attention - deficit / hyperactivity disorder ( adhd ) affects a large number of children . in the united states , rates range from 5% to 6% of school - age children ( guevara et al 2002 ; lesesne et al 2003).the illness is characterized by a triad of symptom clusters which include inattention , hyperactivity , and impulsivity . usually the illness is first detected during the early school years ( goldman et al 1998 ) , but can persist during adolescence and even adulthood . if left untreated , adhd can be associated with a number of poor outcomes including academic failure , delinquency , and problems with substance abuse ( barkley 1990 ; biederman et al 1996 ; dulcan 1997 ; wilens et al 2004 ) . their effect on disruptive behavior was discovered in 1937 , when these drugs proved to increase compliance , improve academic performance , and reduce motor activity in hyperactive children ( bradley 1937 ) . it has proven efficacy on adhd symptoms ( kimko et al 1999 ; greenhill et al 2002 ) . until the introduction of the d - mph ( d - threo-(r , r)-mph , d - mph ) in 2002 , all clinically used mph formulations contained a racemic ( 1:1 ) mixture of d - threo-(r , r)-mph and l - threo-(r , r)-mph isomers ( figure 1 ) . the development of d - mph was based on the findings that similar improvement on sustained attention was achieved after treatment with d - equivalent doses of d - mph and d , l - mph , but not after l - mph ( srinivas et al 1992 ) . it was found that clinical efficacy was highly correlated with plasma concentrations of d - mph . the elimination of the l - isomer does not diminish the efficacy of an acute dose of mph ( quinn et al 2004 ) . the efficacy of the d - isomer was equivalent to the racemic preparation in ameliorating the target symptoms of adhd and increasing academic productivity . thus , it was thought that the efficacy of mph resides in the d - isomer ( lim et al 1986 ; patrick et al 1987 ; srinivas et al 1987 , 1992 ) . other research demonstrated that besides clinical effectiveness , the undesired pressor and anorexic actions of d , l - mph also appear to reside in the d - isomer ( srinivas et al 1992 ; anonymous 2002 ; scheffler et al 2003 ; teo et al 2004 ) . d - mph not only appears to be the more active of the two enantiomers , but also better absorbed ; plasma concentrations of d - mph are many times higher than the l - enantiomer after oral dosing of racemic mph ( hubbard et al 1989 ; ding et al 1997 ; kimko et al 1999 ; modi et al 2000 ) or intravenous administration ( kimko et al 1999 ) . this is seen with both immediate - release ( kimko et al 1999 ) and sustained - released ( hubbard et al 1989 ; kimko et al 1999 ) forms of racemic mph . the pre - systemic metabolism and metabolic clearance of d , l - mph is also an enantioselective process which , too , contributes to markedly higher plasma concentrations of d - mph relative to l - mph ( markowitz et al 2003 ; patrick et al 2005 ) . it was also found that equimolar doses of d - mph yielded similar pharmacokinetics as those noted with administration of the d , l - racemic mixture ( srinivas et al 1992 ) . as a result , the d - mph product was developed , and approved by the fda for clinical use on august 31 2001 . the d - mph product appears to double the therapeutic potency of the racemic d , l - mph ; when only half dose of racemic d , l - mph was used , d - mph produced similar pharmacokinetic parameters ( cmax , tmax , and half - life ) ( anonymous 2002 ; keating and figgitt 2002 ; markowitz et al 2003 ) . the administration of d - mph with food has no significant effect on bioavailability , but with racemic mph , tmax was delayed by 1 hour ( teo et al 2004 ) . in addition , a number of studies ( patrick et al 1981 ; arnold et al 2004 ; quinn et al 2004 ; silva et al 2004 ; wigal et al 2004 ) suggested that d - mph might have a longer duration of action than d , l - mph on tests measuring attention , hyperactivity , and impulsivity , the use of d - mph in adhd allows the administration of lower doses than those currently prescribed with d , l - mph . molecules that are non - superimposable mirror images of one another are termed enantiomers and when equal amounts ( 1:1 ) of enantiomeric molecules are present together , the product is termed racemic . most current commercial formulations of mph consist of the racemic mixture of the threo pair of mph isomers ( d , l - threo mph ) . although mph has two chiral centers , and therefore four isomers , a d , l - erythro - mph pair and a d , l - threo - mph pair , only the racemic mixture of the threo pair of enantiomers ( d , l - threo - mph ) is used therapeutically . this is due to the recognition that it has fewer side - effects than the erythro enantiomers . it should be noted that the phenethylamine moiety of d - mph is shared by dopamine and norepinephrine . it is the phenethylamine structure that provides the transporter receptor affinity and it competes with dopamine for