomography. All patients with CAD had exercise-induced ischemia as assessed from thallium-201 images. Pre- and peak exercise blood samples from each patient and preexercise blood samples from control subjects were assayed for several fibrinolytic components and were also assayed for plasma adrenaline. The extent of ischemia was defined as delta visual uptake score (total visual uptake score in delayed images minus total visual uptake score in initial images) and the severity of CAD as the number of diseased vessels. In the basal condition, plasminogen activator inhibitor (PAI) activity was significantly higher in patients with exercise-induced ischemia as compared to control subjects (p less than 0.01), although there were no significant differences in other fibrinolytic variables between the two groups. Moreover, PAI activity in the basal condition displayed a significantly positive correlation with the extent of ischemia (r = 0.47, p less than 0.01). Patients with exercise-induced ischemia were divided into two groups (24 with single-vessel disease and 23 with multivessel disease). There were no significant differences in coronary risk factors, hemodynamics, or plasma adrenaline levels during exercise between single-vessel and multivessel disease except that delta visual uptake score was significantly higher in multivessel disease (p less than 0.01)

Gender Differences in the Behavioral Symptoms and Neuropsychological Performance of Patients with Attention-Deficit/Hyperactivity Disorder Treated with Methylphenidate: A Two-Year Follow-up Study.

Science.gov (United States)

Wang, Liang-Jen; Chen, Chih-Ken; Huang, Yu-Shu

2015-08-01

This study investigated the gender differences in behavioral symptoms, as rated by various informants, and in neuropsychological performance, among patients with attention-deficit/hyperactivity disorder (ADHD) treated with methylphenidate during 24 months in a clinical setting. Study participants comprised 128 boys (mean age: 13.2±2.4 years) and 26 girls (mean age: 12.8±1.0 years) with ADHD. All patients were prescribed short-acting oral methylphenidate, taken two or three times daily; each dose ranged between 0.3 and 1.0 mg/kg. At the baseline and 6, 12, 18, and 24 months later, behavioral symptoms were evaluated using the parent and teacher forms of the Swanson, Nolan, and Pelham Version IV (SNAP-IV) scale for ADHD and the ADHD Rating Scale (completed by a child psychiatrist). In addition, neuropsychological function was assessed using the Test of Variables of Attention (TOVA) at each interval. Although both the boys and girls exhibited a significant decrease in the ADHD symptoms observed by parents and clinicians, the girls improved more than the boys did. Based on the teacher reports, neither the boys nor the girls exhibited significant decreases in ADHD symptoms. The symptoms rated by teachers were more severe in the boys than in the girls throughout the first 12 months; however, the gender difference lessened after 12 months. Based on the TOVA assessment, a composite score (containing response time, response time variability, and ADHD score obtained using the TOVA) did not indicate differences between genders. However, another composite score (containing omission errors, commission errors, and response sensitivity) suggested significant improvement only in the boys. The results suggested that according to a longitudinal follow-up, behavioral and neuropsychological changes among patients with ADHD might differ between genders. Gathering multidimensional information from patients with ADHD is essential in determining how gender modifies the functional

Resting-state brain activity in the motor cortex reflects task-induced activity: A multi-voxel pattern analysis.

Science.gov (United States)

Kusano, Toshiki; Kurashige, Hiroki; Nambu, Isao; Moriguchi, Yoshiya; Hanakawa, Takashi; Wada, Yasuhiro; Osu, Rieko

2015-08-01

It has been suggested that resting-state brain activity reflects task-induced brain activity patterns. In this study, we examined whether neural representations of specific movements can be observed in the resting-state brain activity patterns of motor areas. First, we defined two regions of interest (ROIs) to examine brain activity associated with two different behavioral tasks. Using multi-voxel pattern analysis with regularized logistic regression, we designed a decoder to detect voxel-level neural representations corresponding to the tasks in each ROI. Next, we applied the decoder to resting-state brain activity. We found that the decoder discriminated resting-state neural activity with accuracy comparable to that associated with task-induced neural activity. The distribution of learned weighted parameters for each ROI was similar for resting-state and task-induced activities. Large weighted parameters were mainly located on conjunctive areas. Moreover, the accuracy of detection was higher than that for a decoder whose weights were randomly shuffled, indicating that the resting-state brain activity includes multi-voxel patterns similar to the neural representation for the tasks. Therefore, these results suggest that the neural representation of resting-state brain activity is more finely organized and more complex than conventionally considered.

Arsenic-induced alteration in intracellular calcium homeostasis induces head kidney macrophage apoptosis involving the activation of calpain-2 and ERK in Clarias batrachus

International Nuclear Information System (INIS)

Banerjee, Chaitali; Goswami, Ramansu; Datta, Soma; Rajagopal, R.; Mazumder, Shibnath

2011-01-01

We had earlier shown that exposure to arsenic (0.50 μM) caused caspase-3 mediated head kidney macrophage (HKM) apoptosis involving the p38-JNK pathway in Clarias batrachus. Here we examined the roles of calcium (Ca 2+ ) and extra-cellular signal-regulated protein kinase (ERK), the other member of MAPK-pathway on arsenic-induced HKM apoptosis. Arsenic-induced HKM apoptosis involved increased expression of ERK and calpain-2. Nifedipine, verapamil and EGTA pre-treatment inhibited the activation of calpain-2, ERK and reduced arsenic-induced HKM apoptosis as evidenced from reduced caspase-3 activity, Annexin V-FITC-propidium iodide and Hoechst 33342 staining. Pre-incubation with ERK inhibitor U 0126 inhibited the activation of calpain-2 and interfered with arsenic-induced HKM apoptosis. Additionally, pre-incubation with calpain-2 inhibitor also interfered with the activation of ERK and inhibited arsenic-induced HKM apoptosis. The NADPH oxidase inhibitor apocynin and diphenyleneiodonium chloride also inhibited ERK activation indicating activation of ERK in arsenic-exposed HKM also depends on signals from NADPH oxidase pathway. Our study demonstrates the critical role of Ca 2+ homeostasis on arsenic-induced HKM apoptosis. We suggest that arsenic-induced alteration in intracellular Ca 2+ levels initiates pro-apoptotic ERK and calpain-2; the two pathways influence each other positively and induce caspase-3 mediated HKM apoptosis. Besides, our study also indicates the role of ROS in the activation of ERK pathway in arsenic-induced HKM apoptosis in C. batrachus. - Highlights: → Altered Ca 2+ homeostasis leads to arsenic-induced HKM apoptosis. → Calpain-2 plays a critical role in the process. → ERK is pro-apoptotic in arsenic-induced HKM apoptosis. → Arsenic-induced HKM apoptosis involves cross talk between calpain-2 and ERK.

Combined ω3 and ω6 supplementation in children with attention-deficit hyperactivity disorder (ADHD) refractory to methylphenidate treatment: a double-blind, placebo-controlled study.

Science.gov (United States)

Perera, Hemamali; Jeewandara, Kamal Chandima; Seneviratne, Sudarshi; Guruge, Chandima

2012-06-01

Children (6-12 years) with attention-deficit hyperactivity disorder (ADHD) being treated with methylphenidate and standard behavior therapy for more than 6 months, whose parents reported no improvement in behavior and academic learning, were randomly assigned to receive supplementation with a combined ω3 and ω6 preparation or a placebo. Outcome was measured at 3 and 6 months after treatment using a self-assessment checklist completed by the parents. Statistically significant improvement was found in the treatment group compared with the placebo group (P parents and teachers. Distractibility failed to show improvement. Effect sizes ranged from 0.3 to 1.1 at 3 months and 0.2 to 1.4 at 6 months for individual symptom variables.

Activation of PPARγ is not involved in butyrate-induced epithelial cell differentiation

International Nuclear Information System (INIS)

Ulrich, S.; Waechtershaeuser, A.; Loitsch, S.; Knethen, A. von; Bruene, B.; Stein, J.

2005-01-01

Histone deacetylase-inhibitors affect growth and differentiation of intestinal epithelial cells by inducing expression of several transcription factors, e.g. Peroxisome proliferator-activated receptor γ (PPARγ) or vitamin D receptor (VDR). While activation of VDR by butyrate mainly seems to be responsible for cellular differentiation, the activation of PPARγ in intestinal cells remains to be elucidated. The aim of this study was to determine the role of PPARγ in butyrate-induced cell growth inhibition and differentiation induction in Caco-2 cells. Treatment with PPARγ ligands ciglitazone and BADGE (bisphenol A diglycidyl) enhanced butyrate-induced cell growth inhibition in a dose- and time-dependent manner, whereas cell differentiation was unaffected after treatment with PPARγ ligands rosiglitazone and MCC-555. Experiments were further performed in dominant-negative PPARγ mutant cells leading to an increase in cell growth whereas butyrate-induced cell differentiation was again unaffected. The present study clearly demonstrated that PPARγ is involved in butyrate-induced inhibition of cell growth, but seems not to play an essential role in butyrate-induced cell differentiation

Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder.

Science.gov (United States)

Schulz, Kurt P; Fan, Jin; Bédard, Anne-Claude V; Clerkin, Suzanne M; Ivanov, Iliyan; Tang, Cheuk Y; Halperin, Jeffrey M; Newcorn, Jeffrey H

2012-09-01

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing psychiatric disorder that affects both children and adults. There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD; however, little is known about the mechanisms by which these different treatments exert their therapeutic effects. OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylphenidate hydrochloride vs the nonstimulant atomoxetine hydrochloride. DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylphenidate (n = 18) or atomoxetine (n = 18) using a parallel-groups design. SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine, New York, New York. PARTICIPANTS Thirty-six youth with ADHD (mean [SD] age, 11.2 [2.7] years; 27 boys) recruited from randomized clinical trials. MAIN OUTCOME MEASURES Changes in brain activation during a go/no-go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version. RESULTS Treatment with methylphenidate vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean (SD) improvements in ratings of ADHD symptoms (55% [30%] vs 57% [25%]). Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments. Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylphenidate in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex. These findings were not attributable to baseline differences in activation. CONCLUSIONS Treatment with methylphenidate and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic

Regulation of radiation-induced protein kinase Cδ activation in radiation-induced apoptosis differs between radiosensitive and radioresistant mouse thymic lymphoma cell lines

International Nuclear Information System (INIS)

Nakajima, Tetsuo; Yukawa, Osami; Tsuji, Hideo; Ohyama, Harumi; Wang, Bing; Tatsumi, Kouichi; Hayata, Isamu; Hama-Inaba, Hiroko

2006-01-01

Protein kinase Cδ (PKCδ) has an important role in radiation-induced apoptosis. The expression and function of PKCδ in radiation-induced apoptosis were assessed in a radiation-sensitive mouse thymic lymphoma cell line, 3SBH5, and its radioresistant variant, XR223. Rottlerin, a PKCδ-specific inhibitor, completely abolished radiation-induced apoptosis in 3SBH5. Radiation-induced PKCδ activation correlated with the degradation of PKCδ, indicating that PKCδ activation through degradation is involved in radiation-induced apoptosis in radiosensitive 3SBH5. In radioresistant XR223, radiation-induced PKCδ activation was lower than that in radiosensitive 3SBH5. Cytosol PKCδ levels in 3SBH5 decreased markedly after irradiation, while those in XR223 did not. There was no apparent change after irradiation in the membrane fractions of either cell type. In addition, basal cytosol PKCδ levels in XR223 were higher than those in 3SBH5. These results suggest that the radioresistance in XR223 to radiation-induced apoptosis is due to a difference in the regulation of radiation-induced PKCδ activation compared to that of 3SBH5. On the other hand, Atm -/- mouse thymic lymphoma cells were more radioresistant to radiation-induced apoptosis than wild-type mouse thymic lymphoma cells. Irradiated wild-type cells, but not Atm -/- cells, had decreased PKCδ levels, indicating that the Atm protein is involved in radiation-induced apoptosis through the induction of PKCδ degradation. The decreased Atm protein levels induced by treatment with Atm small interfering RNA had no effect on radiation-induced apoptosis in 3SBH5 cells. These results suggest that the regulation of radiation-induced PKCδ activation, which is distinct from the Atm-mediated cascade, determines radiation sensitivity in radiosensitive 3SBH5 cells

Reinforcement Enhances Vigilance Among Children With ADHD: Comparisons to Typically Developing Children and to the Effects of Methylphenidate

Science.gov (United States)

Bubnik, Michelle G.; Hawk, Larry W.; Pelham, William E.; Waxmonsky, James G.; Rosch, Keri S.

