Lisdexamfetamine

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Lisdexamfetamine
Lisdexamfetamine-Structural Formula V.1.svg
Lisdexamfetamine.gif
Systematic (IUPAC) name
(2S)-2,6-Diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide
Clinical data
Trade names Tyvense, Elvanse, Venvanse, Vyvanse
AHFS/Drugs.com monograph
MedlinePlus a607047
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability 96.4%[1]
Metabolism Gastro-intestinal (initial); Hepatic (extensively CYP2D6) after conversion to dextroamphetamine
Half-life < 1 hour (prodrug molecule), 10-13 hours (dextroamphetamine)
Excretion Renal: ~2%
Identifiers
CAS number 608137-32-2 YesY
ATC code N06BA12
PubChem CID 11597698
DrugBank DB01255
ChemSpider 9772458 YesY
UNII H645GUL8KJ YesY
ChEMBL CHEMBL1201222 N
Synonyms (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide

(2S)-2,6-Bis(azanyl)-N-[(2S)-1-phenylpropan-2-yl]hexanamide
Chemical data
Formula C15H25N3O 
Mol. mass 263.378 g/mol
 N (what is this?)  (verify)
30mg Vyvanse capsules

Lisdexamfetamine dimesylate (L-lysine-dextroamphetamine dimesylate) is a psychostimulant prodrug of the phenethylamine and amphetamine chemical classes. Its molecular structure consists of dextroamphetamine coupled with the essential amino acid L-lysine. Lisdexamfetamine itself is inactive and acts as a prodrug to dextroamphetamine upon cleavage of the lysine portion of the molecule.

Lisdexamfetamine can be prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) in children six to twelve years and in adults as a part of a treatment program that may include other measures (i.e., psychological, educational, social). The safety and the efficacy of lisdexamfetamine dimesylate in people three to five years old have not been established.[2] Lisdexamfetamine is also being investigated for possible treatment of major depressive disorder, cognitive impairment associated with schizophrenia, excessive daytime sleepiness, and binge eating disorder.[3]

In the United States lisdexamfetamine is a Schedule II controlled substance (DEA number 1205) [4] and the aggregate production quota for 2014 is 23,750 kilograms of anhydrous acid or base.[5] The tradename is Vyvanse in the US. In the United Kingdom, Denmark, Sweden, Germany, Finland, Spain and Norway lisdexamfetamine is available and licensed under the brand name Elvanse (Tyvense in Ireland.[6] It was recently scheduled as a Schedule 2/Class B substance in the United Kingdom, allowing for its medical use but placing strict criminal penalties for its unauthorised production, supply, possession etc. Lisdexamfetamine is currently in Phase II trials in Japan for ADHD, as well as under investigation for the treatment of binge eating disorder.[3]

Uses[edit]

Medical[edit]

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

Lisdexamfetamine is used primarily as a treatment for attention deficit hyperactivity disorder (ADHD) and has similar off-label uses as those of other pharmaceutical amphetamines.[7][8] Long-term amphetamine exposure in some animal species is known to produce abnormal dopamine system development or nerve damage,[9][10] but, in humans with ADHD, amphetamines appear to improve brain development and nerve growth.[11][12][13] Magnetic resonance imaging studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus.[11][12][13]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.[14][15] Controlled trials spanning two years have demonstrated treatment effectiveness and safety.[15][16] One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points and continued improvements in attention, disruptive behaviors, and hyperactivity.[16]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[17] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.[17] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[18][17][19] Approximately 70% of those who use these stimulants see improvements in ADHD symptoms.[20][21] Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans.[14][20] The Cochrane Collaboration's review[note 1] on the treatment of adult ADHD with amphetamines stated that while amphetamines improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[23]

A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine in such people should be avoided.[24] Other Cochrane reviews on the use of amphetamine following stroke or acute brain injury indicated that it may improve recovery, but further research is needed to confirm this.[25][26][27]

Individuals over the age of 65 were not commonly tested in clinical trials of lisdexamfetamine. Therefore, there is insufficient data to determine how older individuals respond. People over the age of 65 should start on the low end of dosing schedules due to the prevalence of decreased hepatic function, decreased renal function, and comorbidities in this population.[7]

