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DEXMETHYLPHENIDATE

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Dexmethylphenidate structure.svg

DEXMETHYLPHENIDATE

SynonymsDexmethylphenidate HCl, UNII1678OK0E08, CAS Number19262-68-1, WeightAverage: 269.77
Chemical FormulaC14H20ClNO2

methyl (2R)-2-phenyl-2-[(2R)-piperidin-2-yl]acetate hydrochloride

Thumb
CAS Number40431-64-9 as HCl: 19262-68-1
PubChem CID154101as HCl: 154100
IUPHAR/BPS7554
DrugBankDB06701 as HCl: DBSALT001458
ChemSpider135807 as HCl: 135806
UNIIM32RH9MFGPas HCl: 1678OK0E08

Trade Name:Focalin® / Attenade®MOA:Norepinephrine-dopamine reuptake inhibitorIndication:Attention deficit hyperactivity disorder (ADHD)Status:ApprovedCompany:Novartis (Originator) , CelgeneSales:$365 Million (Y2015); 
$492 Million (Y2014);
$594 Million (Y2013);
$554 Million (Y2012);
$550 Million (Y2011);ATC Code:N06BA11

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2005-05-26New dosage formFocalin XRAttention deficit hyperactivity disorder (ADHD)Capsule, Extended release5 mg/10 mg/15 mg/20 mg/25 mg/30 mg/35 mg/40 mgNovartis 
2001-11-13Marketing approvalFocalinAttention deficit hyperactivity disorder (ADHD)Tablet2.5 mg/5 mg/10 mgNovartis

Dexmethylphenidate hydrochloride was approved by the U.S. Food and Drug Administration (FDA) on Nov 13, 2001. It was developed and marketed as Focalin® by Novartis in the US.

Dexmethylphenidate hydrochloride is a norepinephrine-dopamine reuptake inhibitor (NDRI). It is indicated for the treatment of attention deficit hyperactivity disorder (ADHD).

Focalin® is available as tablet for oral use, containing 2.5 mg, 5 mg or 10 mg of Dexmethylphenidate hydrochloride. The recommended dose is 10 mg twice daily, at least 4 hours apart.

wdt-17

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Drug Product Name Serdexmethylphenidate and Dexmethylphenidate (SDX/d-MPH)

Dosage Form capsule Strength 26.1/5.2 mg SDX/d-MPH 39.2/7.8 mg SDX/d-MPH 52.3/10.4 mg SDX/d-MPH

Route of Administration oral

Rx/OTC Dispensed Rx

Maximum Daily Dose 52.3 mg serdexmethylphenidate /10.4 mg dmethylphenidate as free base or 56 mg serdexmethylphenidate Chlorid

Dexmethylphenidate, sold under the brand name Focalin among others, is a medication used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years.[3] If no benefit is seen after four weeks it is reasonable to discontinue its use.[3] It is taken by mouth.[3] The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours.[4]

Common side effects include abdominal pain, loss of appetite, and fever.[3] Serious side effects may include abusepsychosissudden cardiac deathmaniaanaphylaxisseizures, and dangerously prolonged erection.[3] Safety during pregnancy and breastfeeding is unclear.[5] Dexmethylphenidate is a central nervous system (CNS) stimulant.[6][3] How it works in ADHD is unclear.[3] It is the more active enantiomer of methylphenidate.[3]

Dexmethylphenidate was approved for medical use in the United States in 2001.[1] It is available as a generic medication.[3] In 2018, it was the 156th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[7][8] It is also available in Switzerland.[9]

SYNRoute 1

Reference:1. US6528530B2.

2. J. Org. Chem. 1998, 63, 9628-9629.Route 2

Reference:1. J. Am. Chem. Soc. 1999, 121,6509-6510.Route 3

Reference:1. Org. Process Res. Dev. 201014, 1473–1475.Route 4

Reference:1. J. Med. Chem. 1998, 41,591-601.Route 5

Reference:1. Org. Lett. 19991, 175-178.

2. Organic Syntheses 198563, 206-212.

Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects.[102][124] The erythro diastereomers are pressor amines, a property not shared with the threo diastereomers. When the drug was first introduced it was sold as a 4:1 mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. “TMP” refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used and it is much more commonly referred to as dexmethylphenidate, d-MPH, or d-threo-methylphenidate. A review on the synthesis of enantiomerically pure (2R,2′R)-(+)-threo-methylphenidate hydrochloride has been published.[125]Methylphenidate synthesis

Methylphenidate synthesis graphic

Method 1: Methylphenidate preparation elucidated by Axten et al. (1998)[126] via Bamford-Stevens reaction.

