Dexmethylphenidate

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Dexmethylphenidate
D-methylphenidate-plane.png
Dextromethylphenidate-based-on-hydrochloride-xtal-1995-3D-balls.png
Systematic (IUPAC) name
(R,R)-(+)-Methyl 2-phenyl-2-(2-piperidyl)acetate
Clinical data
Trade names Focalin, Focalin XR, Attenade
AHFS/Drugs.com monograph
MedlinePlus a603014
Pregnancy cat. C
Legal status Controlled (S8) (AU) Schedule III (CA) Class B (UK) Schedule II (US)
Routes oral
Pharmacokinetic data
Bioavailability 11 – 52%
Protein binding 30%
Metabolism hepatic
Half-life 4 hours
Excretion renal
Identifiers
CAS number 40431-64-9 N
ATC code N06BA11
PubChem CID 154101
DrugBank DB06701
ChemSpider 135807 YesY
UNII M32RH9MFGP YesY
KEGG D07806 YesY
ChEBI CHEBI:51860 YesY
ChEMBL CHEMBL827 YesY
Chemical data
Formula C14H19NO2 
Mol. mass 233.31 g/mol
 N (what is this?)  (verify)

Dexmethylphenidate, otherwise known as d-threo-methylphenidate (D-TMP), is the dextrorotatory enantiomer of methylphenidate. It is a norepinephrine-dopamine reuptake inhibitor (NDRI) and thus a psychostimulant, which affects the CNS. Dexmethylphenidate is sold as Focalin by Novartis, as Attenade by Celgene and as a generic drug by Teva, Mylan, and IntelliPharmaCeutics.[1][2]

It is primarily used for the treatment of ADHD, for which it is generally effective and well-tolerated.[3] Height and weight may be reduced by stimulant therapy in children, although this is not a major concern for most young people.[4] Rarely, treatment emergent psychosis can occur during long-term therapy with dexmethylphenidate; regular psychiatric monitoring of people who are taking methylphenidate is recommended.[5]

Medical uses[edit]

Dexmethylphenidate is used as a treatment for ADHD, usually along with psychological, educational, behavioral or other forms of treatment. It is proposed that stimulants help ameliorate the symptoms of ADHD by making it easier for the user to concentrate, avoid distraction, and control behavior. Dexmethylphenidate may also improve listening skills and organization of tasks, and may help prevent tic disorders. Because it is a psychostimulant, dexmethylphenidate may also help with narcolepsy and in certain cases of major depression.[citation needed]

Efficacy[edit]

Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated.[3] Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo.[3] It also showed greater efficacy than osmotic release oral system (OROS) methylphenidate over the first half of the laboratory classroom day but assessments late in the day favoured OROS methylphenidate.[3]

Adverse effects[edit]

Although the FDA has not concluded that psychostimulants increase the risk of cardiac problems in people without a heart condition, all psychostimulant labels include a warning stating that they may increase the risk of cardiovascular problems or sudden death.

Suicidal thinking has been reported in young people who are taking antidepressants at the same time they are taking an ADHD stimulant and many antidepressants carry a "black box warning" label concerning a possible increase in suicidal ideation in patients under 25 years of age.[6]

Insomnia, dizziness, nausea, stomach pain, euphoria, headache, anxiety, anorexia, and weight loss are possible side effects of dexmethylphenidate.

On occasion, a treatment emergent psychosis can occur during long-term therapy with dexmethylphenidate. Stimulants such as dexmethylphenidate should be avoided in people who have a vulnerability to schizophrenia or drug addiction; however, psychotic symptoms may emerge during therapy with dexmethylphenidate in individuals without these risk factors; regular psychiatric monitoring of people who are taking dexmethylphenidate for adverse effects such as psychotic symptomatology (with regard to the need for dose adjustment or discontinuation of medication) has been recommended.[7]

Height and weight may be reduced by stimulant therapy; this side effect may be dose dependent and children and adolescents catch up in growth overtime or after stopping stimulant therapy. For most young people effects of growth is not a major concern; nevertheless regular monitoring on height and weight by healthcare providers has been recommended.[4]

Rare but more serious side effects include uncontrolled muscle movements (e.g., stiffness, twitching, shaking), hyperthermia, tics, edema of the feet/hands, blurred vision, mental/mood/behavior changes (e.g., agitation, aggression, mood swings, depression, hallucinations, abnormal thoughts/behavior), extreme tiredness, and severe sweating, easy bleeding/bruising, shortness of breath, fainting, chest/jaw/left arm pain, sudden vision changes, signs of infection (fever, persistent sore throat), tachycardia, weakness, seizures, confusion, slurred speech, and severe headaches and in some very rare cases death.[citation needed]

Also, there is a potential for a severe allergic reaction, but it is extremely rare. Trouble breathing, itching, a rash, swelling, or dizziness are all signs/symptoms of this allergic reaction.[citation needed]

Interactions[edit]

