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Drug Metabolism and Disposition: the... Jan 2013Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active... (Comparative Study)
Comparative Study
Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1-2%. Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH). The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPH to l-EPH. Twenty-four healthy volunteers received dl-MPH (0.3 mg/kg) or d-MPH (0.15 mg/kg), with or without ethanol (0.6 g/kg). During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44-99%; P < 0.005). Furthermore, immediately following the ethanol drink the subjective effects of "high," "good," "like," "stimulated," and overall "effect" were significantly potentiated (P ≤ 0.01). Plasma l-EPH concentrations exceeded those of l-MPH. Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanol-induced potentiation of subjective effects was delayed relative to dl-MPH-ethanol. These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d-MPH. Ethanol increased the d-MPH area under the curve (AUC)(0-inf) by 21% following dl-MPH (P < 0.001) and 14% for d-MPH (P = 0.001). In men receiving d-MPH-ethanol, the d-MPH absorption partial AUC(0.5-2 hours) was 2.1 times greater and the time to maximum concentration (T(max)) occurred 1.1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction. More rapid absorption of d-MPH carries implications for increased abuse liability.
Topics: Adult; Area Under Curve; Carboxylesterase; Dexmethylphenidate Hydrochloride; Esterification; Ethanol; Female; Hemodynamics; Humans; Male; Methylphenidate; Stereoisomerism; Young Adult
PubMed: 23104969
DOI: 10.1124/dmd.112.048595 -
European Journal of Clinical... Mar 2013Attention deficit hyperactivity disorder (ADHD) in adulthood is increasingly diagnosed and treated. Methylphenidate is frequently advocated as a first-line... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Attention deficit hyperactivity disorder (ADHD) in adulthood is increasingly diagnosed and treated. Methylphenidate is frequently advocated as a first-line pharmacological treatment.
PURPOSE
The aim of our study was to compare all-cause discontinuation rate of methylphenidate and its pharmaceutical presentations with placebo in adults with ADHD.
METHODS
This was a systematic review and meta-analysis of randomized controlled trials comparing methylphenidate with placebo in adults with ADHD. All-cause treatment discontinuation was the primary endpoint. The efficacy in reducing ADHD symptoms and safety were the secondary endpoints.
RESULTS
Twelve studies (2,496 patients) met the inclusion criteria. Four racemic methylphenidate and one dexmethylphenidate presentations were investigated. The rate of all-cause treatment discontinuation was greater with methylphenidate than with placebo, but this difference was not statistically significant [odds ratio (OR) 1.19, 95 % confidence interval (95 % CI) 0.82-1.74, P = 0.37, I(2) = 64 %] This finding reached the conventional threshold of statistical significance after one outlier study was excluded (OR 1.44, 95 % CI 1.14-1.82, P = 0.002, I(2) = 0). Methylphenidate was more efficacious than placebo for reducing ADHD symptoms and it was associated with a higher proportion of patients dropping out due to adverse effects.
CONCLUSIONS
Despite reducing ADHD symptoms, methylphenidate showed no advantage over placebo in terms of treatment discontinuation. More attention should be given in the future to the endpoint "all-cause treatment discontinuation" when making regulatory decisions and developing clinical guidelines involving the treatment of ADHD in adulthood.
Topics: Adult; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Chi-Square Distribution; Dexmethylphenidate Hydrochloride; Drug Administration Schedule; Endpoint Determination; Female; Humans; Male; Methylphenidate; Odds Ratio; Patient Dropouts; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome
PubMed: 22983311
DOI: 10.1007/s00228-012-1390-7 -
Journal of Clinical Psychopharmacology Oct 2012The objective of this study was to evaluate the safety and efficacy of dexmethylphenidate extended-release (d-MPH-ER) 30 versus 20 mg in children with... (Comparative Study)
Comparative Study Randomized Controlled Trial
A randomized, double-blind study of 30 versus 20 mg dexmethylphenidate extended-release in children with attention-deficit/hyperactivity disorder: late-day symptom control.