2014-01-01

Sustained attention and reinforcement are posited as causal mechanisms in Attention-Deficit/Hyperactivity Disorder (ADHD), but their interaction has received little empirical study. In two studies, we examined the impact of performance-based reinforcement on sustained attention over time, or vigilance, among 9- to 12-year-old children. Study 1 demonstrated the expected vigilance deficit among children with ADHD (n=25; 12% female) compared to typically developing (TD) controls (n=33; 22% female) on a standard continuous performance task (CPT). During a subsequent visit, reinforcement improved attention more among children with ADHD than controls. Study 2 examined the separate and combined effects of reinforcement and acute methylphenidate (MPH) on CPT performance in children with ADHD (n=19; 21% female). Both reinforcement and MPH enhanced overall target detection and attenuated the vigilance decrement that occurred in no-reinforcement, placebo condition. Cross-study comparisons suggested that the combination of MPH and reinforcement eliminated the vigilance deficit in children with ADHD, normalizing sustained attention. This work highlights the clinically and theoretically interesting intersection of reinforcement and sustained attention. PMID:24931776

O metifenidato no Brasil: uma década de publicações Methylphenidate in Brazil: a decade of publications

Directory of Open Access Journals (Sweden)

Francisco Ortega

2013-03-01

Full Text Available O metilfenidato é um estimulante comercializado desde os anos 50 na Suíça, na Alemanha e nos EUA. Mas foi somente a partir de sua associação com o Transtorno do Déficit de Atenção e Hiperatividade (TDAH que suas vendas alavancaram, tornando-se o estimulante mais consumido no mundo. Este artigo tem por objetivo apresentar os resultados de uma análise das publicações brasileiras sobre os usos do metilfenidato no Brasil, ao longo da última década. Com isto, visa compreender como as informações são apresentadas ou omitidas nos diferentes espaços de divulgação impressa. Para tal análise, foram pesquisadas publicações científicas, nos principais periódicos de psiquiatria brasileiros, e reportagens de jornais e revistas nacionais destinados ao público em geral. A pesquisa inclui as publicações do período de 1998 a 2008. Destaca-se como ponto relevante da análise a importante participação dos laboratórios no financiamento dos grupos e pesquisas sobre TDAH. Os achados indicam que a combinação do uso do medicamento com psicoterapias, a dependência do medicamento e a ideia de que existe excesso de prescrição no Brasil são temas controversos nas publicações analisadas.Methylphenidate is frequently associated with Attention Deficit Hyperactivity disorder (ADHD, though this psychostimulant has been on the market in Switzerland, Germany and the US since the 1950s. After its association with ADHD, Ritalin has become the world's most widely used psychostimulant. The scope of this article is to present the results of an analysis of publications concerning the use of Methylphenidate in Brazil over a decade. It seeks to understand how the information is presented or omitted in the different printed materials. For the analysis, the most important Brazilian psychiatric journals as well as major Brazilian newspapers and magazines for the general public for the 1998-2008 period were consulted. One important point that resulted

Characteristics of induced activity from medical linear accelerators

International Nuclear Information System (INIS)

Wang Yizhen; Evans, Michael D.C.; Podgorsak, Ervin B.

2005-01-01

A study of the induced activity in a medical linear accelerator (linac) room was carried out on several linac installations. Higher beam energy, higher dose rate, and larger field size generally result in higher activation levels at a given point of interest, while the use of multileaf collimators (MLC) can also increase the activation level at the isocenter. Both theoretical and experimental studies reveal that the activation level in the morning before any clinical work increases from Monday to Saturday and then decreases during the weekend. This weekly activation picture keeps stable from one week to another during standard clinical operation of the linac. An effective half-life for a given point in the treatment room can be determined from the measured or calculated activity decay curves. The effective half-life for points inside the treatment field is longer than that for points outside of the field in the patient plane, while a larger field and longer irradiation time can also make the effective half-life longer. The activation level reaches its practical saturation value after a 30 min continuous irradiation, corresponding to 12 000 MU at a 'dose rate' of 400 MU/min. A 'dose' of 300 MU was given 20 times in 15 min intervals to determine the trends in the activation level in a typical clinical mode. As well, a long-term (85 h over a long weekend) decay curve was measured to evaluate the long-term decay of room activation after a typical day of clinical linac use. A mathematical model for the activation level at the isocenter has been established and shown to be useful in explaining and predicting the induced activity levels for typical clinical and experimental conditions. The activation level for a 22 MeV electron beam was also measured and the result shows it is essentially negligible

[123I]Iodobenzamide binding to the rat dopamine D2 receptor in competition with haloperidol and endogenous dopamine - an in vivo imaging study with a dedicated small animal SPECT

International Nuclear Information System (INIS)

Nikolaus, Susanne; Larisch, Rolf; Wirrwar, Andreas; Jamdjeu-Noune, Marlyse; Antke, Christina; Beu, Markus; Mueller, Hans-Wilhelm; Schramm, Nils

2005-01-01

This study assessed [ 123 I]iodobenzamide binding to the rat dopamine D 2 receptor in competition with haloperidol and endogenous dopamine using a high-resolution small animal SPECT. Subsequent to baseline quantifications of D 2 receptor binding, imaging studies were performed on the same animals after pre-treatment with haloperidol and methylphenidate, which block D 2 receptors and dopamine transporters, respectively. Striatal baseline equilibrium ratios (V 3 '' ) of [ 123 I]iodobenzamide binding were 1.42±0.31 (mean±SD). After pre-treatment with haloperidol and methylphenidate, V 3 '' values decreased to 0.54±0.46 (p 123 I]iodobenzamide binding induced by pre-treatment with haloperidol reflects D 2 receptor blockade, whereas the decrease in receptor binding induced by pre-treatment with methylphenidate can be interpreted in terms of competition between [ 123 I]IBZM and endogenous dopamine. Findings show that multiple in vivo measurements of [ 123 I]iodobenzamide binding to D 2 receptors in competition with exogenous and endogenous ligands are feasible in the same animal. This may be of future relevance for the in vivo evaluation of novel radioligands as well as for studying the interrelations between pre- and/or postsynaptic radioligand binding and different levels of endogenous dopamine. (orig.)

盐酸哌甲酯控释剂治疗儿童ADHD临床疗效影响因素分析%Factors influencing efficacy of methylphenidate hydrochloride controlled release agent on children with attention deficit hyperactivity disorder

Institute of Scientific and Technical Information of China (English)

王四美; 龚群; 陈津津; 张凤玲; 何琳

2017-01-01

Objective To observe the influencing factors of clinical effect of methylphenidate hydrochloride controlled release agent as central nervous system stimulant on attention deficit hyperactivity disorder (ADHD) in children.Methods Method of self-control was used to select 711 children diagnosed as ADHD and needing therapy in Shanghai Children ' s Hospital during the period of January 2014 to December 2015.After treatment with methylphenidate hydrochloride controlled release agent , therapeutic efficacy was evaluated before and after treatment with Swanson Nolan and Pelham Version IV (SNAP-Ⅳ) and Combined Raven's Test (CRT) at 6 week and 6 month. Results Methylphenidate hydrochloride controlled release agent was more effective to inattentive type and ADHD combined type than to hyperactive-impulsive type (χ2 =73.109,P<0.01).It was better to ADHD children with good cognitive function than to children with cognition dysfunction (χ2 =100.225, P <0.01).Conclusion Methylphenidate hydrochloride controlled release agent is effective to different types of ADHD children , and the therapeutic efficacy is influenced by ADHD subtypes , children ' s intelligence and dosage .%目的 观察中枢神经兴奋剂盐酸哌甲酯控释剂治疗注意缺陷多动障碍(ADHD)患儿临床疗效的影响因素.方法采取自身对照研究方法,选取2014年1月至2015年12月在上海市儿童医院儿保门诊就诊被诊断为ADHD并需要进行治疗的患儿711例;经过盐酸哌甲酯控释剂治疗后,分别于6周、6个月后采用斯诺佩评估量表(SNAP-Ⅳ)的家长使用量表、联合型瑞文测验(CRT)等相关测试,进行治疗前后疗效评估.结果盐酸哌甲酯控释剂对注意力缺陷型和混合型的ADHD患儿治疗效果明显优于多动型/冲动型(χ2=73.109,P<0.01);对认知功能好的ADHD患儿疗效优于合并认知障碍者(χ2=100.225,P<0.01).结论盐酸哌甲酯控释剂治疗儿童不同类型ADHD疗效肯定;疗效受到ADHD类型、患儿智力、药物剂量等的影响.

Ginkgo biloba as an adjunct to methylphenidate in the treatment of attention deficit hyperactivity disorder in children: review of articles

Directory of Open Access Journals (Sweden)

Paria Hebrani

2015-01-01

Full Text Available Attention-deficit/hyperactivity disorder is one of the most common psychiatric disorders in childhood. The medications which inhibit the reuptake of noradrenline and dopamine including psychostimulants such as methylphenidate and dextroamphetamine and non-stimulating pre-frontal cortex noradrenaline reuptake inhibitor such as atomoxetine, are the standard treatment of ADHD. Adverse effects of stimulants have been reported in thirty percent of patients with attention-deficit/hyperactivity disorder. More than fifty percent of the parents of these children have tried one or more complementary or alternative medicines including vitamins in their children. Ginkgo biloba has been described to be effective for various neuropsychiatric symptoms. It was assumed that ginkgo biloba might improve some symptoms of attention deficit disorder as well. Nevertheless, no systematic study reported a possible efficacy of ginkgo biloba in attention deficit disorder. This review article evaluates the available evidence on the efficacy of ginkgo biloba medication in Attention-deficit/hyperactivity disorder children to present an appropriate guidance for this common child disorder.

Chemically induced and light-independent cryptochrome photoreceptor activation.

Science.gov (United States)

Rosenfeldt, Gesa; Viana, Rafael Muñoz; Mootz, Henning D; von Arnim, Albrecht G; Batschauer, Alfred

2008-01-01

The cryptochrome photoreceptors of higher plants are dimeric proteins. Their N-terminal photosensory domain mediates dimerization, and the unique C-terminal extension (CCT) mediates signaling. We made use of the human FK506-binding protein (FKBP) that binds with high affinity to rapamycin or rapamycin analogs (rapalogs). The FKBP-rapamycin complex is recognized by another protein, FRB, thus allowing rapamycin-induced dimerization of two target proteins. Here we demonstrate by bioluminescence resonance energy transfer (BRET) assays the applicability of this regulated dimerization system to plants. Furthermore, we show that fusion proteins consisting of the C-terminal domain of Arabidopsis cryptochrome 2 fused to FKBP and FRB and coexpressed in Arabidopsis cells specifically induce the expression of cryptochrome-controlled reporter and endogenous genes in darkness upon incubation with the rapalog. These results demonstrate that the activation of cryptochrome signal transduction can be chemically induced in a dose-dependent fashion and uncoupled from the light signal, and provide the groundwork for gain-of-function experiments to study specifically the role of photoreceptors in darkness or in signaling cross-talk even under light conditions that activate members of all photoreceptor families.

A synthetic peptide blocking TRPV1 activation inhibits UV-induced skin responses.

Science.gov (United States)

Kang, So Min; Han, Sangbum; Oh, Jang-Hee; Lee, Young Mee; Park, Chi-Hyun; Shin, Chang-Yup; Lee, Dong Hun; Chung, Jin Ho

2017-10-01

Transient receptor potential type 1 (TRPV1) can be activated by ultraviolet (UV) irradiation, and mediates UV-induced matrix metalloproteinase (MMP)-1 and proinflammatory cytokines in keratinocytes. Various chemicals and compounds targeting TRPV1 activation have been developed, but are not in clinical use mostly due to their safety issues. We aimed to develop a novel TRPV1-targeting peptide to inhibit UV-induced responses in human skin. We designed and generated a novel TRPV1 inhibitory peptide (TIP) which mimics the specific site in TRPV1 (aa 701-709: Gln-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr, QRAITILDT), Thr 705 , and tested its efficacy of blocking UV-induced responses in HaCaT, mouse, and human skin. TIP effectively inhibited capsaicin-induced calcium influx and TRPV1 activation. Treatment of HaCaT with TIP prevented UV-induced increases of MMP-1 and pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-α. In mouse skin in vivo, TIP inhibited UV-induced skin thickening and prevented UV-induced expression of MMP-13 and MMP-9. Moreover, TIP attenuated UV-induced erythema and the expression of MMP-1, MMP-2, IL-6, and IL-8 in human skin in vivo. The novel synthetic peptide targeting TRPV1 can ameliorate UV-induced skin responses in vitro and in vivo, providing a promising therapeutic approach against UV-induced inflammation and photoaging. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Induced resistance in tomato by SAR activators during predisposing salinity stress

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Matthew Francis Pye

2013-05-01

Full Text Available Plant activators are chemicals that induce disease resistance. The phytohormone salicylic acid (SA is a crucial signal for systemic acquired resistance (SAR, and SA-mediated resistance is a target of several commercial plant activators, including Actigard (1,2,3-benzothiadiazole-7-thiocarboxylic acid-s-methyl-ester, BTH and Tiadinil (N-(3-chloro-4-methylphenyl-4-methyl-1,2,3-thiadiazole-5-carboxamide, TDL. BTH and TDL were examined for their impact on abscisic acid (ABA-mediated, salt-induced disease predisposition in tomato seedlings. A brief episode of salt stress to roots significantly increased the severity of disease caused by Pseudomonas syringae pv. tomato (Pst and Phytophthora capsici relative to non-stressed plants. Root treatment with TDL induced resistance to Pst in leaves and provided protection in both non-stressed and salt-stressed seedlings in WT and highly susceptible NahG plants. Non-stressed and salt-stressed ABA-deficient sitiens mutants were highly resistant to Pst. Neither TDL nor BTH induced resistance to root infection by P. capsici, nor did they moderate the salt-induced increment in disease severity. Root treatment with these plant activators increased the levels of ABA in roots and shoots similar to levels observed in salt-stressed plants. The results indicate that SAR activators can protect tomato plants from bacterial speck disease under predisposing salt stress, and suggest that some SA-mediated defense responses function sufficiently in plants with elevated levels of ABA.