Dexmethylphenidate should not be used by those who have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) in the past 14 days. The use of dexmethylphenidate by a person chronically taking an MAOI is a medical emergency and should be treated immediately.[8]

Mode of activity[edit]

Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET),[9] which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system.[10] Moreover, it is thought to "increase the release of these monoamines into the extraneuronal space."[11]

Although four stereoisomers of methylphenidate (MPH) are possible, only the threo diastereoisomers are used in modern practice. There is a high eudysmic ratio between the SS and RR enantiomers of MPH. "Dexmethylphenidate" is a preparation of the RR enantiomer of MPH.[12][13] In theory, d-TMP can be anticipated to be twice the strength of the racemic product.[14][9]

Compd[15] DAT (Ki) DA (IC50) NET (Ki) NE (IC50)
D-TMP 161 23 206 39
L-TMP 2250 1600 >10K 980
DL-TMP 121 20 51 788

Pharmacology[edit]

Dexmethylphenidate has a 4-6 hour duration of effect (a long-acting formulation, Focalin XR, which spans 12 hours is also available and has been shown to be as effective as DL-TMP XR (Concerta, Ritalin LA), with flexible dosing and good tolerability.[16][17]) It has also been demonstrated to reduce ADHD symptoms in both children[18] and adults.[19] d-MPH has a similar side-effect profile to MPH[20] and can be administered without regard to food intake.[21]

Dexmethylphenidate has a chemical structure similar to a family of key brain neurotransmitters called monoamines, which include norepinephrine and dopamine.[22]

Typical daily doses of dexmethylphenidate are around 10–20 mg for children and 20–40 mg for adults. As with all psychostimulant compounds, some individuals may respond to a small dose while others will require a larger than average dose around 40–60 mg. Therefore, dosing is usually initiated at a typical range and then titrated to suit the patient.[23]

Usage[edit]

The Focalin XR capsules are sometimes prescribed over other extended release stimulants because the capsules can be opened and their contents mixed with applesauce or pudding to help children who cannot, or will not, swallow large capsules. This is possible due to the SODAS (Spheroidal Oral Drug Absorption System) delivery system, also used in Ritalin LA. Focalin XR comes in five, ten, fifteen, twenty, thirty, and forty milligram capsules. To determine appropriate dosage doctors first prescribe one to four 5 mg capsules. An appropriate treatment plan is then based on the patient's reaction to the initial dose.[24] From there, doctors usually increase the dose by 5 mg to 10 mg until finding the right dosage.

Legal status[edit]

Dexmethylphenidate, due to its abuse potential, is classed as a Schedule II controlled drug in the United States.[25]

References[edit]

