Lisdexamfetamine

Lisdexamfetamine dimesylate ( L -lysine- D -amphetamine; sold as Vyvanse) 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. It was developed for the intention of creating a longer-lasting and more difficult to abuse version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells increases its duration, regardless of the route of ingestion. The drug lisdexamfetamine dimesylate is the first prodrug of its kind. Studies conducted show that lisdexamfetamine dimesylate is less addictive than its counterparts such as Adderall and Concerta. There is no increased onset or effect as occurs with IV administration of dextroamphetamine compared to oral use of the same. Intravenously administered lisdexamfetamine produced likability effects similar to placebo, therefore affirming the drug's ability to reduce abuse potential.

Lisdexamfetamine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children six to twelve years and in adults as an integral part of a total treatment program that may include other measures (i.e., psychological, educational, social). The safety and efficacy of lisdexamfetamine dimesylate in patients three to five years old have not been established. As opposed to Adderall, which contains roughly 75% dextroamphetamine and 25% levoamphetamine, lisdexamfetamine is a single-enantiomer (dextro) amphetamine formula. This pure formulation may reduce side effects, but certain individuals exhibit a better clinical response to the mixed isomer preparation.

Vyvanse is also being investigated for possible treatment of Major Depressive Disorder, cognitive impairment associated with Schizophrenia, Excessive Daytime Sleepiness, and Binge Eating Disorder.

Dosage
Lisdexamfetamine is marketed under the brand name Vyvanse. Vyvanse comes in several dosages (see table below). These are usually labeled to be taken once daily.

25 mg of Vyvanse is molecularly equivalent to 10 mg of Adderall (resulting in or including 7.37 mg versus 7.50 mg dextroamphetamine, respectively), although a 25 mg Vyvanse capsule is not commercially available. However, the molecular equivalence ratio does not mean that the respective doses of Vyvanse and Adderall XR (Spansule) are bioequivalent because the two formulations have slightly different pharmacokinetic profiles. For example, while the area under the curve for the aforementioned pharmaceuticals is equivalent, the peak exposure (Cmax) to the active compound dextroamphetamine is about 50% higher for Vyvanse than for Dexedrine XR. The conversion rate of lisdexamfetamine to dextroamphetamine base is 0.2948, meaning that each milligram of lisdexamfetamine is equivalent to 0.2948 mg of dextroamphetamine base.

Mechanism of action
Although the precise mechanism of action by which amphetamines improve the symptoms of ADHD remains unknown, they are thought to block the reuptake of norepinephrine (noradrenaline) and dopamine into the presynaptic neuron and increase their availability into the extraneuronal space.

Lisdexamfetamine (LDX) is a therapeutically inactive molecule. After oral ingestion, LDX is converted to l-lysine, a naturally occurring essential amino acid, and active d-amphetamine, which is responsible for the drug’s activity. The conversion of LDX to d-amphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times. LDX was developed with the goal of providing a long duration of effect that is consistent throughout the day, with reduced potential for abuse-related liking. Because no free d-amphetamine is present in LDX capsules, d-amphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to obtain d-amphetamine from LDX.

History
Vyvanse was developed by New River Pharmaceuticals, who were bought by Shire Pharmaceuticals shortly before lisdexamfetamine began being marketed. Vyvanse is approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention-deficit hyperactivity disorder.

On April 23, 2008, Vyvanse received FDA approval for the adult population. In a randomized, double-blind, four-week phase III trial in adult patients with ADHD, 30, 50 or 70mg/day of oral lisdexamfetamine caused a significantly greater improvement in ADHD-Rating Scale total score than placebo.

On February 19, 2009, Health Canada approved 30 mg and 50 mg capsules of lisdexamfetamine for treatment of ADHD.

On February 8, 2012, Vyvanse received FDA approval for maintenance treatment of adult ADHD.

Misuse potential
Lisdexamfetamine has less potential for misuse than its active metabolite (dextroamphetamine) due to being initially inactive upon consumption via all methods and the drug level of the active metabolite dextroamphetamine reaching a plateau within a therapeutic dosage range (both results of being a pro-drug). Misuse of lisdexamfetamine may cause the same extent of cardiovascular side-effects as dextro-amphetamine, but again this risk is likely to be reduced due to the method of administration.

Common side effects
Common side effects (side effects that have average rates of presentation; usually presenting in >5% of patients) of lisdexamfetamine use include:


 * Discomfort
 * Erectile Dysfunction
 * Dizziness
 * Mild agitation (restlessness)
 * Nausea
 * Xerostomia (dry mouth)
 * Bruxism (jaw clenching/grinding)
 * Anxiety
 * Diarrhea
 * Emesis (vomiting)
 * Headache
 * Insomnia (inability to sleep)
 * Weight loss (resulting from decreased appetite)
 * Euphoria
 * Diaphoresis (increased sweating)
 * Irritability
 * Parageusia (unpleasant taste)
 * Upper abdominal pain
 * Cold Feet or Hands
 * Rapid Heartbeat

Severe side effects
This medication MUST be taken on a regular schedule. Other side effects can be caused by lisdexamfetamine; these serious reactions include:


 * Severe aggression - some patients have reported sudden mood changes, inability to control rage, physical abuse of others
 * Abnormal muscle weakness or tiredness
 * Anaphylaxis - a severe allergic reaction with effects including a rash, hives, itching, difficulty breathing, and generalized swelling.
 * Changes in vision
 * Dyspnea (shortness of breath)
 * Fever
 * Severe headache
 * Syncope (fainting)


 * Angina pectoris (severe chest pain)
 * Blurred vision
 * Cardiac dysrhythmias - a group of cardiovascular conditions in which the electrical activity of the heart is abnormal with effects ranging from a fast heartbeat to cardiac arrest and sudden death.
 * Seizures
 * Tics - sudden, stereotyped, nonrhythmic and repetitive motor movements and/or vocalizations.


 * Hallucinations
 * Muscle tremors
 * Severe irritability
 * Severe psychomotor agitation
 * Altered sexual ability or desire such as hypersexuality, male impotence, premature ejaculation, etc.
 * Tachycardia (fast heartbeat)
 * Slowed thinking
 * Unstable emotions