Methylphenidate synthesis graphic

Method 2: Classic methylphenidate synthesis[127]

Methylphenidate synthesis graphic

Method 3: Another synthesis route of methylphenidate which applies Darzens reaction to obtain aldehyde as an intermediate. This route is significant for its selectivity.SYNhttps://onlinelibrary.wiley.com/doi/abs/10.1002/jhet.2705SUN

1.9 Synthesis of (R, R), (R, S), (S, S) and (S, R) methyl 2-piperidin-2-yl-phenylacetate hydrochloride (1a1b1c and 1d)

Compound 8a8b8c or 8d (400 mg, 1.3 mmol) was dissolved into methanol solution (15 mL), and then thionyl chloride (1 mL) was added drop-wise. The reaction mixture was stirred for 12 hours and concentrated in vacuum; a white solid was precipitated and filtered to afford the final product. (1a. 0.28 g, 82% yield; 1b. 0.30 g, 84% yield; 1c. 0.31 g, 85% yield; 1d. 0.30 g, 84% yield). The characterization data of the four final products had been reported [2] by us in 2016.

SYN

https://patents.google.com/patent/US20040180928A1/en

  • Dexmethylphenidate, also known as d-threo-methylphenidate, (R,R)-methylphenidate or (R,R)-α-phenyl-2-piperidineacetic acid methyl ester, having the formula:
  • [0029]
    is CNS (central nervous system) stimulant that is chemically and pharmacologically similar to the amphetamines. Dexmethylphenidate’s CNS actions is milder than those of the amphetamines and have more noticeable effects on mental activities than on motor activities.
  • [0030]
    It has been reported by Sporzny (1961) that among racemic mixtures of threo and erythro diastereomers of methylphenidate, only threo-isomer displays stimulant properties. Dexmethylphenidate hydrochloride (i.e. the d-threo enantiomer of methylphenidate hydrochloride) has been reported to be 5 to 38 times more active than the corresponding (S,S)-methylphenidate hydrochloride (Prashad 2000).
  • [0031]
    A commercially available drug is sold under the name Focalin™ (Novartis) and it consists of dexmethylphenidate in the form of the hydrochloride salt. This product is orally administered and clinically used in the treatment of narcolepsy and as adjunctive treatment in children with attention deficit disorder (ADD) and attention-deficit hyperactivity disorder (ADHD).
  • [0032]
    A synthesis of dexmethylphenidate hydrochloride was firstly described in U.S. Pat. No. 2,838,519 and include resolution of erythro-α-phenyl-2-piperidineacetamide to obtain enantiopure (2R,2′S)-α-phenyl-2-piperidineacetamide, which was subjected to epimerization, hydrolysis, and esterification as shown in Scheme 1:
  • [0033]
    Related example of preparation of dexmethylphenidate from erythro-α-phenyl-2-piperidineacetamide was described in U.S. Pat. No. 5,936,091.
  • [0034]
    Preparation of dexmethylphenidate through optical resolution of threo-α-phenyl-2-piperidineacetamide was described in U.S. Pat. No. 5,965,734, as shown in Scheme 2:
  • [0035]
    Synthetic methods for the preparation of racemic mixture of threo- and erythro-α-phenyl-2-piperidineacetamides as raw materials for the preparation of dexmethylphenidate were described by Panizzon (1944) and Patric (1982) and in U.S. Pat. Nos. 2,507,631, 2,838,519, 2,957,880 and 5,936,091, and in WO 01/27070. These methods include using sodium amide as base in the nucleophilic substitution of chlorine in 2-chloropyridine with phenylacetonitrile followed by hydrolysis of the formed nitrile and reduction of a pyridine ring to a piperidine one by hydrogenation on PtO catalyst, as shown in Scheme 3:
  • [0036]
    Alternatively, 2-bromopyridine was used instead of 2-chloropyridine by Deutsch (1996).
  • [0037]
    In some other methods threo-methylphenidate was used as the raw material for the preparation of dexmethylphenidate. Threo-methylphenidate may be prepared by a several routes, inter alia by the following two processes:
  • [0038]