Performance-enhancing[edit]

Therapeutic doses of amphetamine improve cortical network efficiency, resulting in higher performance on working memory tests in all individuals.[18][28] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[18][29][30] Stimulants such as amphetamine can improve performance on difficult and boring tasks,[18][29] and are used by some students as a study and test-taking aid.[31] Based upon studies of self-reported illicit stimulant use, performance-enhancing use, rather than abuse as a recreational drug, is the primary reason that students use stimulants.[32] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and cognitive control.[18][29]

Amphetamine is used by some athletes for its psychological and performance-enhancing effects, such as increased stamina and alertness;[33][34] however, its use is prohibited at sporting events regulated by collegiate, national, and international anti-doping agencies.[35][36] In healthy people at oral therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time.[33][37][38] Like the psychostimulants methylphenidate and bupropion, amphetamine increases stamina and endurance in humans primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.[37][38] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[33][37][38] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[39][40][37]

Contraindications[edit]

Pharmaceutical lisdexamfetamine dimesylate is contraindicated in patients with hypersensitivity to amphetamine or any other ingredients that it contains.[7] It is also contraindicated in in patients who have used a monoamine oxidase inhibitor (MAOI) within the last 14 days.[7][41] Amphetamine products are contraindicated by the United States Food and Drug Administration (USFDA) in people with a history of drug abuse, heart disease, or severe agitation or anxiety, or in those currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension.[42] The USFDA advises anyone with bipolar disorder, depression, elevated blood pressure, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome to monitor their symptoms while taking amphetamine.[42] Amphetamine is classified in US pregnancy category C.[42] This means that detriments to the fetus have been observed in animal studies and adequate human studies have not been conducted; amphetamine may still be prescribed to pregnant women if the potential benefits outweigh the risks.[43] Amphetamine has also been shown to pass into breast milk, so the USFDA advises mothers to avoid breastfeeding when using it.[42] Due to the potential for stunted growth, the USFDA advises monitoring the height and weight of children and adolescents prescribed amphetamines.[42] Prescribing information approved by the Australian Therapeutic Goods Administration further contraindicates anorexia.[44]

Availability[edit]

Lisdexamfetamine dimesylate is a white to off-white powder that is soluble in water (792 mg/mL). Vyvanse capsules contain 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg of lisdexamfetamine dimesylate and the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The capsule shells contain gelatin, titanium dioxide, and one or more of the following: FD&C Red #3, FD&C Yellow #6, FD&C Blue #1, Black Iron Oxide, and Yellow Iron Oxide.[45]

Side effects[edit]

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

Products containing lisdexamfetamine have a side effect profile comparable to those containing amphetamine.[7][39][40]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.[40] Cardiovascular side effects can include irregular heartbeat (usually an increased heart rate), hypertension (high blood pressure) or hypotension (low blood pressure) from a vasovagal response, and Raynaud's phenomenon (reduced blood flow to extremities).[40][34][46] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[40] Abdominal side effects may include stomach pain, loss of appetite, nausea, and weight loss.[40] Other potential side effects include dry mouth, excessive grinding of the teeth, acne, profuse sweating, blurred vision, reduced seizure threshold, and tics (a type of movement disorder).[40][34][46] Dangerous physical side effects are rare at typical pharmaceutical doses.[34]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[34] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[34] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control.[34] The effects of amphetamine on the gastrointestinal tract are unpredictable.[34] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[34] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[34] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opiates.[34]

USFDA commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.[sources 1]

Psychological

Common psychological effects of therapeutic doses can include increased alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elated mood followed by mildly depressed mood), increased initiative, insomnia or wakefulness, self-confidence, and sociability.[40][34] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 2] these effects depend on the user's personality and current mental state.[34] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[39][40][53] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[39][40][54] According to the USFDA, "there is no systematic evidence" that stimulants can produce aggressive behavior or hostility.[40]

Overdose[edit]