Activation of Rho GTPases by Cytotoxic Necrotizing Factor 1 Induces Macropinocytosis and Scavenging Activity in Epithelial Cells

Science.gov (United States)

Fiorentini, Carla; Falzano, Loredana; Fabbri, Alessia; Stringaro, Annarita; Logozzi, Mariaantonia; Travaglione, Sara; Contamin, Stéphanette; Arancia, Giuseppe; Malorni, Walter; Fais, Stefano

2001-01-01

Macropinocytosis, a ruffling-driven process that allows the capture of large material, is an essential aspect of normal cell function. It can be either constitutive, as in professional phagocytes where it ends with the digestion of captured material, or induced, as in epithelial cells stimulated by growth factors. In this case, the internalized material recycles back to the cell surface. We herein show that activation of Rho GTPases by a bacterial protein toxin, the Escherichia coli cytotoxic necrotizing factor 1 (CNF1), allowed epithelial cells to engulf and digest apoptotic cells in a manner similar to that of professional phagocytes. In particular, we have demonstrated that 1) the activation of all Rho, Rac, and Cdc42 by CNF1 was essential for the capture and internalization of apoptotic cells; and 2) such activation allowed the discharge of macropinosomal content into Rab7 and lysosomal associated membrane protein-1 acidic lysosomal vesicles where the ingested particles underwent degradation. Taken together, these findings indicate that CNF1-induced “switching on” of Rho GTPases may induce in epithelial cells a scavenging activity, comparable to that exerted by professional phagocytes. The activation of such activity in epithelial cells may be relevant, in mucosal tissues, in supporting or integrating the scavenging activity of resident macrophages. PMID:11452003

Lytic cell death induced by melittin bypasses pyroptosis but induces NLRP3 inflammasome activation and IL-1β release.

Science.gov (United States)

Martín-Sánchez, Fátima; Martínez-García, Juan José; Muñoz-García, María; Martínez-Villanueva, Miriam; Noguera-Velasco, José A; Andreu, David; Rivas, Luís; Pelegrín, Pablo

2017-08-10

The nucleotide-binding domain and leucine-rich repeat-containing receptor with a pyrin domain 3 (NLRP3) inflammasome is a sensor for different types of infections and alterations of homeostatic parameters, including abnormally high levels of the extracellular nucleotide ATP or crystallization of different metabolites. All NLRP3 activators trigger a similar intracellular pathway, where a decrease in intracellular K + concentration and permeabilization of plasma membrane are key steps. Cationic amphipathic antimicrobial peptides and peptide toxins permeabilize the plasma membrane. In fact, some of them have been described to activate the NLRP3 inflammasome. Among them, the bee venom antimicrobial toxin peptide melittin is known to elicit an inflammatory reaction via the NLRP3 inflammasome in response to bee venom. Our study found that melittin induces canonical NLRP3 inflammasome activation by plasma membrane permeabilization and a reduction in the intracellular K + concentration. Following melittin treatment, the apoptosis-associated speck-like protein, an adaptor protein with a caspase recruitment domain (ASC), was necessary to activate caspase-1 and induce IL-1β release. However, cell death induced by melittin prevented the formation of large ASC aggregates, amplification of caspase-1 activation, IL-18 release and execution of pyroptosis. Therefore, melittin-induced activation of the NLRP3 inflammasome results in an attenuated inflammasome response that does not result in caspase-1 dependent cell death.

Methylphenidate in Adults with Attention Deficit Hyperactivity Disorder and Substance Use Disorders.

Science.gov (United States)

Simon, Nicolas; Rolland, Benjamin; Karila, Laurent

2015-01-01

Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopment disorder occurring during childhood. However, ADHD persists into adulthood in 45.7% of cases. The global prevalence of adult ADHD is estimated to 5.3%, with no difference between Europe and North America. ADHD is often comorbid with substance use disorder (SUD), with Odds Ratio ranges from 1.5 to 7.9, depending on the substance and the dependence level. Conversely, the prevalence of ADHD among patients with SUD is 10.8%, versus 3.8% for patients without SUD. Methylphenidate (MPH) alleviates ADHD symptoms and, as such, is currently considered as a first choice medication. MPH blocks the dopamine and norepinephrine transporters leading to an increase in extracellular dopamine. It should be noted that its subjective effects are highly dependent on the pharmacokinetic and especially on the rate of input, which highlights the importance of choosing a sustained-release formulation. Meanwhile, prescribing MPH to patients with comorbid SUD has always been challenging for clinicians. The aim of this review is to address the benefits and pitfalls of using MPH in adults with ADHD comorbid SUD, depending on each of the following types of SUD: amphetamine, cocaine, nicotine, alcohol, cannabis and opiates. Overall, due to the prevalence of ADHD in SUD and to the benefits of MPH observed in this population, and considering the mild or low side effects observed, the response to MPH treatment should be evaluated individually in adults with comorbid ADHD and SUD. The choice of the formulation should favor sustained- release MPH over immediate release MPH. Cardiovascular parameters also have to be monitored during long-term use.

Association of the GRIN2B rs2284411 polymorphism with methylphenidate response in attention-deficit/hyperactivity disorder.

Science.gov (United States)

Kim, Johanna I; Kim, Jae-Won; Park, Jong-Eun; Park, Subin; Hong, Soon-Beom; Han, Doug Hyun; Cheong, Jae Hoon; Choi, Jae-Won; Lee, Sumin; Kim, Bung-Nyun

2017-08-01

We investigated the possible association between two NMDA subunit gene polymorphisms (GRIN2B rs2284411 and GRIN2A rs2229193) and treatment response to methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD). A total of 75 ADHD patients aged 6-17 years underwent 6 months of MPH administration. Treatment response was defined by changes in scores of the ADHD-IV Rating Scale (ADHD-RS), clinician-rated Clinical Global Impression-Improvement (CGI-I), and Continuous Performance Test (CPT). The association of the GRIN2B and GRIN2A polymorphisms with treatment response was analyzed using logistic regression analyses. The GRIN2B rs2284411 C/C genotype showed significantly better treatment response as assessed by ADHD-RS inattention ( p=0.009) and CGI-I scores ( p=0.009), and there was a nominally significant association in regard to ADHD-RS hyperactivity-impulsivity ( p=0.028) and total ( p=0.023) scores, after adjusting for age, sex, IQ, baseline Clinical Global Impression-Severity (CGI-S) score, baseline ADHD-RS total score, and final MPH dose. The GRIN2B C/C genotype also showed greater improvement at the CPT response time variability ( pADHD.

Induced activity in accelerator structures, air and water

CERN Document Server

Stevenson, Graham Roger

2001-01-01

A summary is given of several 'rules of thumb' which can be used to predict the formation and decay of radionuclides in the structure of accelerators together with the dose rates from the induced radioactivity. Models are also given for the activation of gases (air of the accelerator vault) and liquids (in particular cooling water), together with their transport front the activation region to the release point. (18 refs).

Induced activity in accelerator structures, air and water

International Nuclear Information System (INIS)

Stevenson, G.R.

2001-01-01

A summary is given of several 'rules of thumb' which can be used to predict the formation and decay of radionuclides in the structure of accelerators together with the dose rates from the induced radioactivity. Models are also given for the activation of gases (air of the accelerator vault) and liquids (in particular cooling water), together with their transport from the activation region to the release point. (author)

Activation of Protease-Activated Receptor 2 Induces VEGF Independently of HIF-1

DEFF Research Database (Denmark)

Rasmussen, J.G.; Riis, Simone Elkjær; Frøbert, O.

2012-01-01

Human adipose stem cells (hASCs) can promote angiogenesis through secretion of proangiogenic factors such as vascular endothelial growth factor (VEGF). In other cell types, it has been shown that induction of VEGF is mediated by both protease activated receptor 2 (PAR2) and hypoxia inducible fact...

Protective Activity of Dendropanax Morbifera Against Cisplatin-Induced Acute Kidney Injury

Directory of Open Access Journals (Sweden)

Eun-Sun Kim

2015-01-01

Full Text Available Background/Aims: Drug-induced acute kidney injury (AKI has been a severe threat to hospitalized patients, raising the urgent needs to develop strategies to reduce AKI. We investigated the protective activity of Dendropanax morbifera (DP, a medicinal plant which has been widely used to treat infectious and pain diseases, on acute kidney injury (AKI using cisplatin-induced nephropathic models. Methods: Both in vitro renal tubular cells (NRK-52E and in vivo rat models were used to demonstrate the nephroprotective effect of DP. Results: Methanolic extract from DP significantly reduced cisplatin-induced toxicity in renal tubular cells. Through successive liquid extraction, the extract of DP was separated into n-hexane, CHCl3, EtOAc, n-BuOH, and H2O fractions. Among these, the CHCl3 fraction (DPCF was found to be most potent. The protective activity of DPCF was found to be mediated through anti-oxidant, mitochondrial protective, and anti-apoptotic activities. In in vivo rat models of AKI, treatment with DPCF significantly reversed the cisplatin-induced increase in blood urea nitrogen and serum creatinine and histopathologic damage, recovered the level of anti-oxidant enzymes, and inhibited renal apoptosis. Conclusion: We demonstrated that DP extracts decreased cisplatin-induced renal toxicity, indicating its potential to ameliorate drug-associated acute kidney damage.

Code ACTIVE for calculation of the transmutation, induced activity and decay heat in neutron irradiation

International Nuclear Information System (INIS)

Ioki, Kimihiro; Harada, Yuhei; Asami, Naoto.

1976-03-01

The computer code ACTIVE has been prepared for calculation of the transmutation rate, induced activity and decay heat. Calculations are carried out with activation chain and spatial distribution of neutron energy spectrum. The spatial distribution of secondary gamma-ray source due to the unstable nuclides is also obtainable. Special attension is paid to the short life decays. (auth.)

Estradiol-induced antinociceptive responses on formalin-induced nociception are independent of COX and HPA activation.

Science.gov (United States)

Hunter, Deirtra A; Barr, Gordon A; Amador, Nicole; Shivers, Kai-Yvonne; Kemen, Lynne; Kreiter, Christopher M; Jenab, Shirzad; Inturrisi, Charles E; Quinones-Jenab, Vanya

2011-07-01

Estrogen modulates pain perception but how it does so is not fully understood. The aim of this study was to determine if estradiol reduces nociceptive responses in part via hypothalamic-pituitary-adrenal (HPA) axis regulation of cyclooxygenase (COX)-1/COX-2 activity. The first study examined the effects of estradiol (20%) or vehicle with concurrent injection nonsteroidal antiinflammatory drugs (NSAIDs) on formalin-induced nociceptive responding (flinching) in ovariectomized (OVX) rats. The drugs were ibuprofen (COX-1 and COX-2 inhibitor), SC560 (COX-1 inhibitor), or NS398 (COX-2 inhibitor). In a second study, estradiol's effects on formalin-induced nociception were tested in adrenalectomized (ADX), OVX, and ADX+OVX rats. Serum levels of prostaglandins (PG) PGE(2) and corticosterone were measured. Estradiol significantly decreased nociceptive responses in OVX rats with effects during both the first and the second phase of the formalin test. The nonsteroidal antiinflammatory drugs (NSAIDs) did not alter nociception at the doses used here. Adrenalectomy neither altered flinching responses in female rats nor reversed estradiol-induced antinociceptive responses. Estradiol alone had no effect on corticosterone (CORT) or prostaglandin levels after the formalin test, dissociating the effects of estradiol on behavior and these serum markers. Ibuprofen and NS398 significantly reduced PGE2 levels. CORT was not decreased by OVX surgery or by estradiol below that of ADX. Only IBU significantly increased corticosterone levels. Taken together, our results suggest that estradiol-induced antinociception in female rats is independent of COX activity and HPA axis activation. Copyright © 2010 Wiley-Liss, Inc.

Hepatitis B virus e antigen induces activation of rat hepatic stellate cells

International Nuclear Information System (INIS)

Zan, Yanlu; Zhang, Yuxia; Tien, Po

2013-01-01

Highlights: •HBeAg expression in HSCs induced production of ECM protein and liver fibrotic markers. •The activation and proliferation of HSCs were mediated by TGF-β. •HBeAg protein purified from cell medium directly activated HSCs. -- Abstract: Chronic hepatitis B virus infection is a major cause of hepatic fibrosis, leading to liver cirrhosis and hepatocellular carcinoma. Hepatitis B virus e antigen (HBeAg) is an accessory protein of HBV, not required for viral replication but important for natural infection in vivo. Hepatic stellate cells (HSCs) are the major producers of excessive extracellular matrix during liver fibrogenesis. Therefore, we examined the influence of HBeAg on HSCs. The rat HSC line HSC-T6 was transfected with HBeAg plasmids, and expression of α-smooth muscle actin, collagen I, transforming growth factor-β1 (TGF-β), and tissue inhibitors of metalloproteinase 1 (TIMP-1) was investigated by quantitative real-time PCR. The proliferation of HSCs was determined by MTS analysis. HBeAg transduction induced up-regulation of these fibrogenic genes and proliferation of HSCs. We found that HBeAg induced TGF-β secretion in HSCs, and the activation of HSCs was prevented by a neutralizing anti-TGF-β antibody. Depletion and addition of HBeAg protein in conditioned medium from HSC-T6 cells transduced with HBeAg indicated that HBeAg directly induced the activation and proliferation of rat primary HSCs. Taken together, HBeAg induces the activation and proliferation of HSCs, mainly mediated by TGF-β, and HBeAg protein purified from cell medium can directly activate HSCs

Hepatitis B virus e antigen induces activation of rat hepatic stellate cells

Energy Technology Data Exchange (ETDEWEB)

Zan, Yanlu [Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Zhang, Yuxia, E-mail: yzhang@wehi.edu.au [Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China); Tien, Po, E-mail: tienpo@sun.im.ac.cn [Center for Molecular Virology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101 (China)

2013-06-07

Highlights: •HBeAg expression in HSCs induced production of ECM protein and liver fibrotic markers. •The activation and proliferation of HSCs were mediated by TGF-β. •HBeAg protein purified from cell medium directly activated HSCs. -- Abstract: Chronic hepatitis B virus infection is a major cause of hepatic fibrosis, leading to liver cirrhosis and hepatocellular carcinoma. Hepatitis B virus e antigen (HBeAg) is an accessory protein of HBV, not required for viral replication but important for natural infection in vivo. Hepatic stellate cells (HSCs) are the major producers of excessive extracellular matrix during liver fibrogenesis. Therefore, we examined the influence of HBeAg on HSCs. The rat HSC line HSC-T6 was transfected with HBeAg plasmids, and expression of α-smooth muscle actin, collagen I, transforming growth factor-β1 (TGF-β), and tissue inhibitors of metalloproteinase 1 (TIMP-1) was investigated by quantitative real-time PCR. The proliferation of HSCs was determined by MTS analysis. HBeAg transduction induced up-regulation of these fibrogenic genes and proliferation of HSCs. We found that HBeAg induced TGF-β secretion in HSCs, and the activation of HSCs was prevented by a neutralizing anti-TGF-β antibody. Depletion and addition of HBeAg protein in conditioned medium from HSC-T6 cells transduced with HBeAg indicated that HBeAg directly induced the activation and proliferation of rat primary HSCs. Taken together, HBeAg induces the activation and proliferation of HSCs, mainly mediated by TGF-β, and HBeAg protein purified from cell medium can directly activate HSCs.