    i) by esterification of threo-ritalinic acid which may be prepared from erythro-enriched and threo-α-phenyl-2-piperidineacetamides as shown in Scheme 4:
  • [0039]
    ii) by cyclization of easily available 1-(phenylglyoxylyl)piperidine arenesulfonylhydrazone to (R*,R*)-enriched 7-phenyl-1-azabicyclo[4.2.0]octan-8-one and further converting the β-lactam to threo-methylphenidate hydrochloride, as described by Axten (1998), Corey (1965) and Earle (1969) and in WO 99/36403 and shown in Scheme 5:
  • [0040]
    The resolution of threo-methylphenidate to afford dexmethylphenidate was first reported by Patric (1987) which used (R)-(−)-binaphthyl-2,2′-diyl hydrogen phosphate as the resolving agent. Several new resolutions of threo-methylphenidate have been reported recently by Prashad (1999) and in U.S. Pat. Nos. 6,100,401, 6,121,453, 6,162,919 and 6,242,464 as described in Scheme 6:
  • [0041]
    wherein the chiral acid is one of the following: (R)-(−)-binaphthyl-2,2′-diyl hydrogen phosphate, (−)-menthoxyacetic acid, ditoluoyl-D-tartaric acid or dibenzoyl-D-tartaric acid.
  • [0042]
    Resolution of threo-methylphenidate may be also achieved by enzymatic hydrolysis methods as proposed by Prashad (1998) and in WO 98/25902. Such resolution is described in Scheme 7:
  • [0043]
    Resolution of threo-ritalinic acid hydrochloride with (S)-1-phenylethylamine give complex salt (R,R)-enriched threo-ritalinic acid.HCl.(S)-1-phenylethylamine with 77% ee optical purity of ritalinic acid (U.S. Ser. No. 2002/0019535), Scheme 8: 
  • [0119]
  • [0120]
    Gaseous hydrogen chloride was passed through a boiling solution of (R,R)-N-Boc-ritalinic acid (95.4 g, 299 mmol) in methanol (1.5 L). The mixture was stirred for 12 hours under reflux conditions and concentrated to the volume of 250 mL. Toluene (750 mL) was added to the stirred residue, then methanol lo was removed from boiling suspension under normal pressure. The obtained mixture was stirred overnight at 0-5° C. The precipitated solids were filtered off, washed on the filter with toluene (3×50 mL) and dried under reduced pressure to give 78.4 g (97.2% yield) of dexmethylphenidate hydrochloride as white crystals with mp 222-224° C. and [α]D 25 87.0° (c=1, MeOH).
  • [0117]
  • [0118]
    A mixture of crystalline salt of (R,R)-N-Boc-ritalinic acid and (S)-1-phenylamine with [α]D 20 −28.6° (c=1, MeOH) (133.0 g, 302 mmol), ethyl acetate (1.3 L) and solution of citric acid (164.0 g, 845 mmol) in water (1.3 L) was stirred at 15-25° C. for 1.5 hours. The organic layer was separated, washed lo with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 95.4 g (99%) of (R,R)-N-B
  • [0115]
  • [0116]
    (S)-1-Phenylethylamine (113.8 g, 0.94 mol, 0.6 eq) was added dropwise to a stirred solution of N-Boc-threo-ritalinic acid (500 g, 1.57 mol, 1 eq) in ethyl acetate (5 L) for 1 hour at 20-40° C. The mixture was stirred for 1 hour at 40° C. and overnight at 5° C. The precipitated solids were filtered off, washed on the lo filter with cold ethyl acetate (2×500 mL) and dried under reduced pressure to give 380 g of white crystals with [α]D 20−23.3° (c=1, MeOH). The salt was twice recrystallized from aqueous methanol. The precipitated crystals were filtered off, washed on the filter with cold aqueous methanol and dried under reduced pressure to a constant weight to give 265 g (33.5% yield) of salt of (R,R)-N-Boc-ritalinic acid and (S)
  • [0113]
  • [0114]
    A mixture of solution of N-Boc-threo-ritalinic acid sodium salt (1700 g, 4.98 mmol), citric acid (1150 g, 5.98 mmol) and water (5 mL) was stirred at 15-25° C. for 0.5 hour and extracted with ethyl acetate (3×4 L). Combined organic extracts were washed with brine (2×3 L), dried over sodium sulfate, filtered and evaporated under reduced pressure to constant weight to give 1560 g (98.1% yield) of N-Boc-threo-ritalinic acid with mp 133-134° C. (EtOAc/hexane) and 99.8% purity by HPLC.