The objective of this study was to evaluate the safety and efficacy of dexmethylphenidate extended-release (d-MPH-ER) 30 versus 20 mg in children with attention-deficit/hyperactivity disorder (ADHD) in a 12-hour laboratory classroom setting. In a randomized, double-blind, 3-period × 3-treatment, crossover study, children aged 6 to 12 years with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-diagnosed ADHD previously stabilized on MPH (40-60 mg/d) or D-MPH (20-30 mg/day) [corrected] were randomized to receive D-MPH-ER 20 mg/day, 30 mg/day, [corrected] or placebo for 7 days each. Primary efficacy measurements were change in the average SKAMP-Combined [corrected] score from predose to 10, 11, and 12 hours postdose [Avg(10-12)] between 30 mg [corrected] and 20 mg D-MPH-ER. Safety was assessed by adverse events, (AEs), [corrected] vital sign monitoring, and ECGs. [corrected] A total of 165 children were randomized, and 162 included in the intent-to-treat analysis. Mean Avg (10-12) change from pre-dose [corrected] in SKAMP-Combined score was significantly greater for D-MPH-ER 30 mg (-4.47) compared with D-MPH-ER 20 mg (-2.02; P = 0.002). Most common adverse events (≥ 3% in any group) were decreased appetite (6.1%, 4.9%, and 0%), headache (4.3%, 4.3%, and 1.9%), abdominal pain (3.7%, 3.1%, and 3.1%), and tachycardia (1.2%, 3.1%, and 0.6%) for D-MPH-ER 30 mg, D-MPH-ER 20 mg, and placebo, respectively). Significantly greater improvement in ADHD symptoms was noted with D-MPH-ER 30 mg compared with D-MPH-ER 20 mg at hours 10 through 12. Tolerability was comparable between doses. Dexmethylphenidate extended-release 30-mg dose may provide further benefit to patients who do not maintain optimal symptom control later in the day with D-MPH-ER 20 mg.
Topics: Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Cross-Over Studies; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Methylphenidate; Time Factors; Treatment Outcome
PubMed: 22926597
DOI: 10.1097/JCP.0b013e3182677825 -
The Journal of Clinical Psychiatry Mar 2012Pediatric studies of the long-acting formulation (spheroidal oral drug absorption system [SODAS]) of the isomer dexmethylphenidate have shown a dose-dependent efficacy... (Clinical Trial)
Clinical Trial
Understanding the central pharmacokinetics of spheroidal oral drug absorption system (SODAS) dexmethylphenidate: a positron emission tomography study of dopamine transporter receptor occupancy measured with C-11 altropane.
OBJECTIVE
Pediatric studies of the long-acting formulation (spheroidal oral drug absorption system [SODAS]) of the isomer dexmethylphenidate have shown a dose-dependent efficacy through 12 hours. However, there are no studies of central nervous system (CNS) dopamine transporter occupancies.
METHOD
Eighteen healthy volunteers underwent positron emission tomography (PET) imaging with C-11 altropane before and after administration of oral doses of SODAS dexmethylphenidate. Each group of 6 subjects received 1 of 3 doses (20 mg, 30 mg, 40 mg) before PET imaging at 1, 8, 10, 12 (20 mg and 30 mg), or 1, 8, 10, and 14 (40 mg) hours after dosing. Transporter occupancy was calculated by standard methods. The study was conducted from January 2007 through December 2007.
RESULTS
For all doses, plasma dexmethylphenidate levels and CNS dopamine transporter occupancies were greatest at 8 hours and decreased over time at 10, 12, and 14 hours. Plasma dexmethylphenidate levels were correlated to dose (P < .003). Mean plasma levels were ≥ 6 ng/mL to at least 8 hours with 20 mg (5.7 ng/mL), 10 hours with 30 mg, and 12 hours (extrapolated) with 40 mg. Dopamine transporter occupancies in the right caudate were 47% at 8 hours with 20 mg, 42% at hour 10 with 30 mg, and 46% (extrapolated) at hour 12 with 40 mg. Dopamine transporter occupancy was significantly correlated with plasma concentration of dexmethylphenidate (P < .001).
CONCLUSIONS
These results confirm the study hypothesis that central dopamine transporter occupancy parallels peripheral pharmacokinetic findings in orally administered long-acting dexmethylphenidate in later hours after administration.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00593138.
Topics: Administration, Oral; Adolescent; Adult; Brain; Carbon Radioisotopes; Cocaine; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Male; Methylphenidate; Middle Aged; Positron-Emission Tomography; Radioligand Assay
PubMed: 22154896
DOI: 10.4088/JCP.10m06393 -
Journal of Child and Adolescent... Dec 2011To compare the dose effects of long-acting extended-release dexmethylphenidate (ER d-MPH) and ER mixed amphetamine salts (ER MAS) on attention-deficit/hyperactivity... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To compare the dose effects of long-acting extended-release dexmethylphenidate (ER d-MPH) and ER mixed amphetamine salts (ER MAS) on attention-deficit/hyperactivity disorder (ADHD) symptom dimensions, global and specific impairments, and common adverse events associated with stimulants.