Ouabain exacerbates activation-induced cell death in human peripheral blood lymphocytes

OpenAIRE

Esteves Mabel B.; Marques-Santos Luis F.; Affonso-Mitidieri Ottília R.; Rumjanek Vivian M.

2005-01-01

Lymphocytes activated by mitogenic lectins display changes in transmembrane potential, an elevation in the cytoplasmic Ca2+ concentrations, proliferation and/or activation induced cell death. Low concentrations of ouabain (an inhibitor of Na+,K+-ATPase) suppress mitogen-induced proliferation and increases cell death. To understand the mechanisms involved, a number of parameters were analyzed using fluorescent probes and flow cytometry. The addition of 100nM ouabain to cultures of peripheral b...

Brucella abortus-activated microglia induce neuronal death through primary phagocytosis.

Science.gov (United States)

Rodríguez, Ana M; Delpino, M Victoria; Miraglia, M Cruz; Costa Franco, Miriam M; Barrionuevo, Paula; Dennis, Vida A; Oliveira, Sergio C; Giambartolomei, Guillermo H

2017-07-01

Inflammation has long been implicated as a contributor to pathogenesis in neurobrucellosis. Many of the associated neurocognitive symptoms of neurobrucellosis may be the result of neuronal dysfunction resulting from the inflammatory response induced by Brucella abortus infection in the central nervous system. In this manuscript, we describe an immune mechanism for inflammatory activation of microglia that leads to neuronal death upon B. abortus infection. B. abortus was unable to infect or harm primary cultures of mouse neurons. However, when neurons were co-cultured with microglia and infected with B. abortus significant neuronal loss occurred. This phenomenon was dependent on TLR2 activation by Brucella lipoproteins. Neuronal death was not due to apoptosis, but it was dependent on the microglial release of nitric oxide (NO). B. abortus infection stimulated microglial proliferation, phagocytic activity and engulfment of neurons. NO secreted by B. abortus-activated microglia induced neuronal exposure of the "eat-me" signal phosphatidylserine (PS). Blocking of PS-binding to protein milk fat globule epidermal growth factor-8 (MFG-E8) or microglial vitronectin receptor-MFG-E8 interaction was sufficient to prevent neuronal loss by inhibiting microglial phagocytosis without affecting their activation. Taken together, our results indicate that B. abortus is not directly toxic to neurons; rather, these cells become distressed and are killed by phagocytosis in the inflammatory surroundings generated by infected microglia. Neuronal loss induced by B. abortus-activated microglia may explain, in part, the neurological deficits observed during neurobrucellosis. © 2017 Wiley Periodicals, Inc.

Sequential activation of proteases in radiation induced apoptosis

International Nuclear Information System (INIS)

Watters, D.; Waterhouse, N.

1997-01-01

Full text: Significant advances have been made in recent years in unraveling the molecular mechanisms of apoptosis particularly in relation to Fas- and TNF-mediated cell death, however there are considerable gaps in our knowledge of the processes involved in apoptosis induced by ionizing radiation. We have used the degradation of specific proteolytic targets in a pair of isogenic Burkitt's Iymphoma cells lines (BL30A, sensitive and BL30K resistant) to study the sequence of events in the execution of radiation-induced apoptosis. Fodrin can be cleaved to fragments of 150 kDa and 120 kDa. In the case of Fas-mediated apoptosis both cleavages are inhibited by the caspase inhibitor zVAD-fmk at 10 μM, a concentration which inhibits all the hallmarks of apoptosis. However in radiation-induced apoptosis, inhibition of the clevage of fodrin to the 150 kDa fragment requires 100 μM zVAD-fink while apoptosis itself is inhibited at 10 μM. This suggests that different enzymes are responsible for the generation of the 150 kDa fragment in the two models of apoptosis. Fodrin has been reported to be cleaved by μ-calpain to a 150 kDa fragment however, the involvement of μ-calpain in apoptosis has not yet been established. In murine fodrin there is a caspase cleavage site within 1 kDa of the calpain cleavage site. In vitro studies using purified enzymes showed that only caspase-3 and μ-calpain could cleave fodrin in untreated cell extracts to the same sized fragments as seen during apoptosis in vivo. We provide evidence for the early activation of μ-calpain after ionizing radiation in the sensitive BL30A cell line, and show that the time course of μ-calpain activation parallels that of the appearance of the 150 kDa fragment. Caspase-3 is activated much later and is likely to be responsible for the generation of the 120 kDa fragment. μ-Calpain was not activated in the resistant cell line. Based on these results we propose a model for the proteolytic cascade in radiation-induced

Roles of acid sphingomyelinase activation in neuronal cells apoptosis induced by microwave irradiation

International Nuclear Information System (INIS)

Zhang Lei; Xu Shangcheng; Zhang Guangbin; Yu Zhengping

2009-01-01

The present study is to examine the effect of microwave on acid sphingomyelinase (ASM) activity and expression, and to explore the role of ASM activation in neuronal cells apoptosis induced by microwave irradiation. Primary cultured hippocampal neurons were irradiated by 30 W/cm 2 microwave for 10 min, and ASM activity assay was used to investigate ASM activity alteration. RT-PCR and western blot were used to detect ASM mRNA and protein expression respectively. Apoptosis was observed by Hoechst 33342 fluorescence staining. ASM specific inhibitor imipramine was applied to inhibit ASM activation. It has been found that apoptosis rate of primary cultured hippocampal neurons increased significantly after microwave irradiation. ASM was activated while ASM mRNA and protein expression were upregulated in neurons after microwave irradiation. Pretreatment with imipramine could reverse neuronal apoptosis induced by microwave irradiation. Results show that microwave irradiation causes increment of ASM activation and expression and ASM activation is involved in microwave induced neuronal apoptosis. (authors)

Effect of methylphenidate on enhancement of spatial learning by novel alternated dual task.

Science.gov (United States)

Veetil, Praveen Kottath; Mukkadan, Joseph Kurian

2011-01-01

The novel alternated dual task (ADT) arranged rats to learn T-maze spontaneous alternation task and radial arm maze (RAM) task alternatively, and by doing ADT, rats could acquire the tasks more easily than non alternated dual task (NADT) group. Also retention capacity of ADT group was significantly more and ADT help to learn a complex task faster than learning it in isolation from other tasks. In the present study effect of methylphenidate (MPD), a mood elevator, known to enhance learning and memory, on ADT procedure is assessed. Also effect of ADT procedure and MPD on spatial learning and memory are compared. Different groups were assigned by administering MPD (intraperitoneal injection at a dose of 3 mg/kg body weight) during different phases of behavioural experiments, and control groups received saline injection. MPD administration increased both acquisition and retention capacities. The amelioration attained for retention of complex task by ADT procedure, could be achieved by NADT rats only by administration of MPD. The influence of ADT procedure on acquisition and retention of TM and RAM tasks were similar to the effects of MPD, especially for the RAM task. MPD at low dose is found to enhance the learning and memory capacity in rats, than deteriorating it, supporting the use of MPD as a drug to treat attention deficit hyperactive disorder. The recent reports suggesting the effect of MPD only on retention and not on acquisition could not be confirmed, as enhancement for both acquisition and retention was found in this study.

PPARβ/δ regulates glucocorticoid- and sepsis-induced FOXO1 activation and muscle wasting.

Directory of Open Access Journals (Sweden)

Estibaliz Castillero

Full Text Available FOXO1 is involved in glucocorticoid- and sepsis-induced muscle wasting, in part reflecting regulation of atrogin-1 and MuRF1. Mechanisms influencing FOXO1 expression in muscle wasting are poorly understood. We hypothesized that the transcription factor peroxisome proliferator-activated receptor β/δ (PPARβ/δ upregulates muscle FOXO1 expression and activity with a downstream upregulation of atrogin-1 and MuRF1 expression during sepsis and glucocorticoid treatment and that inhibition of PPARβ/δ activity can prevent muscle wasting. We found that activation of PPARβ/δ in cultured myotubes increased FOXO1 activity, atrogin-1 and MuRF1 expression, protein degradation and myotube atrophy. Treatment of myotubes with dexamethasone increased PPARβ/δ expression and activity. Dexamethasone-induced FOXO1 activation and atrogin-1 and MuRF1 expression, protein degradation, and myotube atrophy were inhibited by PPARβ/δ blocker or siRNA. Importantly, muscle wasting induced in rats by dexamethasone or sepsis was prevented by treatment with a PPARβ/δ inhibitor. The present results suggest that PPARβ/δ regulates FOXO1 activation in glucocorticoid- and sepsis-induced muscle wasting and that treatment with a PPARβ/δ inhibitor may ameliorate loss of muscle mass in these conditions.

Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity

DEFF Research Database (Denmark)

Nellemann, B.; Vendelbo, M.H.; Nielsen, Thomas Svava

2014-01-01

Insulin resistance induced by growth hormone (GH) is linked to promotion of lipolysis by unknown mechanisms. We hypothesized that suppression of the activity of pyruvate dehydrogenase in the active form (PDHa) underlies GH-induced insulin resistance similar to what is observed during fasting....

Substrate Stiffness Influences Doxorubicin-Induced p53 Activation via ROCK2 Expression

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Takahiro Ebata

2017-01-01

Full Text Available The physical properties of the extracellular matrix (ECM, such as stiffness, are involved in the determination of the characteristics of cancer cells, including chemotherapy sensitivity. Resistance to chemotherapy is often linked to dysfunction of tumor suppressor p53; however, it remains elusive whether the ECM microenvironment interferes with p53 activation in cancer cells. Here, we show that, in MCF-7 breast cancer cells, extracellular stiffness influences p53 activation induced by the antitumor drug doxorubicin. Cell growth inhibition by doxorubicin was increased in response to ECM rigidity in a p53-dependent manner. The expression of Rho-associated coiled coil-containing protein kinase (ROCK 2, which induces the activation of myosin II, was significantly higher when cells were cultured on stiffer ECM substrates. Knockdown of ROCK2 expression or pharmacological inhibition of ROCK decreased doxorubicin-induced p53 activation. Our results suggest that a soft ECM causes downregulation of ROCK2 expression, which drives resistance to chemotherapy by repressing p53 activation.

Determinants of adherence to methylphenidate and the impact of poor adherence on maternal and family measures.

Science.gov (United States)

Gau, Susan S F; Shen, Hsin-Yi; Chou, Miao-Churn; Tang, Ching-Shu; Chiu, Yen-Nan; Gau, Churn-Shiouh

2006-06-01

The aim of this study was to examine the association between adherence to immediate-release methylphenidate (IR MPH) and maternal psychological distress, parenting style, parent- child relationship, and perceived family support. The sample consisted of 307 children with attention-deficit hyperactivity disorder (ADHD) (271 boys and 36 girls), 6-17 years of age, who had been treated with IR MPH for the past 6 months. The measures included the Chinese Health Questionnaire, Parental Bonding Instrument, Family APGAR, and Home Behaviors of the Social Adjustment Inventory for Children and Adolescents. Reasons for poor adherence (n = 79; 25.7%) included forgetting medication (72.7%), the medication having no effect (20.0%), and refusing medication (12.7%). Increased age and three-times-daily administration were the major predictors for poor adherence to IR MPH. Poor adherence was associated with increased degree of maternal psychological distress, indifferent parenting, maternal overprotection/control, poor family support, decreased interaction with parents, and increased problems at home. Findings indicate that multiple daily dosing of MPH increases the likelihood of poor adherence, particularly in adolescents, and that poor adherence is associated with impaired maternal/family process. Once-daily administration of MPH is necessary to improve adherence and to decrease the possible exacerbation of tense parent-child relationships caused by poor drug adherence.