Medical uses

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. Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated.[6]

Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo.[6] It also showed greater efficacy than osmotic controlled-release oral delivery system (OROS) methylphenidate over the first half of the laboratory classroom day but assessments late in the day favoured OROS methylphenidate.[6]

CLIP

An Improved and Efficient Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride 

Long-Xuan Xing, Cheng-Wu Shen, Yuan-Yuan Sun, Lei Huang, Yong-Yong Zheng,* Jian-Qi Li*

https://onlinelibrary.wiley.com/doi/abs/10.1002/jhet.2705

The present work describes an efficient and commercially viable process for the synthesis of dexmethylphenidate hydrochloride (1), a mild nervous system stimulant. The overall yield is 23% with ~99.9% purity (including seven chemical steps). Formation and control of possible impurities are also described in this report.

An Improved and Efficient Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride - Xing - 2017 - Journal of Heterocyclic Chemistry - Wiley Online Library

(R)-methyl 2-phenyl-2-((R)-piperidin-2-yl)acetate hydrochloride (1). ………… afford 1 as a white solid (107.6 g, 87.3% yield) with 99.50% purity and 99.70% ee. The crude product (107.6 g, 0.4 mol) was further purified by recrystallization from pure water (100 mL) to obtain the qualified product 1 (98.3 g, 91.4% yield) with 99.92 purity and 99.98% ee.

[α] 25 D +85.6 (MeOH, c 1) (lit [4b]. [α] 25 D +84 (MeOH, c 1));

Mp 222-223 C (lit [4b]. Mp 222– 224°C); MS m/z 234 [M + H]+ .

1 H NMR (400Hz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (br, 1H), 8.97 (br, 1H), 7.41-7.26 (m, 5H), 4.18-4.16 (d, J = 9.2Hz, 1H), 3.77-3.75 (m, 1H), 3.66 (s, 3H), 3.25 (m, 1H), 2.94 (m, 1H), 1.67-1.64 (m, 3H), 1.41-1.25 (m, 3H).

13C NMR (100.6 MHz, DMSO-d6) δ 171.3, 134.2, 129.1, 128.6, 128.2, 56.8, 53.3, 52.6, 44.5, 25.7, 21.5, 21.4.

1H-NMR, and 13C-NMR of compound 1………………………………….. 10-11

DEPT,

COSY, NOESY, GHMBC, and HMQC of compound 1……………… 12-14

COSY

NOESY

GHMBC

HMQC

Contraindications

This section is transcluded from Methylphenidate. (edit | history)

Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine, and tranylcypromine), or individuals with agitation, ticsglaucoma, or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.[10]

The US Food and Drug Administration (FDA) gives methylphenidate a pregnancy category of C, and women are advised to only use the drug if the benefits outweigh the potential risks.[11] Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development.[12] In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it “is not a major human teratogen”.[13]

Adverse effects

Part of this section is transcluded from Methylphenidate. (edit | history)

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate.[14]

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Methylphenidate was ranked 13th in dependence, 12th in physical harm, and 18th in social harm.[15]

The most common adverse effects include appetite lossdry mouthanxiety/nervousnessnausea, and insomniaGastrointestinal adverse effects may include abdominal pain and weight lossNervous system adverse effects may include akathisia (agitation/restlessness), irritabilitydyskinesia (tics), lethargy (drowsiness/fatigue), and dizzinessCardiac adverse effects may include palpitations, changes in blood pressure and heart rate (typically mild), and tachycardia (rapid heart rate).[16] Smokers with ADHD who take methylphenidate may increase their nicotine dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3 cigarettes per day.[17] Ophthalmologic adverse effects may include blurred vision and dry eyes, with less frequent reports of diplopia and mydriasis.[18]

There is some evidence of mild reductions in height with prolonged treatment in children.[19] This has been estimated at 1 centimetre (0.4 in) or less per year during the first three years with a total decrease of 3 centimetres (1.2 in) over 10 years.[20][21]

Hypersensitivity (including skin rashurticaria, and fever) is sometimes reported when using transdermal methylphenidate. The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.[22]

Methylphenidate can worsen psychosis in people who are psychotic, and in very rare cases it has been associated with the emergence of new psychotic symptoms.[23] It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania.[24] There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link.[19] Logorrhea is occasionally reported. Libido disorders, disorientation, and hallucinations are very rarely reported. Priapism is a very rare adverse event that can be potentially serious.[25]