METHODS
Fifty-six children and adolescents with ADHD participated in an 8-week, double-blind, crossover study comparing ER d-MPH (10, 20, 25-30 mg) and ER MAS (10, 20, 25-30) with a week of randomized placebo within each drug period. Efficacy was assessed with the ADHD Rating Scale-IV (ADHD-RS-IV), whereas global and specific domains of impairment were assessed with the Clinical Global Impressions Severity and Improvement Scales and the parent-completed Weiss Functional Impairment Scale, respectively. Insomnia and decreased appetite, common stimulant-related adverse events, were measured with the parent-completed Stimulant Side Effects Rating Scale.
RESULTS
Both ER d-MPH and ER MAS were associated with significant reductions in ADHD symptoms. Improvement in Total ADHD and Hyperactivity/Impulsivity symptoms were strongly associated with increasing dose, whereas improvements in Inattentive symptoms were only moderately associated with dose. About 80% demonstrated reliable change on ADHD-RS-IV at the highest dose level of ER MAS compared with 79% when receiving ER d-MPH. Decreased appetite and insomnia were more common at higher dose levels for both stimulants. Approximately 43% of the responders were preferential responders to only one of the stimulant formulations.
CONCLUSIONS
Dose level, rather than stimulant class, was strongly related to medication response.
Topics: Adolescent; Amphetamines; Appetite; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Cross-Over Studies; Delayed-Action Preparations; Dexmethylphenidate Hydrochloride; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Methylphenidate; Psychiatric Status Rating Scales; Sleep Initiation and Maintenance Disorders
PubMed: 22136094
DOI: 10.1089/cap.2011.0018 -
Revista Da Associacao Medica Brasileira... 2011Cancer-related fatigue is the most prevalent cancer symptom, reported in 50%-90% of patients and severely impacts quality of life and functional capacity. The condition... (Review)
Review
Cancer-related fatigue is the most prevalent cancer symptom, reported in 50%-90% of patients and severely impacts quality of life and functional capacity. The condition remains underreported and often goes untreated. Guidelines suggest screening for fatigue at the initial visit, when the diagnosis of advanced disease is made, and at each chemotherapy session, as well as the identification of treatable contributing factors such as anemia, hypothyroidism, depression and sleep disorders. Brief assessment tools such as the Brief Fatigue Inventory or the Visual Analog Scale may be appropriate in the initial scoring of fatigue severity, but the initial approach to treatment usually requires a more comprehensive assessment, education, and the determination of an individualized treatment plan. Patients with moderate or severe fatigue may benefit from both pharmacological and non-pharmacological interventions, whereas mild fatigue that does not interfere with quality of life can be treated with non-pharmacological measures alone. Non-pharmacological measures that have shown to be promising include cognitive-behavioral interventions such as energy conservation and activity management (ECAM), exercise and perhaps sleep therapy. Many other modalities may be beneficial and can be used on an individual basis, but there is insufficient evidence to promote any single treatment. Pharmacological therapies that have shown to be promising include the psycho-stimulants methylphenidate and dexmethylphenidate, modafinil (in severely fatigued patients only), and erythropoietin-stimulating agents in patients with chemotherapy-associated anemia and hemoglobin levels < 10 g/dL. Recently, our group reported impressive results with the use of the dry extract of Guarana (Paullinia cupana), with no significant side effects and at low cost, for the treatment of physical and mental cancer-related fatigue.
Topics: Fatigue; Humans; Neoplasms; Quality of Life
PubMed: 21537710
DOI: 10.1590/s0104-42302011000200021 -
Methods and Findings in Experimental... Nov 2010Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from...