  1. ^ "IPCI: FDA Approves First Focalin XR ANDA; Positive Incremental Step Toward Approval and October Launch for IPCI". 
  2. ^ Teva press release. January 30, 2007 Teva Receives Approval for Generic Focalin™ Tablets
  3. ^ a b c d Moen M, Keam S.Dexmethylphenidate Extended Release: A Review of its Use in the Treatment of Attention-Deficit Hyperactivity Disorder. CNSDrugs 2009; 23(12):1057-1083. doi:10.2165/11201140-000000000-00000.
  4. ^ a b Faraone, SV.; Biederman, J.; Morley, CP.; Spencer, TJ. (Sep 2008). "Effect of stimulants on height and weight: a review of the literature.". J Am Acad Child Adolesc Psychiatry 47 (9): 994–1009. doi:10.1097/CHI.0b013e31817e0ea7. PMID 18580502. 
  5. ^ Kraemer M, Uekermann J, Wiltfang J, Kis B (July 2010). "Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature". Clin Neuropharmacol 33 (4): 204–6. doi:10.1097/WNF.0b013e3181e29174. PMID 20571380. 
  6. ^ Rader, R.; Mccauley, L.; Callen, E. C. (2009). "Current strategies in the diagnosis and treatment of childhood attention-deficit/hyperactivity disorder". American family physician 79 (8): 657–665. PMID 19405409.  edit
  7. ^ Kraemer, M.; Uekermann, J.; Wiltfang, J.; Kis, B. (2010). "Methylphenidate-Induced Psychosis in Adult Attention-Deficit/Hyperactivity Disorder". Clinical Neuropharmacology 33 (4): 204–206. doi:10.1097/WNF.0b013e3181e29174. PMID 20571380.  edit
  8. ^ Scharman, E. J.; Erdman, A. R.; Cobaugh, D. J.; Olson, K. R.; Woolf, A. D.; Caravati, E. M.; Chyka, P. A.; Booze, L. L.; Manoguerra, A. S.; Nelson, L. S.; Christianson, G.; Troutman, W. G.; American Association of Poison Control Centers (2007). "Methylphenidate poisoning: an evidence-based consensus guideline for out-of-hospital management*". Clinical Toxicology 45 (7): 737–752. doi:10.1080/15563650701665175. PMID 18058301.  edit
  9. ^ a b Markowitz, J.; Patrick, K. (2008). "Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter?". Journal of Clinical Psychopharmacology 28 (3 Suppl 2): S54–S61. doi:10.1097/JCP.0b013e3181733560. PMID 18480678.  edit
  10. ^ Schweri, M. M.; Skolnick, P.; Rafferty, M. F.; Rice, K. C.; Janowsky, A. J.; Paul, S. M. (1985). "3HThreo-(+/-)-methylphenidate binding to 3,4-dihydroxyphenylethylamine uptake sites in corpus striatum: correlation with the stimulant properties of ritalinic acid esters". Journal of Neurochemistry 45 (4): 1062–1070. doi:10.1111/j.1471-4159.1985.tb05524.x. PMID 4031878.  edit
  11. ^ Novartis: FOCALIN XR Overview PDF: FOCALIN XR - Full Prescribing Information
  12. ^ Ding, Y. S.; Fowler, J. S.; Volkow, N. D.; Dewey, S. L.; Wang, G. J.; Logan, J.; Gatley, S. J.; Pappas, N. (1997). "Chiral drugs: comparison of the pharmacokinetics of 11Cd-threo and L-threo-methylphenidate in the human and baboon brain". Psychopharmacology 131 (1): 71–78. doi:10.1007/s002130050267. PMID 9181638.  edit
  13. ^ Ding, Y.; Gatley, S.; Thanos, P.; Shea, C.; Garza, V.; Xu, Y.; Carter, P.; King, P.; Warner, D.; Taintor, N. B.; Park, D. J.; Pyatt, B.; Fowler, J. S.; Volkow, N. D. (2004). "Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration". Synapse 53 (3): 168–175. doi:10.1002/syn.20046. PMID 15236349.  edit
  14. ^ Davids, E.; Zhang, K.; Tarazi, F.; Baldessarini, R. (2002). "Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning". Psychopharmacology 160 (1): 92–98. doi:10.1007/s00213-001-0962-5. PMID 11862378.  edit
  15. ^ Williard, R.; Middaugh, L.; Zhu, H.; Patrick, K. (2007). "Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity". Behavioural Pharmacology 18 (1): 39–51. doi:10.1097/FBP.0b013e3280143226. PMID 17218796.  edit
  16. ^ McGough, J.; Pataki, C. S.; Suddath, R. (2005). "Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder". Expert Review of Neurotherapeutics 5 (4): 437–441. doi:10.1586/14737175.5.4.437. PMID 16026226.  edit
  17. ^ Silva, R.; Tilker, H. A.; Cecil, J. T.; Kowalik, S.; Khetani, V.; Faleck, H.; Patin, J. (2004). "Open-label study of dexmethylphenidate hydrochloride in children and adolescents with attention deficit hyperactivity disorder". Journal of child and adolescent psychopharmacology 14 (4): 555–563. doi:10.1089/cap.2004.14.555. PMID 15662147.  edit
  18. ^ Arnold, L.E., et al. (2004). "A double-blind, placebo-controlled withdrawal trial of dexmethylphenidate hydrochloride in children with attention deficit hyperactivity disorder". J Child Adolesc Psychopharmacol. 2004 Winter;14(4):542-54.
  19. ^ Spencer, T.; Adler, L.; Mcgough, J.; Muniz, R.; Jiang, H.; Pestreich, L.; Adult Adhd Research, G. (2007). "Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder". Biological Psychiatry 61 (12): 1380–1387. doi:10.1016/j.biopsych.2006.07.032. PMID 17137560.  edit
  20. ^ Keating, G. M.; Figgitt, D. P. (2002). "Dexmethylphenidate". Drugs 62 (13): 1899–1904; discussion 1904–8. doi:10.2165/00003495-200262130-00009. PMID 12215063.  edit
  21. ^ Teo, S. K.; Scheffler, M. R.; Wu, A.; Stirling, D. I.; Thomas, S. D.; Stypinski, D.; Khetani, V. D. (2004). "A single-dose, two-way crossover, bioequivalence study of dexmethylphenidate HCl with and without food in healthy subjects". Journal of clinical pharmacology 44 (2): 173–178. doi:10.1177/0091270003261899. PMID 14747426.  edit
  22. ^ "[1]".
  23. ^ Quinn, D. (2008). "Does chirality matter? Pharmacodynamics of enantiomers of methylphenidate in patients with attention-deficit/hyperactivity disorder". Journal of Clinical Psychopharmacology 28 (3 Suppl 2): S62–S66. doi:10.1097/JCP.0b013e3181744aa6. PMID 18480679.  edit
  24. ^ "Focalin XR for ADHD".
  25. ^ "Dexmethylphenidate--Novartis/Celgene. Focalin, D-MPH, D-methylphenidate hydrochloride, D-methylphenidate, dexmethylphenidate, dexmethylphenidate hydrochloride". Drugs in R&D 3 (4): 279–282. 2002. PMID 12455205.  edit

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