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden deathheart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.[26]

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.[27]

A 2018 Cochrane review found that methylphenidate might be associated with serious side effects such as heart problems, psychosis, and death; the certainty of the evidence was stated as very low and the actual risk might be higher.[28]

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomitingnauseaagitationtremorshyperreflexia, muscle twitching, euphoria, confusion, hallucinations, deliriumhyperthermia, sweating, flushing, headache, tachycardiaheart palpitationscardiac arrhythmiashypertensionmydriasis, and dryness of mucous membranes.[29][30] A severe overdose may involve symptoms such as hyperpyrexiasympathomimetic toxidromeconvulsionsparanoiastereotypy (a repetitive movement disorder), rapid muscle breakdowncoma, and circulatory collapse.[29][30][31] A methylphenidate overdose is rarely fatal with appropriate care.[31] Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.[32]

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychoticsα-adrenoceptor agonists and propofol serving as second-line therapies.[31]

Addiction and dependence[edit]

ΔFosB accumulation from excessive drug use 
Top: this depicts the initial effects of high dose exposure to an addictive drug on gene expression in the nucleus accumbens for various Fos family proteins (i.e., c-FosFosBΔFosBFra1, and Fra2).
Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these phosphorylated (35–37 kilodalton) ΔFosB isoforms persist in the D1-type medium spiny neurons of the nucleus accumbens for up to 2 months.[33][34]

Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine. It has moderate liability among addictive drugs;[35][36] accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug.[36][37] When used above the medical dose range, stimulants are associated with the development of stimulant psychosis.[38] As with all addictive drugs, the overexpression of ΔFosB in D1-type medium spiny neurons in the nucleus accumbens is implicated in methylphenidate addiction.[37][39]

Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon methamphetamine.[40] Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine addiction[41][42][43][44] in the same way that methadone is used as a replacement drug for physical dependence upon heroin. Its effectiveness in treatment of cocaine or psychostimulant addiction, or psychological dependence has not been proven and further research is needed.[45]

Biomolecular mechanisms

Further information: Addiction § Biomolecular mechanisms

Methylphenidate has the potential to induce euphoria due to its pharmacodynamic effect (i.e., dopamine reuptake inhibition) in the brain’s reward system.[39] At therapeutic doses, ADHD stimulants do not sufficiently activate the reward system, or the reward pathway in particular, to the extent necessary to cause persistent increases in ΔFosB gene expression in the D1-type medium spiny neurons of the nucleus accumbens;[36][39][46] consequently, when taken as directed in doses that are commonly prescribed for the treatment of ADHD, methylphenidate use lacks the capacity to cause an addiction.[36][39][46] However, when methylphenidate is used at sufficiently high recreational doses through a bioavailable route of administration (e.g., insufflation or intravenous administration), particularly for use of the drug as a euphoriant, ΔFosB accumulates in the nucleus accumbens.[36][39] Hence, like any other addictive drug, regular recreational use of methylphenidate at high doses eventually gives rise to ΔFosB overexpression in D1-type neurons which subsequently triggers a series of gene transcription-mediated signaling cascades that induce an addiction.[39][46][47]

Overdose

This section is transcluded from Methylphenidate. (edit | history)

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomitingnauseaagitationtremorshyperreflexia, muscle twitching, euphoria, confusion, hallucinations, deliriumhyperthermia, sweating, flushing, headache, tachycardiaheart palpitationscardiac arrhythmiashypertensionmydriasis, and dryness of mucous membranes.[29][30] A severe overdose may involve symptoms such as hyperpyrexiasympathomimetic toxidromeconvulsionsparanoiastereotypy (a repetitive movement disorder), rapid muscle breakdowncoma, and circulatory collapse.[29][30][31] A methylphenidate overdose is rarely fatal with appropriate care.[31] Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.[32]

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychoticsα-adrenoceptor agonists and propofol serving as second-line therapies.[31]

Interactions

This section is transcluded from Methylphenidate. (edit | history)

Methylphenidate may inhibit the metabolism of vitamin K anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants, and selective serotonin reuptake inhibitors). Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations.[48] There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.[49][50][51][52]

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification,[53][54] not unlike the hepatic formation of cocaethylene from cocaine and ethanol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.[55][54]

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.[56]

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity.[57]