The Effects of Methylphenidate Administration on the Histological Alterations of the Lymphatic System in the Mice

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Ali Louei Monfared

2016-12-01

Full Text Available Abstract Background: The lymphatic system as a key component in the organism's body can be affected by used drugs. Methylphenidate or Ritalin is widely used for treatment of behavioral disorders in children and some depressed people. This study carried out to examine the immunotoxic effects of Ritalin. Materials and Methods: A total of 16 healthy adult female mice were selected and randomly divided into a control and three experimental groups. The experimental groups received Ritalin as 0.5,5 and 50 mg/kg body weight and control groups received distillated water by gavage method for 21 consecutive days. At the end of experiment, the structure and function of the lymphoid organs were evaluated. Results were analyzed by ANOVA and Duncan’s test (p<0.05. Results: Significant alterations including a reduction in the size and number of lymphoid follicles, increasing in the megakaryocytes numbers as well as spleen capsular thickens were seen following Ritalin administration. The atrophy of the lymph nodes together with significant reduction in the number and size of lymph follicles but an increasing in the parenchyma hyperemia were seen. Also lymphocyte numbers increased while the monocytes numbers decreased (p<0.05. Conclusion: The consumption of Ritalin could be exerted detrimental effects on the lymphoid organs in the mouse model.

Kainate-induced network activity in the anterior cingulate cortex.

Science.gov (United States)

Shinozaki, R; Hojo, Y; Mukai, H; Hashizume, M; Murakoshi, T

2016-06-14

Anterior cingulate cortex (ACC) plays a pivotal role in higher order processing of cognition, attention and emotion. The network oscillation is considered an essential means for integration of these CNS functions. The oscillation power and coherence among related areas are often dis-regulated in several psychiatric and pathological conditions with a hemispheric asymmetric manner. Here we describe the network-based activity of field potentials recorded from the superficial layer of the mouse ACC in vitro using submerged type recordings. A short activation by kainic acid administration to the preparation induced populational activities ranging over several frequency bands including theta (3-8Hz), alpha (8-12Hz), beta (13-30Hz), low gamma (30-50Hz) and high gamma (50-80Hz). These responses were repeatable and totally abolished by tetrodotoxin, and greatly diminished by inhibitors of ionotropic and metabotropic glutamate receptors, GABAA receptor or gap-junctions. These observations suggest that the kainate-induced network activity can be a useful model of the network oscillation in the ACC circuit. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Mediators of methylphenidate effects on math performance in children with attention-deficit hyperactivity disorder.

Science.gov (United States)

Froehlich, Tanya E; Antonini, Tanya N; Brinkman, William B; Langberg, Joshua M; Simon, John O; Adams, Ryan; Fredstrom, Bridget; Narad, Megan E; Kingery, Kathleen M; Altaye, Mekibib; Matheson, Heather; Tamm, Leanne; Epstein, Jeffery N

2014-01-01

Stimulant medications, such as methylphenidate (MPH), improve the academic performance of children with attention-deficit hyperactivity disorder (ADHD). However, the mechanism by which MPH exerts an effect on academic performance is unclear. We examined MPH effects on math performance and investigated possible mediation of MPH effects by changes in time on-task, inhibitory control, selective attention, and reaction time variability. Children with ADHD aged 7 to 11 years (N = 93) completed a timed math worksheet (with problems tailored to each individual's level of proficiency) and 2 neuropsychological tasks (Go/No-Go and Child Attention Network Test) at baseline, then participated in a 4-week, randomized, controlled, titration trial of MPH. Children were then randomly assigned to their optimal MPH dose or placebo for 1 week (administered double-blind) and repeated the math and neuropsychological tasks (posttest). Baseline and posttest videorecordings of children performing the math task were coded to assess time on-task. Children taking MPH completed 23 more math problems at posttest compared to baseline, whereas the placebo group completed 24 fewer problems on posttest versus baseline, but the effects on math accuracy (percent correct) did not differ. Path analyses revealed that only change in time on-task was a significant mediator of MPH's improvements in math productivity. MPH-derived math productivity improvements may be explained in part by increased time spent on-task, rather than improvements in neurocognitive parameters, such as inhibitory control, selective attention, or reaction time variability.

Treatment of fatigue with methylphenidate, modafinil and amantadine in multiple sclerosis (TRIUMPHANT-MS): Study design for a pragmatic, randomized, double-blind, crossover clinical trial.

Science.gov (United States)

Nourbakhsh, Bardia; Revirajan, Nisha; Waubant, Emmanuelle

2018-01-01

Fatigue is the most common symptom of multiple sclerosis (MS). Amantadine, modafinil and amphetamine-like stimulants are commonly used in clinical practice for treatment of fatigue; however, the evidence supporting their effectiveness is sparse and conflicting. To describe the design of a trial study funded by Patient-Centered Outcome Research Institute (PCORI) that will compare the efficacy of commonly used fatigue medications in patients with MS. The study is a randomized, placebo-controlled, crossover, four-sequence, four-period, double-blind, multicenter trial of three commonly used medications for the treatment of MS-related fatigue (amantadine, modafinil, methylphenidate) versus placebo in fatigued subjects with MS. Adult patients with MS, with an Expanded Disability Status Scale of MS-related fatigue. Clinicaltrials.gov registration number: NCT03185065. Copyright © 2017 Elsevier Inc. All rights reserved.

Artemisinin induces ROS-mediated caspase3 activation in ASTC-a-1 cells

Science.gov (United States)

Xiao, Feng-Lian; Chen, Tong-Sheng; Qu, Jun-Le; Liu, Cheng-Yi

2010-02-01

Artemisinin (ART), an antimalarial phytochemical from the sweet wormwood plant or a naturally occurring component of Artemisia annua, has been shown a potential anticancer activity by apoptotic pathways. In our report, cell counting kit (CCK-8) assay showed that treatment of human lung adenocarcinoma (ASTC-a-1) cells with ART effectively increase cell death by inducing apoptosis in a time- and dose-dependent fashion. Hoechst 33258 staining was used to detect apoptosis as well. Reactive oxygen species (ROS) generation was observed in cells exposed to ART at concentrations of 400 μM for 48 h. N-acetyl-L-cysteine (NAC), an oxygen radical scavenger, suppressed the rate of ROS generation and inhibited the ART-induced apoptosis. Moreover, AFC assay (Fluorometric assay for Caspase3 activity) showed that ROS was involved in ART-induced caspase3 acitvation. Taken together, our data indicate that ART induces ROS-mediated caspase3 activation in a time-and dose-dependent way in ASCT-a-1 cells.

Involvement of microglia activation in the lead induced long-term potentiation impairment.

Directory of Open Access Journals (Sweden)

Ming-Chao Liu

Full Text Available Exposure of Lead (Pb, a known neurotoxicant, can impair spatial learning and memory probably via impairing the hippocampal long-term potentiation (LTP as well as hippocampal neuronal injury. Activation of hippocampal microglia also impairs spatial learning and memory. Thus, we raised the hypothesis that activation of microglia is involved in the Pb exposure induced hippocampal LTP impairment and neuronal injury. To test this hypothesis and clarify its underlying mechanisms, we investigated the Pb-exposure on the microglia activation, cytokine release, hippocampal LTP level as well as neuronal injury in in vivo or in vitro model. The changes of these parameters were also observed after pretreatment with minocycline, a microglia activation inhibitor. Long-term low dose Pb exposure (100 ppm for 8 weeks caused significant reduction of LTP in acute slice preparations, meanwhile, such treatment also significantly increased hippocampal microglia activation as well as neuronal injury. In vitro Pb-exposure also induced significantly increase of microglia activation, up-regulate the release of cytokines including tumor necrosis factor-alpha (TNF-α, interleukin-1β (IL-1β and inducible nitric oxide synthase (iNOS in microglia culture alone as well as neuronal injury in the co-culture with hippocampal neurons. Inhibiting the microglia activation with minocycline significantly reversed the above-mentioned Pb-exposure induced changes. Our results showed that Pb can cause microglia activation, which can up-regulate the level of IL-1β, TNF-α and iNOS, these proinflammatory factors may cause hippocampal neuronal injury as well as LTP deficits.

Extracellular adenosine-induced Rac1 activation in pulmonary endothelium: Molecular mechanisms and barrier-protective role.

Science.gov (United States)

Kovacs-Kasa, Anita; Kim, Kyung Mi; Cherian-Shaw, Mary; Black, Stephen M; Fulton, David J; Verin, Alexander D

2018-08-01

We have previously shown that Gs-coupled adenosine receptors (A2a) are primarily involved in adenosine-induced human pulmonary artery endothelial cell (HPAEC) barrier enhancement. However, the downstream events that mediate the strengthening of the endothelial cell (EC) barrier via adenosine signaling are largely unknown. In the current study, we tested the overall hypothesis that adenosine-induced Rac1 activation and EC barrier enhancement is mediated by Gs-dependent stimulation of cAMP-dependent Epac1-mediated signaling cascades. Adenoviral transduction of HPAEC with constitutively-active (C/A) Rac1 (V12Rac1) significantly increases transendothelial electrical resistance (TER) reflecting an enhancement of the EC barrier. Conversely, expression of an inactive Rac1 mutant (N17Rac1) decreases TER reflecting a compromised EC barrier. The adenosine-induced increase in TER was accompanied by activation of Rac1, decrease in contractility (MLC dephosphorylation), but not Rho inhibition. Conversely, inhibition of Rac1 activity attenuates adenosine-induced increase in TER. We next examined the role of cAMP-activated Epac1 and its putative downstream targets Rac1, Vav2, Rap1, and Tiam1. Depletion of Epac1 attenuated the adenosine-induced Rac1 activation and the increase in TER. Furthermore, silencing of Rac1 specific guanine nucleotide exchange factors (GEFs), Vav2 and Rap1a expression significantly attenuated adenosine-induced increases in TER and activation of Rac1. Depletion of Rap1b only modestly impacted adenosine-induced increases in TER and Tiam1 depletion had no effect on adenosine-induced Rac1 activation and TER. Together these data strongly suggest that Rac1 activity is required for adenosine-induced EC barrier enhancement and that the activation of Rac1 and ability to strengthen the EC barrier depends, at least in part, on cAMP-dependent Epac1/Vav2/Rap1-mediated signaling. © 2017 Wiley Periodicals, Inc.

Minocycline attenuates sevoflurane-induced cell injury via activation of Nrf2.

Science.gov (United States)

Tian, Yue; Wu, Xiuying; Guo, Shanbin; Ma, Ling; Huang, Wei; Zhao, Xiaochun

2017-04-01

Minocycline has been demonstrated to exert neuroprotective effects in various experimental models. In the present study, we investigated the mechanisms underlying the protective effects of minocycline on cell injury induced by the inhalation of the anesthetic, sevoflurane. In our in vivo experiments using rats, minocycline attenuated sevoflurane-induced neuronal degeneration and apoptosis in the rat hippocampus, and this effect was associated with the minocycline-mediated suppression of oxidative stress in the hippocampus. In in vitro experiments, minocycline inhibited sevoflurane-induced apoptosis and the production of reactive oxygen species (ROS) in H4 human neuroglioma cells. In addition, minocycline suppressed the sevoflurane-induced upregulation of interleukin (IL)-6 and the activation of the nuclear factor-κB (NF-κB) signaling pathway in H4 cells. Furthermore, we found that nuclear factor E2-related factor 2 (Nrf2), an activator of the stress response, was upregulated and activated upon sevoflurane treatment both in the rat hippocampus and in H4 cells. In addition, minocycline further augmented the upregulation and activation of Nrf2 when used in conjunction with sevoflurane. Moreover, the knockdown of Nrf2 in H4 cells by small interfering RNA (siRNA) diminished the cytoprotective effect of minocycline, and attenuated the inhibitory effect of minocycline on ROS production, IL-6 upregulation and the activation of the NF-κB signaling pathway. On the whole, our findings indicate that minocycline may exert protective effects against sevoflurane-induced cell injury via the Nrf2-modulated antioxidant response and the inhibition of the activation of the NF-κB signaling pathway.

Active-interrogation measurements of fast neutrons from induced fission in low-enriched uranium

International Nuclear Information System (INIS)

Dolan, J.L.; Marcath, M.J.; Flaska, M.; Pozzi, S.A.; Chichester, D.L.; Tomanin, A.; Peerani, P.

2014-01-01

A detection system was designed with MCNPX-PoliMi to measure induced-fission neutrons from U-235 and U-238 using active interrogation. Measurements were then performed with this system at the Joint Research Centre in Ispra, Italy on low-enriched uranium samples. Liquid scintillators measured induced fission neutrons to characterize the samples in terms of their uranium mass and enrichment. Results are presented to investigate and support the use of organic liquid scintillators with active interrogation techniques to characterize uranium containing materials. -- Highlights: • We studied low-enriched uranium using active-interrogation experiments including a deuterium–tritium neutron generator and an americium–lithium isotopic neutron source. • Liquid scintillators measured induced-fission neutrons from the active-interrogation methods. • Fast-neutron (DT) and thermal-neutron (Am–Li) interrogation resulted in the measurement of trends in uranium mass and 235 U enrichment respectively. • MCNPX-PoliMi, the Monte Carlo transport code, simulated the measured induced-fission neutron trends in the liquid scintillators

Active-interrogation measurements of fast neutrons from induced fission in low-enriched uranium

Energy Technology Data Exchange (ETDEWEB)

Dolan, J.L., E-mail: jldolan@umich.edu [Department of Nuclear Engineering and Radiological Sciences, University of Michigan, Ann Arbor, MI 48109 (United States); Marcath, M.J.; Flaska, M.; Pozzi, S.A. [Department of Nuclear Engineering and Radiological Sciences, University of Michigan, Ann Arbor, MI 48109 (United States); Chichester, D.L. [Idaho National Laboratory, Idaho Falls, ID 83415 (United States); Tomanin, A.; Peerani, P. [European Commission, Joint Research Centre, Institute for Transuranium Elements, Ispra (Italy)

2014-02-21

A detection system was designed with MCNPX-PoliMi to measure induced-fission neutrons from U-235 and U-238 using active interrogation. Measurements were then performed with this system at the Joint Research Centre in Ispra, Italy on low-enriched uranium samples. Liquid scintillators measured induced fission neutrons to characterize the samples in terms of their uranium mass and enrichment. Results are presented to investigate and support the use of organic liquid scintillators with active interrogation techniques to characterize uranium containing materials. -- Highlights: • We studied low-enriched uranium using active-interrogation experiments including a deuterium–tritium neutron generator and an americium–lithium isotopic neutron source. • Liquid scintillators measured induced-fission neutrons from the active-interrogation methods. • Fast-neutron (DT) and thermal-neutron (Am–Li) interrogation resulted in the measurement of trends in uranium mass and {sup 235}U enrichment respectively. • MCNPX-PoliMi, the Monte Carlo transport code, simulated the measured induced-fission neutron trends in the liquid scintillators.

