Adderall XR * 1/4 dextroamphetamine saccharate * 1/4 dextroamphetamine sulfate * 1/4 (racemic dextro/levo-amphetamine) aspartate monohydrate * 1/4 (racemic dextro/levo-amphetamine) sulfate http://en.wikipedia.org/wiki/Racemic "In chemistry, a racemic mixture, or racemate, is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid," which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid." "Adderall XR utilizes the Microtrol extended-release delivery system, incorporating two types of beads. The first dissolves immediately, releasing half of the medication, while the second type dissolves much more slowly releasing the remaining medication four hours later. Maximum plasma concentration is achieved in seven hours, compared to instant-release Adderall, which reaches maximum plasma concentration within three hours. As a result of its high bioavailability, Adderall XR's effectiveness is not altered by food absorption in the gastrointestinal tract. However, mean plasma concentration is prolonged by 2.5 hours (using a 900 calorie standard high-fat meal as the control). Medications that alter urinary pH will cause variations in amount and method of excretion and usage should be monitored when taken concurrently with Adderall." Microtrol extended-release delivery system "Microtrol is an extended-release drug delivery system.[1] It is used in certain medications like Adderall and incorporates two types of beads. The first dissolves immediately, releasing half of the medication, while the second type dissolves much more slowly releasing the remaining medication four hours later. Maximum plasma concentration is achieved in seven hours, compared to instant-release which reaches maximum concentration in three hours.[citation needed] Microtrol is manufactured by Supernus Pharmaceuticals, Inc.[2]" Supernus Pharmaceuticals, Inc. http://www.supernuspharma.com/ "The new product is formulated using patented Microtrol technology, based on the use of coated or uncoated 'multiparticulates' or beadlets that can be filled into capsules or compressed into tablets. These beads then release the therapeutic drug into the body at certain points, depending on pH. The same technology is used in the existing Adderall XR ADHD drug. " "Supernus was founded by the former Shire Laboratories president and chief executive Jack Khattar and aims to develop products for its own portfolio and in partnership with other pharmaceutical companies. Mr Khattar said: "Our decision to acquire SLI's [Shire Laboratories] product formulation and development business was based on SLI's success and proven track record in developing advanced products? utilising its unique technology platforms and capabilities. "We will be applying those same technology platforms and capabilities to build our own pipeline of specialty products and to continue to support our partners." The main technologies that Supernus has under its belt are ProScreen and OptiScreen for lead selection and formulation optimisation, and the oral controlled release technologies Microtrol, Solutrol and EnSoTrol. " Jack A. Khattar, CEO of Supernus, former Shire Laboratories president and chief executive David Schappelle, human resources at Supernus @ Rockville Jim Barrett, Supernus board member Michael Bigham, Supernus board member ".REDI, a public-private partnership spun off from the city of Rockville, was intent on keeping the jobs it saw as key to the area's growing biotechnology industry." "It all came together when Khattar landed venture capital from New York-based OrbiMed and Baltimore-based New Enterprise Associates (NEA)" http://nea.com/ http://abingworth.com/ Supernus Contacts Jack Khattar President & CEO Tel: 301 838-2500 1550 E Gude Drive Rockville, MD 20850 www.supernuspharma.com Woody Bryan VP Business Development Tel: 301 838-2681 Email Contact # 301-838-2500 1550 E Gude Drive, Rockville, MD 20850 http://maps.google.com/maps?f=q&source=s_q&hl=en&geocode=&q=1550+E+Gude+Drive,+Rockville,+MD+20850&sll=37.0625,-95.677068&sspn=32.939885,65.302734&ie=UTF8&ll=39.095351,-77.13244&spn=0.001969,0.003986&t=h&z=18 at inception, Supernus had 51 employees (down from 78 of the original). East Gude Road office levoamphetamine urinary pH stomach pH Alkalinity increases bioavailability and acidity causes the drug to be excreted sooner. Adderall XR utilizes the Microtrol extended-release delivery system, incorporating two types of beads. The first dissolves immediately, releasing half of the medication, while the second type dissolves much more slowly releasing the remaining medication four hours later. Maximum plasma concentration is achieved in seven hours, compared to instant-release Adderall, which reaches maximum plasma concentration within three hours. The authors found that sustained-release dexamphetamine (the main isomeric-amphetamine component of Adderall) had a longer duration of action, though D-amphetamine