Mode of activity

Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET),[58] which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system.[59] Moreover, it is thought to “increase the release of these monoamines into the extraneuronal space.”[2]

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 (d-threo-methylphenidate) is a preparation of the RR enantiomer of methylphenidate.[60][61] In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product.[58][62]

Compd[63]DAT (Ki)DA (IC50)NET (Ki)NE (IC50)
D-TMP1612320639
L-TMP22501600>10K980
DL-TMP1212078851

Pharmacology

Main article: Methylphenidate § Pharmacology

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 (dextro-, levo-)-TMP (threo-methylphenidate) XR (extended release) (Concerta, Ritalin LA), with flexible dosing and good tolerability.[64][65]) It has also been demonstrated to reduce ADHD symptoms in both children[66] and adults.[67] d-MPH has a similar side-effect profile to MPH[14] and can be administered without regard to food intake.[68]

 

References

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  34. ^ Nestler EJ (December 2012). “Transcriptional mechanisms of drug addiction”Clinical Psychopharmacology and Neuroscience10 (3): 136–43. doi:10.9758/cpn.2012.10.3.136PMC 3569166PMID 23430970The 35–37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. … As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. … ΔFosB overexpression in nucleus accumbens induces NFκB
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  36. Jump up to:a b c d e Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 15: Reinforcement and Addictive Disorders”. In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 368. ISBN 9780071481274Cocaine, [amphetamine], and methamphetamine are the major psychostimulants of abuse. The related drug methylphenidate is also abused, although it is far less potent. These drugs elicit similar initial subjective effects ; differences generally reflect the route of administration and other pharmacokinetic factors. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
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  46. Jump up to:a b c Nestler EJ (December 2013). “Cellular basis of memory for addiction”Dialogues in Clinical Neuroscience15 (4): 431–43. doi:10.31887/DCNS.2013.15.4/enestlerPMC 3898681PMID 24459410Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. … A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal’s sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement … Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. … Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.4
  47. ^ Ruffle JK (November 2014). “Molecular neurobiology of addiction: what’s all the (Δ)FosB about?”. The American Journal of Drug and Alcohol Abuse40 (6): 428–37. doi:10.3109/00952990.2014.933840PMID 25083822S2CID 19157711
    The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. …
    Conclusions
    ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch(34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.

     Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). “Epigenetic regulation in drug addiction”. Annals of Agricultural and Environmental Medicine19(3): 491–6. PMID 23020045For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken … In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription
     Robison AJ, Nestler EJ (October 2011). “Transcriptional and epigenetic mechanisms of addiction”Nature Reviews. Neuroscience12 (11): 623–37. doi:10.1038/nrn3111PMC 3272277PMID 21989194ΔFosB has been linked directly to several addiction-related behaviors … Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
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External links

Clinical data
Trade namesFocalin, Focalin XR, Attenade, others
Other namesd-threo-methylphenidate (D-TMP)
AHFS/Drugs.comMonograph
MedlinePlusa603014
License dataUS DailyMedDexmethylphenidate
Dependence
liability
Physical: None Psychological: High
Routes of
administration
By mouth
ATC codeN06BA11 (WHO)
Legal status
Legal statusAU: S8 (Controlled drug)CASchedule IIIDEAnlage III (Special prescription form required)UK: Class BUS: Schedule II [1][2]In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability11–52%
Protein binding30%
MetabolismLiver
Elimination half-life4 hours
ExcretionKidney
Identifiers
showIUPAC name
CAS Number40431-64-9 as HCl: 19262-68-1
PubChem CID154101as HCl: 154100
IUPHAR/BPS7554
DrugBankDB06701 as HCl: DBSALT001458
ChemSpider135807 as HCl: 135806
UNIIM32RH9MFGPas HCl: 1678OK0E08
KEGGD07806 as HCl: D03721 
ChEBICHEBI:51860 
ChEMBLChEMBL827 as HCl: ChEMBL904
CompTox Dashboard (EPA)DTXSID70893769 
Chemical and physical data
FormulaC14H19NO2
Molar mass233.311 g·mol−1
3D model (JSmol)Interactive imageas HCl: Interactive image
showSMILES
showInChI

///////////DEXMETHYLPHENIDATE, FDA 2021, APPROVALS 2021

Cl.[H][C@@](C(=O)OC)(C1=CC=CC=C1)[C@@]1([H])CCCCN1

wdt-18

NEW DRUG APPROVALS

ONE TIME

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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