binding ( kimko et al 1999 ) . the predominant metabolic pathway of mph is de - esterification to form pharmacologically inactive d- or l - ritalinice acid by the carboxyesterase - i isoform , ces1a1 ( sun et al 2004 ) . it was shown that d , l - threo - methylphenidate was stereoselectively metabolized in humans ( lim et al 1986 ; srinivas et al 1987 ) , with l - threo - mph being eliminated faster than d - threo - mph ( srinivas et al 1992 ; sun et al 2004 ) . in a double - blind , four - way , randomized , crossover study , l - mph showed no difference vs placebo in improving the sustained attention in humans . moreover , a 5-mg dose of d - threo - mph has the same attention improvement effect as a 10-mg dose of d , l - threo - mph racemic mixture . hence , the clinical effect of mph is attributed to the d - enantiomer ( srinivas et al 1992 ) . the brand name for d - mph is focalin . in terms of its chemical composition , d - mph hydrochloride is methyl -phenyl-2-piperidineacetate hydrochloride , ( r , r)-(+)- . although its mechanism is poorly understood , pharmacodynamic studies have suggested that the therapeutic effect of mph in the treatment of adhd appears to lie primarily in increasing the synaptic concentration of dopamine by blocking dopamine transporters ( dat ) ( gatley et al 1996 ; ding et al 1997 ; davids et al 2002 ) , as well as in blocking norepinephrine transporters . this is in agreement with recent reports that there is significantly increased expression of dat in adhd patients ( volkow et al 2002 ) and the effects of mph administration is associated with a decrease in dat receptor concentration in the striatum ( krause et al 2000 ) . however , in methamphetamine abusers , the number of dat also are reduced ( volkow et al 2001a , 2001b ) . recovery of dat receptors is evident with protracted abstinence ( volkow et al 2001a ) . the binding of d - mph to dat in the striatum is reduced by cocaine in a dose - dependent manner ( fowler et al 1998 ) . studies in humans , baboons , and rats seem to indicate that the pharmacological specificity of mph resides predominantly in its d - isomer ( srinivas et al 1992 ; ding et al 1997 ; anonymous 2002 ) . thus , in vivo binding measures of radiolabeled d - mph to dopamine transporter in the brain with positron emission tomography ( pet ) or microdialysis have not only become a valuable technique to analyze pharmacodynamics of mph and its enantiomers ( ding et al 1995 , 1997 , 2004 ; gatley et al 1995 ; logan et al 1996 , 2001 ; volkow et al 2002 ; kilbourn 2004 ) , but also served as an effective tool to assess expression or density of dopamine transporters in tissues of humans and animals ( volkow et al 1995 , 1996b , 2001a , 2001b ; fowler et al 1998 ; gatley et al 1999 ) . pet studies provide a quantitative measure of distribution volume ratios , which represent specific radioligand binding ( volkow et al 1995 ; wang et al 1995 ) . measures of distribution volume ratios are based upon the following assumptions : ( i ) even if the plasma concentration of the radiolabeled tracer is unknown ( for example , without blood samples from patients ) ,  non - invasive  quantification is still possible using a reference region with graphical analysis ( logan et al 1996 ) ; ( ii ) for neuroreceptor  transporter modeling , no specific binding occurs in the reference region ( volkow et al 2002 ) ; ( iii ) the distribution volume of the reference region is the same as the distribution volume of the first compartment ( free and non - specifically bound tracer ) in the target region . since the basal ganglia of striatum expresses more dopamine transporters ( dat ) , it is considered as the target region for d - mph , while the cerebellum does not express dat , so it usually is considered the reference region ( volkow et al 2002 ; kilbourn 2004 ) . thus , the tissue distribution volume ratio of [ c]d - mph in the basal ganglia containing the specific binding to that in the cerebellum which demonstrates non - specific binding should be considered to be a reflection of dopamine transporter availability . recent results from pet and other imaging studies for the two enantiomers of racemic mph demonstrated that [ c]d - mph bound to the dopamine transporter in the basal ganglia is highly specific and reproducible ( ding et al 1997 ) . however , there is no evidence of regional specific binding for [ c]l - threo - mph in the brain . these results suggest that the binding of mph to dat in the striatum is enantiospecific . these data are also in agreement with those from basic and clinical studies showing that d - mph at therapeutic doses exerts much stronger effects than racemic mph or l - threo - mph on extracellular dopamine in rats and on improvement in sustained attention in children ( srinivas et al 1992 ; patrick et al 1987 ) . moreover , d- and l - mph also undergo enantioselective metabolism ( srinivas et al 1987 ; hubbard et al 1989 ; anonymous 2002 ; sun et al 2004 ) , as evidenced by the following findings . first , as mentioned before , because of rapid pre - systemic metabolism , orally administered l - threo - mph is poorly absorbed in humans thus , the absolute bioavailability of d - mph is significantly greater than that of l - threo - mph ( srinivas et al 1993 ; sun et al 2004 ) . second , because there is a correlation between plasma concentrations and dat occupancy , the plasma concentration could serve as an indicator for dat binding ( srinivas et al 1992 ) . however , dat binding by d - mph could also be obtained from calculated tissue distribution volume without patients blood samples ( logan et al 1996 ) . third , while the rate of brain uptake for both enantiomers was not significantly different , the rate of clearance after 1.5 hours from the brain or plasma was much slower for d - mph than that of l - threo - mph ( volkow et al 2002 ) . fourth , greater than 50% dat binding in the basal ganglia by d - mph may be required for therapeutic efficacy for adhd . however , despite greater than 50% dat occupancy by d - mph when administered intravenously or orally , the reinforcing effects were not perceived by patients receiving oral d - mph ( volkow et al 2002 ) . this phenomenon is possibly due to slower blockade of dat by oral d - mph and may explain why intravenous injection of mph may lead to addiction . finally , there is no inter - conversion between the enantiomers after oral administration of pure d- and l - mph separately ( volkow et al 2002 ) . the recent in vitro binding study of markowitz et al ( 2005 ) found that d - mph exhibited prominent effects at the norepinephrine transporter site , even exceeding the activity at the dat . the result demonstrated that affinity for catecholaminergic sites largely resides in the d - isomer . animal toxicology studies showed that the toxicity of d - mph and d , l - mph were comparable at equimolar doses ( teo et al 2002 ) . a recent comparative study assessing the acute behavioral toxicity of d - mph , l - mph , and d , l - mph in rats has revealed that females were more sensitive than males to some toxic behavioral effects of the l - isomer and d , l - mph ( racemic ) , suggesting a possible sex difference in sensitivity ( teo et al 2003d ) . in related studies , increased incidence of dilated pupils and vocalization was found with d , l - mph compared with the pure d - mph given at half the dose ( teo et al 2002 ) . in the same study , no other significant toxic effects were found in perinatal or postnatal rats at a dose 25 times the maximum daily human therapeutic dose ( teo et al 2002 ) . another toxicology study in beagle dogs demonstrated that only minimal reversible toxicity such as reduced appetite and weight loss were found in male and female dogs receiving 10 mg / kg of d - mph and 20 mg / kg of d , l - mph for 90 days ( teo et al 2003c ) . neither d - mph nor d , l - mph were found to be carcinogenic or clastogenic in either in vitro or in vivo studies , although very high oral doses of the l - mph produce behavioral , and even lethal , effects in mice ( teo et al 2003a ) . the authors believed that d - mph and d , l - mph do not present carcinogenic risk to humans . animal studies in rats and rabbits also suggested that d - mph and d , l - mph were not teratogenic ( teo et al 2003b ) . the same study suggested that some negative behaviors in pregnant animals may be attributed to l - mph because inclusion of the l - isomer , when comparing d , l - mph and d - mph at half the dose , resulted in repetitive pawing , dilated pupil , and aggressive behavior . a recent study , using pet and micropet to trace orally administered , as well as radiola - beled d- and l - mph , in the brain of baboons and rats , suggested that l - mph may not be pharmacologically active . additionally , l - mph might contribute to the behavioral and side - effect profiles of d , l - mph during the treatment of adhd ( ding et al 2004 ) . the immediate - release ( ir ) d - mph product is deemed to provide effective management of adhd at half the dose of racemic mph products and was shown to be effective and well tolerated in clinical trials ( swanson et al 2002 ; arnold et al 2004 ; quinn et al 2004 ; wigal et al 2004 ) . an initial pharmacokinetic study showed that after an oral dose of d - mph , plasma d - mph concentration increased rapidly , reaching maximum levels at 11.5 hours post - dose in fasting states . plasma pharmacokinetics of d - mph were similar to d , l - mph given the equimolar amounts of d - mph . the mean plasma elimination half - life for d - mph is approximately 2.2 hours ( anonymous 2002 ) . however , recent studies , including one post hoc analysis ( weiss et al 2004 ) , one open - labeled ( silva et al 2004 ) , and three placebo - controlled clinical studies ( arnold et al 2004 ; quinn et al 2004 ; wigal et al 2004 ) in children with adhd , suggested that ir d - mph may produce a longer duration of