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

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[41][55] The severity of overdose symptoms vary positively with dosage and inversely with drug tolerance to amphetamine.[34][41] Tolerant individuals have been known to take as much as 5 grams of amphetamine, roughly 100 times the maximum daily therapeutic dose, in a day.[41] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[39][34] Chronic overdose of amphetamine poses a high risk of developing an addiction, since high doses result in increased expression of the addiction gene ΔFosB. Consistent aerobic exercise appears to magnitude-dependently reduce this risk.[56]

Overdose symptoms by system
System Minor or moderate overdose[39][34][41] Severe overdose[sources 3]
Cardiovascular
Central nervous
system
Musculoskeletal
Respiratory
  • Rapid breathing
Urinary
Other

Addiction

Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to arise from typical medical use at therapeutic doses.[39][59][34] Tolerance develops rapidly in amphetamine abuse, so periods of extended use require increasingly larger doses of the drug in order to achieve the same effect.[60][61]

Biomolecular mechanisms

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens.[62][63][64] The most important transcription factors[note 2] that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB).[63] ΔFosB is the most significant factor in drug addiction, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the associated neural adaptations that occur;[63] it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, opiates, phenylcyclidine, and substituted amphetamines.[63][66][67] ΔJunD is the transcription factor which directly opposes ΔFosB.[63] Increases in nucleus accumbens ΔJunD expression using viral vectors can reduce or, with a large increase, even block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[63] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[63][66][68] Since natural rewards induce expression of ΔFosB just like drugs of abuse do, chronic acquisition of these rewards can result in a similar pathological state of addiction.[66][63] Consequently, ΔFosB is the key transcription factor involved in amphetamine addiction and amphetamine-induced sex addictions, a phenomenon known as dopamine dysregulation syndrome which has been observed in some patients taking dopaminergic medications.[66][68][69]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[64] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[64] The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor.[64]

Pharmacological treatments

A Cochrane Collaboration review on amphetamine and methamphetamine addiction and abuse indicates that the current evidence on effective treatments is extremely limited.[70] The review indicated that fluoxetine[note 3] and imipramine[note 4] have some limited benefits in treating abuse and addiction, but concluded that there is currently no effective pharmacological treatment for amphetamine addiction or abuse.[70] A corroborating review indicated that amphetamine addiction is mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the mesolimbic dopamine pathway (a pathway in the brain that connects the ventral tegmental area to the nucleus accumbens).[71] This review also noted that magnesium ions and serotonin inhibit NMDA receptors and that the magnesium ions do so by blocking the receptor's calcium channels.[71] It also suggested that, based upon animal testing, pathological (addiction-inducing) amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.[71] Supplemental magnesium,[note 5] like fluoxetine treatment, has been shown to reduce amphetamine self-administration (doses given to oneself) in both humans and lab animals.[70][71]

Behavioral treatments

Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant addiction.[72] Additionally, research on the neurobiological effects of physical exercise suggests that consistent aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct (supplemental) treatment for amphetamine addiction.[56][66] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[56] In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces opposite effects on striatal dopamine receptor D2 (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density).[66]

Withdrawal

According to another Cochrane Collaboration review on withdrawal in highly addicted amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[73] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week.[73] Amphetamine withdrawal symptoms can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.[73] The review indicated that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[73] Manufacturer prescribing information does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.[74][75][76]

Psychosis

The main section for this topic is on the page Stimulant psychosis, in the section Substituted amphetamines.

Abuse of amphetamine can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia and delusions).[53] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely.[53][77] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[53] Psychosis very rarely arises from therapeutic use.[54][42]

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized as reduced transporter and receptor function.[78] There is no evidence that amphetamine is directly neurotoxic in humans.[79][80] High-dose amphetamine can cause indirect neurotoxicity as a result of increased oxidative stress from reactive oxygen species and autoxidation of dopamine.[9][81][82]

Interactions[edit]

  • Acidifying Agents: Drugs that acidify the urine, such as ascorbic acid, increase urinary excretion of amphetamines thus decreasing the half-life time of lisdexamfetamine in the body.[7]
  • Alkalinizing Agents: Drugs that alkalinize the urine, such as sodium bicarbonate, decrease urinary excretion of amphetamines thus increasing the half-life time of lisdexamfetamine in the body.[7]

Pharmacology[edit]

The main section for this topic is on the page Amphetamine, in the section Pharmacology.