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Thomson Reuters Integrity(SM), the drug discovery and development portal, http://www.thomsonreutersintegrity.com. This issue focuses on the following selection of drugs: Abatacept, Adalimumab, AdCD40L, Adefovir, Aleglitazar, Aliskiren fumarate, AM-103, Aminolevulinic acid methyl ester, Amlodipine, Anakinra, Aprepitant, Aripiprazole, Atazanavir sulfate, Axitinib; Belimumab, Bevacizumab, Bimatoprost, Bortezomib, Bupropion/naltrexone; Calcipotriol/betamethasone dipropionate, Certolizumab pegol, Ciclesonide, CYT-997; Darbepoetin alfa, Darunavir, Dasatinib, Desvenlafaxine succinate, Dexmethylphenidate hydrochloride cogramostim; Eltrombopag olamine, Emtricitabine, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Everolimus-eluting coronary stent, Exenatide, Ezetimibe; Fenretinide, Filibuvir, Fludarabine; Golimumab; Hepatitis B hyperimmunoglobulin, HEV-239, HP-802-247, HPV-16/18 AS04, HPV-6/11/16/18, Human albumin, Human gammaglobulin; Imatinib mesylate, Inotuzumab ozogamicin, Invaplex 50 vaccine; Lapatinib ditosylate, Lenalidomide, Liposomal doxorubicin, Lopinavir, Lumiliximab, LY-686017; Maraviroc, Mecasermin rinfabate; Narlaprevir; Ocrelizumab, Oral insulin, Oritavancin, Oxycodone hydrochloride/naloxone; Paclitaxel-eluting stent, Palonosetron hydrochloride, PAN-811, Paroxetine, Pazopanib hydrochloride, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Pitavastatin calcium, Posaconazole, Pregabalin, Prucalopride succinate; Raltegravir potassium, Ranibizumab, RHAMM R3 peptide, Rosuvastatin calcium; Salclobuzic acid sodium salt, SCY-635, Selenate sodium, Semapimod hydrochloride, Silodosin, Siltuximab, Silybin, Sirolimus-eluting stent, SIR-Spheres, Sunitinib malate; Tapentadol hydrochloride, Tenofovir disoproxil fumarate, Tocilizumab, Tositumomab/iodine (I131) tositumomab, Trabectedin, TransVax™ hepatitis C vaccine; Ustekinumab; V-260, Valspodar, Varenicline tartrate, VCL-IPT1, Vildagliptin, VRC-HIVADV014-00-VP, VRC-HIVDNA009-00-VP, VRC-HIVDNA016-00-VP; Yttrium 90 (90Y) ibritumomab tiuxetan, Yttrium Y90 Epratuzumab; Zibotentan, Zotarolimus-eluting stent.
Topics: Clinical Trials as Topic; Humans
PubMed: 21225019
DOI: 10.1358/mf.2010.32.9.1563109 -
The Primary Care Companion For CNS... 2011To review the efficacy, safety, and abuse liability of approved treatments in adults with attention-deficit/hyperactivity disorder (ADHD), with a focus on once-daily...
OBJECTIVE
To review the efficacy, safety, and abuse liability of approved treatments in adults with attention-deficit/hyperactivity disorder (ADHD), with a focus on once-daily medications.
DATA SOURCES
PubMed was searched for relevant studies/reviews in English from 2002 to 2011 on adult ADHD treatments.
STUDY SELECTION
Keywords used in the search were ADHD, adults, and treatment. Limits included only clinical trials, meta-analyses, randomized controlled trials, and reviews including adults (aged ≥ 19 years).
DATA EXTRACTION
Selection criteria returned 471 publications. Retrieved studies were excluded if they primarily focused on children, treatments not indicated for ADHD, or ADHD and comorbid conditions.
DATA SYNTHESIS
An epidemiologic survey revealed that 10.9% of adults identified with ADHD had received treatment during the prior 12 months. Treatments for ADHD in adults include pharmacologic and nonpharmacologic options. US Food and Drug Administration-approved long-acting stimulants and a nonstimulant with proven efficacy and safety profiles have been developed and include osmotic-release oral system methylphenidate hydrochloride (OROS-methylphenidate), extended-release dexmethylphenidate hydrochloride, mixed amphetamine salts extended release (MAS-XR), the nonstimulant atomoxetine hydrochloride, and the prodrug lisdexamfetamine dimesylate. Long-acting stimulants differ in formulation characteristics used to achieve extended release, with OROS-methylphenidate employing an osmotic-release technology, extended-release dexmethylphenidate hydrochloride and MAS-XR using pH-dependent beads, and lisdexamfetamine dimesylate using prodrug technology. These features variably affect pharmacokinetic characteristics, duration of action, and abuse liability. While all long-acting medications have varied pharmacokinetic features, mechanism of action, and duration of effect, all are generally efficacious and safety profiles are similar.