was less effective in the first few hours. http://www.healthsystem.virginia.edu/internet/pediatrics/pharma-news/v8n3.pdf Differential Effects of Amphetamine Isomers on Dopamine in the Rat Striatum and Nucleus Accumbens Core Michael Yasick http://shire.com/ http://adderallxr.com/ http://www.shirestudyresults.org/ An Interim Analysis of the Quality of Life, Effectiveness, Safety, and Tolerability (QU.E.S.T.) Evaluation of Mixed Amphetamine Salts Extended Release in Adults With ADHD. D.W. Goodman, L. Ginsberg, R.H. Weisler, et al. CNS Spectrums,2005;10(12,Suppl 20):26-34. http://www.shirestudyresults.org/documents/ http://www.google.com/patents?id=uLoUAAAAEBAJ&dq=microtrol+%22Shire+Laboratories%22+OR+%22Shire+Labs%22 Inventors: Richard A. Couch, Beth A. Burnside, Rong-Kun Chang Obetrol http://en.wikipedia.org/wiki/Obetrol "Obetrol contained (Per 10mg tablet)[1]: * 2.5mg methamphetamine Saccharate * 2.5mg methamphetamine hydrochloride * 2.5mg (racemic dextro/levo-amphetamine) sulfate * 2.5mg dextroamphetamine sulfate " Rasmussen, Nicolas (2008-03-01). "On Speed: The Many Lives of Amphetamine". New York University Press. pp. p.148 Fig. 33. http://hist-phil.arts.unsw.edu.au/staff/staff.php?first=Nicolas&last=Rasmussen. Retrieved on 2009-01-27 patent # 2748052 http://www.google.com/patents?id=5OtKAAAAEBAJ&printsec=abstract&zoom=4&dq=patent:2748052&as_drrb_ap=q&as_minm_ap=0&as_miny_ap=&as_maxm_ap=0&as_maxy_ap=&as_drrb_is=q&as_minm_is=0&as_miny_is=&as_maxm_is=0&as_maxy_is=&num=100&source=gbs_summary_r&cad=0_0 Inventor: Armin Rosner http://www.shire.com/shire/Products/products.jsp?country=us dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, USP, amphetamine sulfate USP gelatin capsules, hydroxypropyl methylcellulose, methacrylic acid copolymer, opadry beige, sugar spheres, talc, and triethyl citrate. Gelatin capsules contain edible inks, kosher gelatin, and titanium dioxide. The 5 mg, 10 mg, and 15 mg capsules also contain FD&C Blue #2. The 20 mg, 25 mg, and 30 mg capsules also contain red iron oxide and yellow iron oxide. Manufactured for Shire US Inc., Wayne, PA, 19087. Enantiomeric amphetamine compositions (R.A. Couch) http://www.google.com/patents?id=6WafAAAAEBAJ&dq=ENANTIOMERIC+AMPHETAMINE+COMPOSITIONS+FOR+THE+TREATMENT+OF+ADHD&num=100 Richard A. Couch, Alex Michaels, Paul Hodgkins AM Michaels http://cogres.com/ShowPage.asp?page=GaryKay.asp Simulated Driving Changes in Young Adults With ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine Paul S Hodgkins Some Metabotropic Glutamate Receptor Ligands Reduce Kynurenate Synthesis in Rats by Intracellular Inhibition of Kynurenine Aminotransferase II. kynurenic acid (tryptophan metabolism?) http://www.bcbsms.com/index.php?id=155&articleid=621482 "Elevated brain levels of a compound called kynurenic acid are associated with problem-solving deficits in people with schizophrenia, according to U.S. researchers." (John P. Bruno) "Kynurenic acid is present in all human brains and has useful functions. However, an excessive amount of the compound interferes with other chemical processes involved in the ability to pay attention and think strategically under changing circumstances, said Bruno and colleagues, who conducted their research in rats." ""So, we've already got problems with these neurotransmitters, and then to make matters worse, we've got all this extra kynurenic acid antagonizing the alpha-7 receptors, which just throws gasoline on the fire," Bruno said. "If we can design drugs that are able to inhibit the enzymes that are responsible for overproducing kynurenic acid, we may improve cognitive performance in these patients."" Stimulation of cortical acetylcholine release following blockade of ionotropic glutamate receptors in nucleus accumbens "In vivo microdialysis techniques were used to determine the ability of glutamate receptors within the nucleus accumbens to trans-synaptically modulate the basal forebrain cortical cholinergic system. Rats were implanted with a dialysis probe in the medial prefrontal cortex to measure changes in cortical acetylcholine efflux and in the ipsilateral nucleus accumbens to locally manipulate glutamate receptor activity. Intra-accumbens perfusion of the broad spectrum ionotropic glutamate receptor antagonist kynurentate (1.0, 5.0 mm) led to a dose-dependent increase (maximum of 200%) in cortical acetylcholine efflux. This stimulated efflux was reproduced with the intra-accumbens perfusion of the AMPA/kainate antagonist DNQX (0.1, 0.25, 2.5 mm; maximum increase of 200%) or the NMDA antagonist D-CPP (10.0, 100.0, 200 µM; maximum increase of 400%). These results reveal a significant glutamatergic tone within the accumbens of awake rats and support the hypothesis that accumbens efferents to basal forebrain modulate the excitability of the basal forebrain cortical cholinergic system." Hyperdopaminergic Mutant Mice Have Higher "Wanting" But Not "Liking" for Sweet Rewards "These results indicate that chronically elevated extracellular dopamine facilitates "wanting" and learning of an incentive motivation task for a sweet reward, but elevated dopamine does not increase "liking" reactions to the hedonic impact of sweet tastes." Mice with Chronically Elevated Dopamine Exhibit Enhanced Motivation, but not Learning, for a Food Reward "The increase in dopamine is associated with elevated levels of dynorphin and Fos B expression in the dorsal caudate-putamen and the core but not the shell subregion of the nucleus accumbens" http://researchnews.osu.edu/archive/kynacid.htm "Excess levels of kynurenic acid inhibit the work of the alpha-7 receptors, meaning they suppress the release of these neurotransmitters even more." "“So we’ve already got problems with these neurotransmitters, and then to make matters worse, we’ve got all this extra kynurenic acid antagonizing the alpha-7 receptors, which just throws gasoline onto the fire,” Bruno said. “If we can design drugs that are able to inhibit the enzymes that are responsible for overproducing kynurenic acid, we may improve cognitive performance in these patients.”" Coauthors on the studies are Ohio State researchers and graduate students Amy Zmarowski, Katie Alexander, Åsa Konradsson, Clelland Gash and Julie Brooks, as well as Robert Schwarcz and Hui-Qiu Wu of the University of Maryland School of Medicine. Amy Zmarowski Katie Alexander Åsa Konradsson Clelland Gash Julie Brooks Robert Schwarcz Hui-Qiu Wu Contact: John Bruno, (614) 292-1770; Bruno.1@osu.edu http://faculty.psy.ohio-state.edu/bruno/ "We are also studying nicotinic receptor agonists as a means of potentiating the release of ACh in cortex." "In the rat striatum, S-ESBA produced a 35% reduction in extracellular KYNA, which was accompanied by a 270% increase in extracellular DA." "KYNA synthesis was dose-dependently reduced by L-leucine or L-phenylalanine, two amino acids that compete with L-kynurenine for cellular uptake, and by aminooxyacetate, a non-specific aminotransferase inhibitor." alpha 7 nicotinic acetylcholine receptor CHRNA7 http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1139&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum regulation of the expression of CHRNA7 ? alpha-bungarotoxin inhibits a7NAChRs "Excess levels of kynurenic acid inhibit the work of the alpha-7 receptors, meaning they suppress the release of these neurotransmitters even more." "In the mammalian brain, KYNA can be produced by several kynurenine aminotransferases (KATs), of which KAT II appears to be the most functionally relevant (Guidetti et al., 2007a). This enzyme is almost exclusively localized in astrocytes (Guidetti et al., 2007b), which promptly release newly formed KYNA into the extracellular millieu (Turski et al., 1989) [avoid: alpha-bungarotoxin] [avoid: tryptophan] L-leucine L-phenylalanine S-ESBA (S-ethylsulfonylbenzoylalanine) indicates indo-3-pyruvate and cysteine as efficient inhibitors for hKAT-I, L-α-aminoadipate aminotransferase; EC 2.6.1.39; 2-Oxoacids Regulate Kynurenic Acid Production in the Rat Brain: Studies In Vitro and In Vivo. "This study was designed to examine the role of 2-oxoacids in the enzymatic transamination of L-kynurenine to the excitatory amino acid receptor antagonist, kynurenate, in the rat brain. In brain tissue slices incubated in Krebs-Ringer buffer with a physiological concentration of L-kynurenine, pyruvate, and several other straight- and branched-chain 2-oxoacids, substantially restored basal kynurenate production in a dose-dependent manner without increasing the intracellular concentration of L-kynurenine. All 2-oxoacids tested also reversed or attenuated the hypoglycemia-induced decrease in kynurenate synthesis, but only pyruvate and oxaloacetate also substantially restored intracellular L-kynurenine accumulation. Thus, 2-oxoacids increase kynurenate formation in the brain primarily by functioning as co-substrates of the transamination reaction. This was supported further by the fact that the nonspecific kynurenine aminotransferase inhibitors (aminooxy)acetic acid and dichlorovinylcysteine prevented the effect of pyruvate on kynurenate production in a dose-dependent manner. Moreover, all 2-oxoacids tested attenuated or prevented the effects of veratridine, quisqualate, or L-[alpha]-aminoadipate, which reduce the transamination of L-kynurenine to kynurenate. Finally, dose-dependent increases in extracellular kynurenate levels in response to an intracerebral perfusion with pyruvate or [alpha]-ketoisocaproate were demonstrated by in vivo microdialysis. Taken together, these data show that 2-oxoacids can directly augment the de novo production of kynurenate in several areas of the rat brain. 2-Oxoacids may therefore provide a novel pharmacological approach for the manipulation of excitatory amino acid receptor function and dysfunction."