Mechanism of action[edit]

Pharmacodynamics of amphetamine enantiomers in a dopamine neuron

A pharmacodynamic model of amphetamine and TAAR1
via AADC
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol (yellow-orange area). When amphetamine binds to TAAR1, it reduces dopamine receptor firing rate via potassium channels and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation. PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport. PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.

Lisdexamfetamine is an inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound which is responsible for the drug’s activity.[83] After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L-lysine, a naturally occurring essential amino acid, and dextroamphetamine.[7] The conversion of lisdexamfetamine to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times.[7][84]

The optical isomers of amphetamine, i.e., dextroamphetamine and levoamphetamine, are TAAR1 agonists and vesicular monoamine transporter 2 inhibitors that can enter monoamine neurons;[85][86] this allows them to release monoamine neurotransmitters (dopamine, norepinephrine, and serotonin, among others) from their storage sites and the presynaptic neuron, as well as prevent the reuptake of these neurotransmitters from the synaptic cleft.[85][86]

Lisdexamfetamine was developed with the goal of providing a long duration of effect that is consistent throughout the day, with reduced potential for abuse. The attachment of the amino acid lysine slows down the relative amount of dextroamphetamine available to the blood stream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to produce dextroamphetamine from lisdexamfetamine.[84] As opposed to Adderall, which contains roughly equal parts of racemic amphetamine and dextroamphetamic salts, lisdexamfetamine is a single-enantiomer dextroamphetamine formula.[83][87] Studies conducted show that lisdexamfetamine dimesylate may have less abuse potential than dextroamphetamine and an abuse profile similar to diethylpropion at dosages that are FDA-approved for treatment of ADHD, but still has a high abuse potential when this dosage is exceeded by over 100%.[84]

History, society, and culture[edit]

Lisdexamfetamine was developed by New River Pharmaceuticals, who were bought by Shire Pharmaceuticals shortly before lisdexamfetamine began being marketed. It was developed for the intention of creating a longer-lasting and less-easily abused version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells increases its duration of action, regardless of the route of ingestion.[88] The drug lisdexamfetamine dimesylate is the first prodrug of its kind.

On April 23, 2008, Vyvanse received FDA approval for the adult population.[89] In a randomized, double-blind, four-week phase III trial in adult patients with ADHD, dosages of 30, 50 or 70 mg/day of oral lisdexamfetamine caused a significantly greater improvement in ADHD-Rating Scale total score than placebo.[90] On February 19, 2009, Health Canada approved 30 mg and 50 mg capsules of lisdexamfetamine for treatment of ADHD.[91] On February 8, 2012, Vyvanse received FDA approval for maintenance treatment of adult ADHD.[92] In February 2014, Shire announced that two late-stage clinical trials had shown that Vyvanse was not an effective treatment for depression.[93]

Brand names[edit]

Lisdexamfetamine is sold as Tyvense (IE), Elvanse (UK), Venvanse (BR), Vyvanse (CA, US).

Notes[edit]

  1. ^ Cochrane Collaboration reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[22]
  2. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[65]
  3. ^ During short-term treatment, fluoxetine may decrease drug craving.[70]
  4. ^ During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.[70]
  5. ^ The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[71] other forms of magnesium were not mentioned.

Reference notes[edit]

References[edit]

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  2. ^ "Lisdexamfetamine dimesylate (generic)." Brown University Psychopharmacology Update 19.7 (2008): 1-2. Academic Search Premier. EBSCO. Web. 12 September 2010.
  3. ^ a b http://www.shire.com/shireplc/en/rd/pipeline
  4. ^ "DEA - Department of Justice". http://www.justice.gov/dea/pr/multimedia-library/publications/drug_of_abuse.pdf#page=38. DEA - Department of Justice. Retrieved 1 July 2014. 
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