therapeutic action (  6 hours ) which can not be explained solely on the basis of the agent s pharmacokinetics . some authors have postulated that the need for a midday dose for ir mph products may erode social functioning and sometimes the self - esteem of children with adhd . thus , an extended - release form of d - mph ( d - mph - xr ) was designed , known as focalin xr , and approved by fda for clinical use in may 2005 . this product is a modified release capsule formulation of d - mph specifically engineered to deliver a bimodal ( biphasic ) release of d - mph that mimics a twice daily d - mph dosing ( ie , two distinct peaks approximately 4 hours apart ) . the d - mph - xr product uses the same proprietary sodas ( spheroidal oral drug absorption system ) technology as one of the racemic mph products ( ritalin - la ) currently on the market . for each of these products , capsules are filled with a mixture of 50% immediate - release beads and 50% enteric - coated , delayed - release beads , thus providing immediate release and a second delayed - release component . after administration of d - mph - xr , the first peak concentration ( cmax1 ) of d - mph occurs on average after 1.5 hours ( typical range 14 hours ) . the mean time to the inter - peak minimum is slightly shorter , and time to the second peak ( tmax2 ) is slightly longer for d - mph- xr given once daily ( about 6.5 hours , range 4.57 hours ) compared with the ir d - mph given in two doses 4 hours apart . the d - mph - xr product given once daily exhibits a lower second peak concentration ( cmax2 ) , higher inter - peak minimum concentrations , and fewer peak and trough fluctuations than the ir form of the agent , given in two doses 4 hours apart . the area under the plasma concentration - time curve ( auc ) after administration of d - mph - xr given once daily is equivalent to the same total dose of ir d - mph tablets given in two doses 4 hours apart ( novartis pharmaceuticals corporation 2005 ) . the clinical efficacy as well as safety of d - mph - xr in treating children with adhd was demonstrated in a randomized , double - blind , placebo - controlled clinical trial ( greenhill et al 2005 ) . in this study , flexible dosing schedules of between 5 and 30 mg of d - mph - xr were administered once daily over a 7-week period . greenhill et al ( 2005 ) reported that d - mph - xr was associated with significantly improved attention and behavior in children with adhd . silva et al ( 2005 , 2006 ) , in two separate studies , demonstrated that the therapeutic effect significantly differentiated from placebo during each time point of the 12-hour laboratory classroom studies . both of these studies employed a double - blind , placebo - controlled , crossover design . the sample sizes were slightly more than 50 patients in each trial ; all subjects satisfied dsm - iv criteria for adhd . in the two studies , swanson , kotkin , agler , m - flynn , and pelham ( skamp ) scales and math tests were administered . significant differences were observed across all measures and in each of the subscales at each of the time points studied . another noteworthy observation is related to the elapsed time at which efficacy was first detected . in the silva et al ( 2005 ) study significant differences were noted at the first time point measured , which was half an hour after medication administration . based on the information we have reviewed it seems that d - mph is a useful agent in the treatment of adhd . furthermore , it should be noted it is the only mph product approved for the treatment of this disorder in adults . the literature reviewed identified that there are meaningful differences in the clinical efficacy and pharmacokinetic profile between the d- and l - isomers of mph . when comparing the single isomer with the racemic compound , a consistently noted difference across studies is that d - mph has a longer duration of action than d , l - mph . further study is required to more fully understand the side - effect differences between the d - isomer and its racemic counterpart .
attention - deficit / hyperactivity disorder ( adhd ) affects a large number of children . for decades , 
 the stimulants have been the mainstay of pharmacological treatment for adhd . 
 dexmethylphenidate ( d - mph ) , the d - isomer of the traditional racemic mixtures of d , l - threo-(r , r)-mph , was recently introduced as another potential option in the stimulant class of medications . 
 this paper reviews and summarizes the available research literature on d - mph regarding pharmacodynamic , pharmacokinetic , chemical structure , receptor binding , toxicology , and clinical perspectives . 
 d - mph potentially may offer some advantages in the realms of absorption and duration of action compared with its racemic counterpart . the differences in pharmacokinetics and clinical implications of the immediate - release and extended - release forms of d - mph are also compared and contrasted .