CONCLUSION
Approved long-acting treatments in adults with ADHD were effective in improving symptoms and were generally well tolerated.
PubMed: 22454805
DOI: 10.4088/PCC.11r01168 -
Journal of Child and Adolescent... Aug 2010The aim of this study was to conduct a pilot study testing whether single-dose, immediate-release dexmethylphenidate (dMPH) can facilitate tic suppression in children... (Randomized Controlled Trial)
Randomized Controlled Trial
Testing tic suppression: comparing the effects of dexmethylphenidate to no medication in children and adolescents with attention-deficit/hyperactivity disorder and Tourette's disorder.
OBJECTIVE
The aim of this study was to conduct a pilot study testing whether single-dose, immediate-release dexmethylphenidate (dMPH) can facilitate tic suppression in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and Tourette's disorder (TD) or chronic tic disorders. The primary hypothesis is that dMPH will improve behaviorally reinforced tic suppression in a standard tic suppression paradigm (TSP).
METHODS
Ten children with ADHD and TD were given dMPH on one visit and no medication on another, using a random crossover design. On both days, following a baseline period, subjects were reinforced for suppressing tics using a standard TSP.
RESULTS
Thirteen subjects were enrolled; 10 subjects (mean age 12.7 +/- 2.6; 90% male) completed all study procedures. Relative to the no-medication condition, tics were reduced when children were given a single dose of dMPH. Behavioral reinforcement of tic suppression resulted in lower rates of tics compared to baseline, but dMPH did not enhance this suppression.
CONCLUSION
Preliminary results indicate replication of prior studies of behavioral tic suppression in youths with TD and without ADHD. In addition, our findings indicate tic reduction (and not tic exacerbation) with acute dMPH challenge in children and adolescents with ADHD and TD.
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Combined Modality Therapy; Cross-Over Studies; Dexmethylphenidate Hydrochloride; Female; Humans; Male; Methylphenidate; Pilot Projects; Reinforcement, Psychology; Tics; Tourette Syndrome
PubMed: 20807066
DOI: 10.1089/cap.2010.0032 -
The Annals of Pharmacotherapy Oct 2010To review the efficacy and safety of psychostimulants for negative behavioral symptoms (ie, apathy, excessive daytime sedation) and cognition in patients with dementia. (Review)
Review
OBJECTIVE
To review the efficacy and safety of psychostimulants for negative behavioral symptoms (ie, apathy, excessive daytime sedation) and cognition in patients with dementia.
DATA SOURCES
Literature was accessed through PubMed and MEDLINE (1966-June 2010), using the terms stimulant, psychostimulant, methylphenidate, dexmethylphenidate, amphetamine, dextroamphetamine, lisdexamfetamine, atomoxetine, modafinil, armodafinil, dementia, Alzheimer disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, therapy, treatment, and therapeutic. Additional references identified from the initial search were reviewed.
STUDY SELECTION AND DATA EXTRACTION
All relevant clinical trials published in English and involving primarily older adults with dementia were included. Case reports, review articles, and other preclinical literature were included as appropriate.
DATA SYNTHESIS
Psychostimulants have been employed as a treatment for cognitive and behavioral symptoms in dementia for decades, but the literature has lagged behind this practice. Eight reports on use of psychostimulants as a treatment of apathy in dementia were reviewed. Methylphenidate was the most frequently studied medication and improvements in apathy were consistently noted; however, the magnitude and duration of effect remain unclear. Six studies examining the cognitive effects of a variety of psychostimulants in patients with dementia were reviewed; psychostimulants had little to no effect on cognition. A lack of studies exists to draw conclusions about the use of psychostimulants for the treatment of excessive daytime sedation in dementia. The possibility of psychostimulants to increase blood pressure; elevate heart rate; and lead to irritability, agitation, and psychosis makes careful patient selection critical, especially in older adults with severe cardiovascular disease or other underlying cardiac abnormalities.
CONCLUSIONS
Based on limited studies, methylphenidate is a possible treatment for apathy in patients with dementia. Psychostimulants, as a group, do not appear to be broadly effective treatments for behavioral or cognitive symptoms of dementia. The potential utility of psychostimulants must be balanced with careful patient selection.
Topics: Aged; Apathy; Behavioral Symptoms; Central Nervous System Stimulants; Dementia; Disorders of Excessive Somnolence; Humans; Psychomotor Agitation
PubMed: 20736422
DOI: 10.1345/aph.1P341