Troglitazone induced apoptosis via PPARγ activated POX-induced ROS formation in HT29 cells.

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Wang, Jing; Lv, XiaoWen; Shi, JiePing; Hu, XiaoSong; DU, YuGuo

2011-08-01

In order to investigate the potential mechanisms in troglitazone-induced apoptosis in HT29 cells, the effects of PPARγ and POX-induced ROS were explored. [3- (4, 5)-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay, Annexin V and PI staining using FACS, plasmid transfection, ROS formation detected by DCFH staining, RNA interference, RT-PCR & RT-QPCR, and Western blotting analyses were employed to investigate the apoptotic effect of troglitazone and the potential role of PPARγ pathway and POX-induced ROS formation in HT29 cells. Troglitazone was found to inhibit the growth of HT29 cells by induction of apoptosis. During this process, mitochondria related pathways including ROS formation, POX expression and cytochrome c release increased, which were inhibited by pretreatment with GW9662, a specific antagonist of PPARγ. These results illustrated that POX upregulation and ROS formation in apoptosis induced by troglitazone was modulated in PPARγ-dependent pattern. Furthermore, the inhibition of ROS and apoptosis after POX siRNA used in troglitazone-treated HT29 cells indicated that POX be essential in the ROS formation and PPARγ-dependent apoptosis induced by troglitazone. The findings from this study showed that troglitazone-induced apoptosis was mediated by POX-induced ROS formation, at least partly, via PPARγ activation. Copyright © 2011 The Editorial Board of Biomedical and Environmental Sciences. Published by Elsevier B.V. All rights reserved.

Role of Bioavailable Iron in Coal Dust-Induced Activation of Activator Protein-1 and Nuclear Factor of Activated T Cells

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Huang, Chuanshu; Li, Jingxia; Zhang, Qi; Huang, Xi

2010-01-01

Activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT) are two important transcription factors responsible for the regulation of cytokines, which are involved in cell proliferation and inflammation. Coal workers’ pneumoconiosis (CWP) is an occupational lung disease that may be related to chronic inflammation caused by coal dust exposure. In the present study, we demonstrate that coal from the Pennsylvania (PA) coalmine region, which has a high prevalence of CWP, can activate both AP-1 and NFAT in JB6 mouse epidermal cells. In contrast, coal from the Utah (UT) coalmine region, which has a low prevalence of CWP, has no such effects. The PA coal stimulates mitogen-activated protein kinase (MAPK) family members of extracellular signal-regulated kinases (ERKs) and p38 MAPK but not c-Jun-NH2-terminal kinases, as determined by the phosphorylation assay. The increase in AP-1 by the PA coal was completely eliminated by the pretreatment of cells with PD98059, a specific MAPK kinase inhibitor, and SB202190, a p38 kinase inhibitor, further confirming that the PA coal-induced AP-1 activation is mediated through ERKs and p38 MAPK pathways. Deferoxamine (DFO), an iron chelator, synergistically enhanced the PA coal-induced AP-1 activity, but inhibited NFAT activity. For comparison, cells were treated with ferrous sulfate and/or DFO. We have found that iron transactivated both AP-1 and NFAT, and DFO further enhanced iron-induced AP-1 activation but inhibited NFAT. These results indicate that activation of AP-1 and NFAT by the PA coal is through bioavailable iron present in the coal. These data are in agreement with our previous findings that the prevalence of CWP correlates well with levels of bioavailable iron in coals from various mining regions. PMID:12397016

Natural Product Vibsanin A Induces Differentiation of Myeloid Leukemia Cells through PKC Activation.

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Yu, Zu-Yin; Xiao, He; Wang, Li-Mei; Shen, Xing; Jing, Yu; Wang, Lin; Sun, Wen-Feng; Zhang, Yan-Feng; Cui, Yu; Shan, Ya-Jun; Zhou, Wen-Bing; Xing, Shuang; Xiong, Guo-Lin; Liu, Xiao-Lan; Dong, Bo; Feng, Jian-Nan; Wang, Li-Sheng; Luo, Qing-Liang; Zhao, Qin-Shi; Cong, Yu-Wen

2016-05-01

All-trans retinoic acid (ATRA)-based cell differentiation therapy has been successful in treating acute promyelocytic leukemia, a unique subtype of acute myeloid leukemia (AML). However, other subtypes of AML display resistance to ATRA-based treatment. In this study, we screened natural, plant-derived vibsane-type diterpenoids for their ability to induce differentiation of myeloid leukemia cells, discovering that vibsanin A potently induced differentiation of AML cell lines and primary blasts. The differentiation-inducing activity of vibsanin A was mediated through direct interaction with and activation of protein kinase C (PKC). Consistent with these findings, pharmacological blockade of PKC activity suppressed vibsanin A-induced differentiation. Mechanistically, vibsanin A-mediated activation of PKC led to induction of the ERK pathway and decreased c-Myc expression. In mouse xenograft models of AML, vibsanin A administration prolonged host survival and inhibited PKC-mediated inflammatory responses correlated with promotion of skin tumors in mice. Collectively, our results offer a preclinical proof of concept for vibsanin A as a myeloid differentiation-inducing compound, with potential application as an antileukemic agent. Cancer Res; 76(9); 2698-709. ©2016 AACR. ©2016 American Association for Cancer Research.

Creatine kinase activity in dogs with experimentally induced acute inflammation

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Dimitrinka Zapryanova

2013-01-01

Full Text Available The main purpose of this study was to investigate the effect of acute inflammation on total creatine kinase (CK activity in dogs. In these animals, CK is an enzyme found predominantly in skeletal muscle and significantly elevated serum activity is largely associated with muscle damage. Plasma increases in dogs are associated with cell membrane leakage and will therefore be seen in any condition associated with muscular inflammation. The study was induced in 15 mongrel male dogs (n=9 in experimental group and n=6 in control group at the age of two years and body weight 12-15 kg. The inflammation was reproduced by inoculation of 2 ml turpentine oil subcutaneously in lumbar region. The plasma activity of creatine kinase was evaluated at 0, 6, 24, 48, 72 hours after inoculation and on days 7, 14 and 21 by a kit from Hospitex Diagnostics. In the experimental group, the plasma concentrations of the CK-activity were increased at the 48th hour (97.48±6.92 U/L and remained significantly higher (p<0.05 at the 72 hour (97.43±2.93 U/L compared to the control group (77.08±5.27 U/L. The results of this study suggest that the evaluation of creatine kinase in dogs with experimentally induced acute inflammation has a limited diagnostic value. It was observed that the creatine kinase activity is slightly affected by the experimentally induced acute inflammation in dogs.

Modern g,d,p,n-induced activation-transmutation systems

International Nuclear Information System (INIS)

Sublet, J.Ch.

2010-01-01

Document available in abstract form only. Full text of publication follows: The European Activation System (EASY) includes as the source of nuclear data the European Activation File (EAF) and as its engine the FISPACT activation-transmutation code. The latest version of the EAF, EAF-2010, contains cross-section data for gamma-, deuteron- and proton-induced reactions in addition to the traditional neutron-induced data. The main reason for the addition of these data to EAF is to enable activation-transmutation calculations to be performed for even more nuclear facilities, including 'accelerator'-driven devices with incident upper energy limit of 60 or 200 MeV. EAF-2010 has benefited from the generation and maintenance of comprehensive activation files in the past and the development of the processing code SAFEPAQ-II and model code TALYS. TALYS is the source for all gamma-, proton- and deuteron-induced data and a fair share of the neutron-induced data. Cross-section validation exercises against both experimental data and systematic, which were started in 1995, enable a comprehensive assessment of the data. Although EAF-2010 is certainly the most-validated activation neutron cross-section library in the world, currently less than 3% of all the reactions can be compared with experimental information, and even then only for a very limited, and not always application-relevant, energy range. As with EAF-2010, -2003, -2005 and -2007 results of integral experiments have been used to correct, adjust and validate data. This can be done using SAFEPAQ II by inputting the measured effective cross-sections. Validation using integral data has been performed by means of direct comparison with measurements of various materials under relevant particle spectra. A tool has recently been developed which is important now that the libraries contain so much TALYS-calculated data. Statistical analysis of cross-sections (SACS) is used to look for trends in the library data for a particular

PPARγ ligands decrease hydrostatic pressure-induced platelet aggregation and proinflammatory activity.

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Fang Rao

Full Text Available Hypertension is known to be associated with platelet overactivity, but the direct effects of hydrostatic pressure on platelet function remain unclear. The present study sought to investigate whether elevated hydrostatic pressure is responsible for platelet activation and to address the potential role of peroxisome proliferator-activated receptor-γ (PPARγ. We observed that hypertensive patients had significantly higher platelet volume and rate of ADP-induced platelets aggregation compared to the controls. In vitro, Primary human platelets were cultured under standard (0 mmHg or increased (120, 180, 240 mmHg hydrostatic pressure for 18 h. Exposure to elevated pressure was associated with morphological changes in platelets. Platelet aggregation and PAC-1 (the active confirmation of GPIIb/IIIa binding were increased, CD40L was translocated from cytoplasm to the surface of platelet and soluble CD40L (sCD40L was released into the medium in response to elevated hydrostatic pressure (180 and 240 mmHg. The PPARγ activity was up-regulated as the pressure was increased from 120 mmHg to 180 mmHg. Pressure-induced platelet aggregation, PAC-1 binding, and translocation and release of CD40L were all attenuated by the PPARγ agonist Thiazolidinediones (TZDs. These results demonstrate that platelet activation and aggregation are increased by exposure to elevated pressure and that PPARγ may modulate platelet activation induced by high hydrostatic pressure.

PPARγ ligands decrease hydrostatic pressure-induced platelet aggregation and proinflammatory activity.

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Rao, Fang; Yang, Ren-Qiang; Chen, Xiao-Shu; Xu, Jin-Song; Fu, Hui-Min; Su, Hai; Wang, Ling

2014-01-01

Hypertension is known to be associated with platelet overactivity, but the direct effects of hydrostatic pressure on platelet function remain unclear. The present study sought to investigate whether elevated hydrostatic pressure is responsible for platelet activation and to address the potential role of peroxisome proliferator-activated receptor-γ (PPARγ). We observed that hypertensive patients had significantly higher platelet volume and rate of ADP-induced platelets aggregation compared to the controls. In vitro, Primary human platelets were cultured under standard (0 mmHg) or increased (120, 180, 240 mmHg) hydrostatic pressure for 18 h. Exposure to elevated pressure was associated with morphological changes in platelets. Platelet aggregation and PAC-1 (the active confirmation of GPIIb/IIIa) binding were increased, CD40L was translocated from cytoplasm to the surface of platelet and soluble CD40L (sCD40L) was released into the medium in response to elevated hydrostatic pressure (180 and 240 mmHg). The PPARγ activity was up-regulated as the pressure was increased from 120 mmHg to 180 mmHg. Pressure-induced platelet aggregation, PAC-1 binding, and translocation and release of CD40L were all attenuated by the PPARγ agonist Thiazolidinediones (TZDs). These results demonstrate that platelet activation and aggregation are increased by exposure to elevated pressure and that PPARγ may modulate platelet activation induced by high hydrostatic pressure.

Methylphenidate increases glucose uptake in the brain of young and adult rats.

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Réus, Gislaine Z; Scaini, Giselli; Titus, Stephanie E; Furlanetto, Camila B; Wessler, Leticia B; Ferreira, Gabriela K; Gonçalves, Cinara L; Jeremias, Gabriela C; Quevedo, João; Streck, Emilio L

2015-10-01

Methylphenidate (MPH) is the drug of choice for pharmacological treatment of attention deficit hyperactivity disorder. Studies have pointed to the role of glucose and lactate as well as in the action mechanisms of drugs used to treat these neuropsychiatric diseases. Thus, this study aims to evaluate the effects of MPH administration on lactate release and glucose uptake in the brains of young and adult rats. MPH (1.0, 2.0 and 10.0mg/kg) or saline was injected in young and adult Wistar male rats either acutely (once) or chronically (once daily for 28 days). Then, the levels of lactate release and glucose uptake were assessed in the prefrontal cortex, hippocampus, striatum, cerebellum and cerebral cortex. Chronic MPH treatment increased glucose uptake at the dose of 10.0mg/kg in the prefrontal cortex and striatum, and at the dose of 2.0mg/kg in the cerebral cortex of young rats. In adult rats, an increase in glucose uptake was observed after acute administration of MPH at the dose of 10.0mg/kg in the prefrontal cortex. After chronic treatment, there was an increase in glucose uptake with MPH doses of 2.0 and 10.0mg/kg in the prefrontal cortex, and at an MPH dose of 2.0mg/kg in the striatum of adult rats. The lactate release did not change with either acute or chronic treatments in young or adult rats. These findings indicate that MPH increases glucose consumption in the brain, and that these changes are dependent on age and posology. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Anti-apoptotic BFL-1 is the major effector in activation-induced human mast cell survival.

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Maria Ekoff

Full Text Available Mast cells are best known for their role in allergic reactions, where aggregation of FcεRI leads to the release of mast cell mediators causing allergic symptoms. The activation also induces a survival program in the cells, i.e., activation-induced mast cell survival. The aim of the present study was to investigate how the activation-induced survival is mediated. Cord blood-derived mast cells and the mast cell line LAD-2 were activated through FcεRI crosslinking, with or without addition of chemicals that inhibit the activity or expression of selected Bcl-2 family members (ABT-737; roscovitine. Cell viability was assessed using staining and flow cytometry. The expression and function of Bcl-2 family members BFL-1 and MCL-1 were investigated using real-time quantitative PCR and siRNA treatment. The mast cell expression of Bfl-1 was investigated in skin biopsies. FcεRI crosslinking promotes activation-induced survival of human mast cells and this is associated with an upregulation of the anti-apoptotic Bcl-2 family member Bfl-1. ABT-737 alone or in combination with roscovitine decreases viability of human mast cells although activation-induced survival is sustained, indicating a minor role for Bcl-X(L, Bcl-2, Bcl-w and Mcl-1. Reducing BFL-1 but not MCL-1 levels by siRNA inhibited activation-induced mast cell survival. We also demonstrate that mast cell expression of Bfl-1 is elevated in birch-pollen-provocated skin and in lesions of atopic dermatitis and psoriasis patients. Taken together, our results highlight Bfl-1 as a major effector in activation-induced human mast cell survival.

CD36 participates in PrP(106-126-induced activation of microglia.

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Mohammed Kouadir

Full Text Available Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The molecular mechanisms that underlie prion-induced microglial activation are not very well understood. In the present study, we investigated the role of the class B scavenger receptor CD36 in microglial activation induced by neurotoxic prion protein (PrP fragment 106-126 (PrP(106-126. We first examined the time course of CD36 mRNA expression upon exposure to PrP(106-126 in BV2 microglia. We then analyzed different parameters of microglial activation in PrP(106-126-treated cells in the presence or not of anti-CD36 monoclonal antibody (mAb. The cells were first incubated for 1 h with CD36 monoclonal antibody to block the CD36 receptor, and were then treated with neurotoxic prion peptides PrP(106-126. The results showed that PrP(106-126 treatment led to a rapid yet transitory increase in the mRNA expression of CD36, upregulated mRNA and protein levels of proinflammatory cytokines (IL-1β, IL-6 and TNF-α, increased iNOS expression and nitric oxide (NO production, stimulated the activation of NF-κB and caspase-1, and elevated Fyn activity. The blockade of CD36 had no effect on PrP(106-126-stimulated NF-κB activation and TNF-α protein release, abrogated the PrP(106-126-induced iNOS stimulation, downregulated IL-1β and IL-6 expression at both mRNA and protein levels as well as TNF-α mRNA expression, decreased NO production and Fyn phosphorylation, reduced caspase-1 cleavage induced by moderate PrP(106-126-treatment, but had no effect on caspase-1 activation after treatment with a high concentration of PrP(106-126. Together, these results suggest that CD36 is involved in PrP(106-126-induced microglial activation and that the participation of CD36 in the interaction between PrP(106-126 and microglia may be mediated by Src tyrosine kinases. Our findings provide new insights into the mechanisms underlying the activation of microglia by neurotoxic prion peptides

Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

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Mark R. Hutchinson

2007-01-01

Full Text Available This review will introduce the concept of toll-like receptor (TLR–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward. Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine level of analysis. Moreover, a novel antagonism of TLR4 by (+- and (˗-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia and unwanted (tolerance, dependence, and reward actions of opioids, thereby improving the safety and efficacy of their use.

A Single-Dose, Single-Period Pharmacokinetic Assessment of an Extended-Release Orally Disintegrating Tablet of Methylphenidate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

Science.gov (United States)

Childress, Ann; Newcorn, Jeffrey; Stark, Jeffrey G; McMahen, Russ; Tengler, Mark; Sikes, Carolyn

2016-08-01

To determine the pharmacokinetic (PK) profile of a proprietary formulation of methylphenidate (MPH) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in a phase 1 study. Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) combine two technologies in a single-tablet formulation-an extended-release profile that was designed for once-daily dosing in an ODT that does not require water or chewing for ingestion. This was a single-dose, open-label, single-period, single-treatment study, in which 32 children with ADHD who were receiving MPH in doses of 40 or 60 mg before beginning the study each received a 60-mg dose (2 × 30 mg) of MPH XR-ODT. The following plasma PK parameters of MPH were determined for participants grouped by age (6-7, 8-9, 10-12, and 13-17 years old): maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T½), area under the curve from 0 hours to infinity (AUCinf), oral clearance (CL/F), and volume of distribution in the terminal phase (Vz/F). Safety and tolerability were also assessed. A total of 32 participants received the study drug. For all participants, plasma concentration-time profiles of MPH exhibited a broad peak after administration of MPH XR-ODT through ∼8 hours, indicating extended release from the formulation, followed by an apparent first-order elimination phase. As age increased, MPH exposure decreased and mean estimates of CL/F increased; however, weight-normalized CL/F values were comparable across age groups. Similarly, mean estimates of Vz/F increased with age, but weight-normalization decreased differences across age groups, with the exception of the youngest age group, which had higher values. All adverse events (AEs) were mild. This XR-ODT formulation of MPH demonstrated weight-normalized clearance rates that were consistent across all age groups, a PK profile consistent with once-daily dosing, and an AE profile consistent with

Oscillatory brain activity in spontaneous and induced sleep stages in flies.

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Yap, Melvyn H W; Grabowska, Martyna J; Rohrscheib, Chelsie; Jeans, Rhiannon; Troup, Michael; Paulk, Angelique C; van Alphen, Bart; Shaw, Paul J; van Swinderen, Bruno

2017-11-28

Sleep is a dynamic process comprising multiple stages, each associated with distinct electrophysiological properties and potentially serving different functions. While these phenomena are well described in vertebrates, it is unclear if invertebrates have distinct sleep stages. We perform local field potential (LFP) recordings on flies spontaneously sleeping, and compare their brain activity to flies induced to sleep using either genetic activation of sleep-promoting circuitry or the GABA A agonist Gaboxadol. We find a transitional sleep stage associated with a 7-10 Hz oscillation in the central brain during spontaneous sleep. Oscillatory activity is also evident when we acutely activate sleep-promoting neurons in the dorsal fan-shaped body (dFB) of Drosophila. In contrast, sleep following Gaboxadol exposure is characterized by low-amplitude LFPs, during which dFB-induced effects are suppressed. Sleep in flies thus appears to involve at least two distinct stages: increased oscillatory activity, particularly during sleep induction, followed by desynchronized or decreased brain activity.

The hydroxyflavone, fisetin, suppresses mast cell activation induced by interaction with activated T cell membranes

Science.gov (United States)

Nagai, K; Takahashi, Y; Mikami, I; Fukusima, T; Oike, H; Kobori, M

2009-01-01

Background and purpose: Cell-to-cell interactions between mast cells and activated T cells are increasingly recognized as a possible mechanism in the aetiology of allergic or non-allergic inflammatory disorders. To determine the anti-allergic effect of fisetin, we examined the ability of fisetin to suppress activation of the human mast cell line, HMC-1, induced by activated Jurkat T cell membranes. Experimental approach: HMC-1 cells were incubated with or without fisetin for 15 min and then co-cultured with Jurkat T cell membranes activated by phorbol-12-myristate 13-acetate for 16 h. We determined gene expression in activated HMC-1 cells by DNA microarray and quantitative reverse transcription (RT)-PCR analysis. We also examined activation of the transcription factor NF-κB and MAP kinases (MAPKs) in activated HMC-1 cells. Key results: Fisetin suppresses cell spreading and gene expression in HMC-1 cells stimulated by activated T cell membranes. Additionally, we show that these stimulated HMC-1 cells expressed granzyme B. The stimulatory interaction also induced activation of NF-κB and MAPKs; these activations were suppressed by fisetin. Fisetin also reduced the amount of cell surface antigen CD40 and intercellular adhesion molecule-1 (ICAM-1) on activated HMC-1 cells. Conclusions and implications: Fisetin suppressed activation of HMC-1 cells by activated T cell membranes by interfering with cell-to-cell interaction and inhibiting the activity of NF-κB and MAPKs and thereby suppressing gene expression. Fisetin may protect against the progression of inflammatory diseases by limiting interactions between mast cells and activated T cells. PMID:19702784

Glucose-induced serum- and glucocorticoid-regulated kinase activation in oncofetal fibronectin expression

International Nuclear Information System (INIS)

Khan, Zia A.; Barbin, Yousef P.; Farhangkhoee, Hana; Beier, Norbert; Scholz, Wolfgang; Chakrabarti, Subrata

2005-01-01

Preferential expression of oncofetal extra domain-B fibronectin (EDB + FN), a proposed angiogenic marker, has been shown in proliferative diabetic retinopathy. High levels of glucose also increase EDB + FN expression in endothelial cells (ECs) via transforming growth factor-β1 (TGF-β1) and endothelin-1 (ET-1). The present study was aimed at elucidating the role of serum- and glucocorticoid-regulated kinase (SGK-1) in glucose-induced EDB + FN expression. Using human macro- and microvascular ECs, we show that high levels of glucose, TGF-β1, and ET-1 increase the EDB + FN expression via SGK-1 alteration at the mRNA, protein, and activity levels. Inhibition of TGF-β1 and ET-1 prevented glucose-induced SGK-1 activation and the EDB + FN expression. Furthermore, using siRNA-mediated SGK-1 gene silencing, we show that glucose-induced EDB + FN expression can be completely prevented. These findings provide first evidence of glucose-induced SGK-1 activation in altered EDB + FN expression and provide novel avenues for therapeutic modalities

Abnormal-induced theta activity supports early directed-attention network deficits in progressive MCI.

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Deiber, Marie-Pierre; Ibañez, Vicente; Missonnier, Pascal; Herrmann, François; Fazio-Costa, Lara; Gold, Gabriel; Giannakopoulos, Panteleimon

2009-09-01

The electroencephalography (EEG) theta frequency band reacts to memory and selective attention paradigms. Global theta oscillatory activity includes a posterior phase-locked component related to stimulus processing and a frontal-induced component modulated by directed attention. To investigate the presence of early deficits in the directed attention-related network in elderly individuals with mild cognitive impairment (MCI), time-frequency analysis at baseline was used to assess global and induced theta oscillatory activity (4-6Hz) during n-back working memory tasks in 29 individuals with MCI and 24 elderly controls (EC). At 1-year follow-up, 13 MCI patients were still stable and 16 had progressed. Baseline task performance was similar in stable and progressive MCI cases. Induced theta activity at baseline was significantly reduced in progressive MCI as compared to EC and stable MCI in all n-back tasks, which were similar in terms of directed attention requirements. While performance is maintained, the decrease of induced theta activity suggests early deficits in the directed-attention network in progressive MCI, whereas this network is functionally preserved in stable MCI.

Sex differences in attentional performance and their modulation by methylphenidate in children with attention-deficit/hyperactivity disorder.

Science.gov (United States)

Günther, Thomas; Herpertz-Dahlmann, Beate; Konrad, Kerstin

2010-06-01

Still little is known about neuropsychological differences between boys and girls with attention-deficit/hyperactivity disorder (ADHD) and whether there are sex-specific differences in the modulation of attentional performance by methylphenidate (MPH). In this study, 27 males and 27 females between 8-12 years old and with ADHD were investigated in a double-blind, placebo-controlled trial on five computerized attention tests (0.25 vs. 0.5 mg/kg MPH as a single dose, versus placebo). Boys and girls with ADHD did not differ with respect to age, intelligence quotient (IQ), symptom severity, co-morbidity patterns, and ADHD subtype. However, ADHD boys were more impulsive on a sustained attention task, whereas girls with ADHD had more deficits on tasks measuring selective attention. Attentional performance increased differentially as a function of MPH dose, with some tasks showing linear improvement with higher dosage whereas more complex tasks in particular showed inverse U-shaped patterns of MPH effects. However, these effects were comparable between girls and boys. Our data suggest that there are some gender differences in attentional performance in subjects with ADHD in a clinical sample, even if symptom severity and co-morbidity are controlled; however, modulation of attention by MPH does not seem to differ between sexes.

Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis

International Nuclear Information System (INIS)

Wang, Bing; Wang, Xin-bao; Chen, Li-yu; Huang, Ling; Dong, Rui-zen

2013-01-01

Highlights: •Belinostat activates AMPK in cultured pancreatic cancer cells. •Activation of AMPK is important for belinostat-induced cytotoxic effects. •ROS and TAK1 are involved in belinostat-induced AMPK activation. •AMPK activation mediates mTOR inhibition by belinostat. -- Abstract: Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancer cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC-1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-β-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl-Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat-induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS-TAK1-AMPK signaling axis in cultured pancreatic cancer cells

Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis

Energy Technology Data Exchange (ETDEWEB)

Wang, Bing, E-mail: wangbin69@yahoo.com; Wang, Xin-bao; Chen, Li-yu; Huang, Ling; Dong, Rui-zen

2013-07-19

Highlights: •Belinostat activates AMPK in cultured pancreatic cancer cells. •Activation of AMPK is important for belinostat-induced cytotoxic effects. •ROS and TAK1 are involved in belinostat-induced AMPK activation. •AMPK activation mediates mTOR inhibition by belinostat. -- Abstract: Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancer cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC-1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-β-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl-Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat-induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS-TAK1-AMPK signaling axis in cultured pancreatic cancer cells.

Methylphenidate use and poly-substance use among undergraduate students attending a South African university

Directory of Open Access Journals (Sweden)

Francois Steyn

2016-03-01

Full Text Available Background: Methylphenidate hydrochloride (MPH is used in the treatment of attention deficit hyperactivity disorder (ADHD. The non-medical use of MPH by learners and students has been reported by numerous studies from abroad. The practice stems from beliefs about the benefits of MPH in achieving academic success. Little is known about the use of MPH in South African student populations. Objectives: The study set out to determine (1 the extent and dynamics associated with MPH use and (2 poly-substance use among undergraduate students attending a South African university. Methods: 818 students took part in a written, group-administered survey. Data analysis resulted in descriptive results regarding MPH use and tests of association identified differences in MPH and poly-substance use among respondents. Results: One in six respondents (17.2% has used MPH in the past, although only 2.9% have been diagnosed with ADHD. Nearly a third (31.7% of users obtained MPH products illegally. The majority (69.1% used MPH only during periods of academic stress. A significant association ( p < 0.001 was found between MPH use and the frequency of using alcohol, tobacco, cannabis, hard drugs (e.g. cocaine and prescription medication. Conclusion: MPH use among students appears similar to experiences abroad, especially in the absence of clinical diagnosis for ADHD. Institutions of higher education should inform parents and students about the health risks associated with the illicit use of MPH. Prescribers and dispensers of MPH products should pay close attention to practices of stockpiling medication and poly-substance use among students who use MPH.

Methylphenidate and environmental enrichment ameliorate the deleterious effects of prenatal stress on attention functioning.

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Zubedat, Salman; Aga-Mizrachi, Shlomit; Cymerblit-Sabba, Adi; Ritter, Ami; Nachmani, Maayan; Avital, Avi

2015-01-01

Either pre- or post-natal environmental factors seem to play a key role in brain and behavioral development and to exert long-term effects. Increasing evidence suggests that exposure to prenatal stress (PS) leads to motor and learning deficits and elevated anxiety, while enriched environment (EE) shows protective effects. The dopaminergic system is also sensitive to environmental life circumstances and affects attention functioning, which serves as the preliminary gate to cognitive processes. However, the effects of methylphenidate (MPH) on the dopaminergic system and attentional functioning, in the context of these life experiences, remain unclear. Therefore, we aimed to examine the effects of EE or PS on distinct types of attention, along with possible effects of MPH exposure. We found that PS impaired selective attention as well as partial sustained attention, while EE had beneficial effects. Both EE and MPH ameliorated the deleterious effects of PS on attention functioning. Considering the possible psychostimulant effect of MPH, we examined both anxiety-like behavior as well as motor learning. We found that PS had a clear anxiogenic effect, whereas EE had an anxiolytic effect. Nevertheless, the treatment with both MPH and/or EE recovered the deleterious effects of PS. In the motor-learning task, the PS group showed superior performance while MPH led to impaired motor learning. Performance decrements were prevented in both the PS + MPH and EE + MPH groups. This study provides evidence that peripubertal exposure to EE (by providing enhanced sensory, motor, and social opportunities) or MPH treatments might be an optional therapeutic intervention in preventing the PS long-term adverse consequences.

Cognitive and emotional behavioural changes associated with methylphenidate treatment: a review of preclinical studies.

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Britton, Gabrielle B

2012-02-01

There is evidence from animal studies that repeated exposure to methylphenidate (MPH), a widely used psychostimulant for the treatment of attention deficit hyperactivity disorder (ADHD), produces behavioural, structural and neurochemical changes that persist long after drug administration has ended. However, the translational utility of much of this work is compromised by the use of drug doses and routes of administration that produce plasma and brain MPH levels that fall outside the clinical range, i.e. experimental parameters more relevant to drug abuse than ADHD. We used PubMed to identify pre-clinical studies that employed repeated MPH administration at low doses in young rodents and examined long-term effects on cognition, emotion, and brain structure and function. A review of this work suggests that repeated MPH treatment during early development can modify a number of cognitive, behavioural and brain processes, but these are reduced when low therapeutic doses are employed. Moreover, MPH sites of action extend beyond those implicated in ADHD. Studies that combined neurobiological and behavioural approaches provide important insights into the mechanisms underlying MPH-produced effects on cognitive and behavioural processes, which may be relevant to MPH therapeutic efficacy. There is an emerging consensus that pharmacological treatment of childhood psychiatric disorders produces persistent neuroadaptations, highlighting the need for studies that assess long-term effects of early developmental pharmacotherapy. In this regard, studies that mimic clinical therapy with rodents are useful experimental approaches for defining the behavioural and neural plasticity associated with stimulant therapy in paediatric populations.

Effects of methylphenidate on attentional set-shifting in a genetic model of attention-deficit/hyperactivity disorder.

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Cao, Ai-hua; Yu, Lin; Wang, Yu-wei; Wang, Jun-mei; Yang, Le-jin; Lei, Ge-Fei

2012-02-28

Although deficits of attentional set-shifting have been reported in individuals with attention deficit/hyperactivity disorder (ADHD), it is rarely examined in animal models. This study compared spontaneously hypertensive rats (SHRs; a genetic animal model of ADHD) and Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats (normoactive control strains), on attentional set-shifting task (ASST) performance. Furthermore, the dose-effects of methylphenidate (MPH) on attentional set-shifting of SHR were investigated. In experiment 1, ASST procedures were conducted in SHR, WKY and SD rats of 8 each at the age of 5 weeks. Mean latencies at the initial phase, error types and numbers, and trials to criteria at each stage were recorded. In experiment 2, 24 SHR rats were randomly assigned to 3 groups of 8 each-- MPH-L (lower dose), MPH-H (higher dose), and SHR-vehicle groups. From 3 weeks, they were administered 2.5 mg/kg or 5 mg/kg MPH or saline respectively for 14 consecutive days. All rats were tested in the ASST at the age of 5 weeks. The SHRs generally exhibited poorer performance on ASST than the control WKY and SD rats. Significant strain effects on mean latency [F (2, 21) = 639.636, p attentional set-shifting. Our study provides evidence that MPH may improve the SHR's performance on attentional set-shifting and lower dose is more effective than higher dose.

Lung vagal afferent activity in rats with bleomycin-induced lung fibrosis.

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Schelegle, E S; Walby, W F; Mansoor, J K; Chen, A T

2001-05-01

Bleomycin treatment in rats results in pulmonary fibrosis that is characterized by a rapid shallow breathing pattern, a decrease in quasi-static lung compliance and a blunting of the Hering-Breuer Inflation Reflex. We examined the impulse activity of pulmonary vagal afferents in anesthetized, mechanically ventilated rats with bleomycin-induced lung fibrosis during the ventilator cycle and static lung inflations/deflations and following the injection of capsaicin into the right atrium. Bleomycin enhanced volume sensitivity of slowly adapting stretch receptors (SARs), while it blunted the sensitivity of these receptors to increasing transpulmonary pressure. Bleomycin treatment increased the inspiratory activity, while it decreased the expiratory activity of rapidly adapting stretch receptors (RARs). Pulmonary C-fiber impulse activity did not appear to be affected by bleomycin treatment. We conclude that the fibrosis-related shift in discharge profile and enhanced volume sensitivity of SARs combined with the increased inspiratory activity of RARs contributes to the observed rapid shallow breathing of bleomycin-induced lung fibrosis.

Methylphenidate and comorbid anxiety disorder in children with both chronic multiple tic disorder and ADHD.

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Gadow, Kenneth D; Nolan, Edith E

2011-04-01

To determine if comorbid anxiety disorder is associated with differential response to immediate release methylphenidate (MPH-IR) in children with both ADHD and chronic multiple tic disorder (CMTD). Children with (n = 17) and without (n = 37) diagnosed anxiety disorder (ANX) were evaluated in an 8-week, placebo-controlled trial with rating scales and laboratory measures. The +ANX group obtained more severe parent, teacher, and child ratings of anxiety and more severe parent ratings of depression, tics, oppositional defiant disorder (ODD), and peer aggression than the -ANX group. Treatment with short-term MPH-IR was associated with improvement in ADHD, ODD, and peer aggression in the +ANX group. When controlling for ODD severity, there were no apparent group differences in therapeutic response to MPH-IR in children ±ANX. There was little evidence that MPH-IR contributed to improvement in anxiety or depression symptoms in the +ANX group. There was some indication that children with comorbid anxiety may differentially experience greater increase in systolic blood pressure (0.5 mg/kg of MPH-IR > placebo). Findings suggest that the co-occurrence of diagnosed CMTD+ADHD+ANX represents a particularly troublesome clinical phenotype, at least in the home setting. Comorbid anxiety disorder was not associated with a less favorable response to MPH-IR in children with ADHD+CMTD, but replication with larger samples is warranted before firm conclusions can be drawn about potential group differences.

Anesthetic propofol attenuates the isoflurane-induced caspase-3 activation and Aβ oligomerization.

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Yiying Zhang

Full Text Available Accumulation and deposition of β-amyloid protein (Aβ are the hallmark features of Alzheimer's disease. The inhalation anesthetic isoflurane has been shown to induce caspase activation and increase Aβ accumulation. In addition, recent studies suggest that isoflurane may directly promote the formation of cytotoxic soluble Aβ oligomers, which are thought to be the key pathological species in AD. In contrast, propofol, the most commonly used intravenous anesthetic, has been reported to have neuroprotective effects. We therefore set out to compare the effects of isoflurane and propofol alone and in combination on caspase-3 activation and Aβ oligomerization in vitro and in vivo. Naïve and stably-transfected H4 human neuroglioma cells that express human amyloid precursor protein, the precursor for Aβ; neonatal mice; and conditioned cell culture media containing secreted human Aβ40 or Aβ42 were treated with isoflurane and/or propofol. Here we show for the first time that propofol can attenuate isoflurane-induced caspase-3 activation in cultured cells and in the brain tissues of neonatal mice. Furthermore, propofol-mediated caspase inhibition occurred when there were elevated levels of Aβ. Finally, isoflurane alone induces Aβ42, but not Aβ40, oligomerization, and propofol can inhibit the isoflurane-mediated oligomerization of Aβ42. These data suggest that propofol may mitigate the caspase-3 activation by attenuating the isoflurane-induced Aβ42 oligomerization. Our findings provide novel insights into the possible mechanisms of isoflurane-induced neurotoxicity that may aid in the development of strategies to minimize potential adverse effects associated with the administration of anesthetics to patients.

Allergen-Removed Rhus verniciflua Extract Induces Ovarian Cancer Cell Death via JNK Activation.

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Kang, Se-Hui; Hwang, In-Hu; Son, Eunju; Cho, Chong-Kwan; Choi, Jong-Soon; Park, Soo-Jung; Jang, Byeong-Churl; Lee, Kyung-Bok; Lee, Zee-Won; Lee, Jong Hoon; Yoo, Hwa-Seung; Jang, Ik-Soon

2016-01-01

Nuclear factor-[Formula: see text]B (NF-[Formula: see text]B)/Rel transcription factors are best known for their central roles in promoting cell survival in cancer. NF-[Formula: see text]B antagonizes tumor necrosis factor (TNF)-[Formula: see text]-induced apoptosis through a process involving attenuation of the c-Jun-N-terminal kinase (JNK). However, the role of JNK activation in apoptosis induced by negative regulation of NF-[Formula: see text]B is not completely understood. We found that allergen-removed Rhus verniciflua Stokes (aRVS) extract-mediated NF-[Formula: see text]B inhibition induces apoptosis in SKOV-3 ovarian cancer cells via the serial activation of caspases and SKOV-3 cells are most specifically suppressed by aRVS. Here, we show that in addition to activating caspases, aRVS extract negatively modulates the TNF-[Formula: see text]-mediated I[Formula: see text]B/NF-[Formula: see text]B pathway to promote JNK activation, which results in apoptosis. When the cytokine TNF-[Formula: see text] binds to the TNF receptor, I[Formula: see text]B dissociates from NF-[Formula: see text]B. As a result, the active NF-[Formula: see text]B translocates to the nucleus. aRVS extract (0.5[Formula: see text]mg/ml) clearly prevented NF-[Formula: see text]B from mobilizing to the nucleus, resulting in the upregulation of JNK phosphorylation. This subsequently increased Bax activation, leading to marked aRVS-induced apoptosis, whereas the JNK inhibitor SP600125 in aRVS extract treated SKOV-3 cells strongly inhibited Bax. Bax subfamily proteins induced apoptosis through caspase-3. Thus, these results indicate that aRVS extract contains components that inhibit NF-[Formula: see text]B signaling to upregulate JNK activation in ovarian cancer cells and support the potential of aRVS as a therapeutic agent for ovarian cancer.