Lisdexamfetamine (contracted from L - lys ine dex tro amphetamine ) is a prodrug of the central nervous system (CNS) of the dextroamphetamine stimulant, the phenethylamine of the amphetamine class used in the treatment of attention deficit hyperactivity disorder (ADHD) and eating disorders. Its chemical structure consists of dextroamphetamine combined with the essential amino acid L -sysine. Lisdexamfetamine itself is inactive before its absorption and subsequent limited enzymatic cleavage-the subsequent quantity of the L -sysine molecule, which produces the active metabolite (dextroamphetamine).
Lisdexamfetamine may be prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and children six and older, as well as for moderate to severe eating disorders in adults. The safety and efficacy of lisdexamfetamine dimesylate in children with ADHD for three to five years has not been established.
Lisdexamfetamine is a Class B/Schedule II substance in the United Kingdom and Schedule II regulators in the United States (DEA number 1205) and the aggregate production quota for 2016 in the United States is 29,750 kilograms of acid or anhydrous base. Lisdexamfetamine is currently in Phase III trials in Japan for ADHD.
Video Lisdexamfetamine
Usage
Medical
Lisdexamfetamine is used primarily as a treatment for attention deficit hyperactivity disorder (ADHD) and eating disorders; it has the use of off-label similar to that of other pharmaceutical amphetamines. Individuals over 65 are unusually tested in the lisdexamfetamine clinical trial for ADHD. Long-term exposure to high doses of amphetamines in some animal species is known to result in the development of abnormal dopamine systems or nerve damage, but in humans with ADHD, pharmaceutical amphetamines appear to promote brain development and neuronal growth. Magnetic resonance imaging research (MRI) reviews indicate that long-term treatment with amphetamines reduces abnormalities in brain structures and function found in subjects with ADHD, and improves function in some parts of the brain, such as the right caudate nucleus of the basal ganglia.
Research reviews of clinical stimulants have established the safety and effectiveness of long-term sustained use of amphetamines for the treatment of ADHD. Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD covering 2 years have demonstrated the effectiveness and safety of treatment. Two reviews have shown that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (ie, hyperactivity, poor attention, and impulsivity), improving quality of life and academic achievement, and resulting in improvements in a large number of functional outcomes in 9 outcome categories related to academics, antisocial behavior, driving, non-drug use, obesity, employment, self-esteem, use of services (ie, academic, occupational, health, financial, and legal services), and social functions. One review highlights nine months of randomized controlled trials of amphetamine treatment for ADHD in children who found an average increase in IQ points of 4.5, a continuous increase in attention, and a steady decline in disruptive and hyperactive behaviors. Other reviews indicate that, based on the longest follow-up study conducted to date, lifelong stimulation therapy initiated during childhood continues to be effective in controlling the symptoms of ADHD and reducing the risk of developing substance use disorders as adults.
Current ADHD models suggest that this is associated with functional impairment in some brain neurotransmitter systems; this functional impairment involves the interruption of dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projection of the coeruleus locus to the prefrontal cortex. Psychostimulants such as methylphenidate and amphetamine are effective in treating ADHD because they increase the activity of neurotransmitters in this system. About 80% of those using this stimulant see improvement in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better at school, are less distracted and impulsive, and have longer attention spans. The Cochrane Collaboration review on ADHD treatment in children, adolescents, and adults with pharmaceutical amphetamines states that while these drugs improve short-term symptoms, they have higher rates of discontinuation than non-stimulant drugs because of adverse side effects. A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders such as Tourette syndrome suggests that generalized stimulants do not make tics worse, but high doses of dextroamphetamine may exacerbate tics in some individuals.
Improved performance
Cognitive performance
In 2015, a systematic review and high quality meta-analysis of clinical trials found that, when used at low doses (therapeutic), amphetamines resulted in simple but unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and several aspects attention, in normal healthy adults; this cognitive enhancement effect of amphetamines is known to be partially mediated through the indirect activation of both dopamine receptors D 1 and adrenoceptors? 2 in the prefrontal cortex. A systematic review of 2014 found that low doses of amphetamines also increased memory consolidation, which in turn led to increased memory of information. Therapeutic doses of amphetamine also increase the efficiency of cortical tissue, an effect that mediates improvement in working memory in all individuals. Amphetamine and other ADHD stimulants also enhance the meaning of the task (motivation to perform the task) and increase the passion (wake), in turn promoting the behavior directed towards the goal. Stimulants such as amphetamines can improve performance on difficult and tedious tasks and are used by some students as a study and test aid. Based on a self-reported study of self-reported stimulants, 5-35% students use a transferable ADHD stimulant, primarily used for performance improvement rather than recreational drugs. However, high doses of amphetamines above the therapeutic range may interfere with memory work and other aspects of cognitive control.
Physical performance
Amphetamines are used by some athletes for the effect of improving psychological and athletic performance, such as increased endurance and alertness; however, the use of non-medical amphetamines is prohibited at sporting events organized by college, national, and international anti-doping agencies. In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance under anaerobic conditions, and endurance (ie, delay onset of fatigue), while increasing reaction time. Amphetamine increases endurance and reaction time primarily through reuptake inhibition and smoothing of dopamine in the central nervous system. Amphetamines and other dopaminergic drugs also increase the power output at a steady level of perceived power by ignoring the "safety switch" which allows the increased core temperature limit to access the normally forbidden reserve capacity. In therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; however, at much higher doses, amphetamines can cause devastating effects on performance, such as rapid muscle breakdown and increased body temperature.
Maps Lisdexamfetamine
Contraindications
Pharmaceutical lisdexamfetamine dimesylate is contraindicated in patients with hypersensitivity to amphetamine products or one of the inactive formulations ingredients. It is also contraindicated in patients who have used monoamine oxidase inhibitors (MAOI) in the last 14 days. Amphetamine products are contraindicated by the US 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. The USFDA advises anyone with bipolar disorder, depression, high blood pressure, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette's syndrome to monitor their symptoms while taking amphetamines. Amphetamines are classified into the category of US C pregnancies. This means that fetal damage has been observed in animal studies and inadequate human studies have not been done; amphetamines may still be prescribed for pregnant women if their potential benefits outweigh the risks. Amphetamine has also been shown to pass to breast milk, so the USFDA advises mothers to avoid breastfeeding when using it. Because of potential stunted growth, the USFDA recommends high monitoring and weighting of children and adolescents who are prescribed amphetamines. Providing information that is approved by the Australian Therapeutic Goods Administration further contraindicated anorexia.
Side effects
Products containing lisdexamfetamine have a side-effect profile comparable to that containing amphetamine.
Physical
At normal therapeutic doses, the physical side effects of amphetamines vary greatly by age and from person to person. Cardiovascular side effects may include hypertension or hypotension of the vasovagal response, Raynaud's phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate). Sexual side effects in men may include erectile dysfunction, frequent erections, or prolonged erections. Abdominal side effects may include abdominal pain, loss of appetite, nausea, and weight loss. Other potential side effects include blurred vision, dry mouth, excessive teeth grinding, nosebleeds, sweating, medicamentous rhinitis (drug-induced nasal congestion), reduced seizure threshold, and tics (a movement disorder). Hazardous physical side effects are rare in certain pharmaceutical doses.
Amphetamine stimulates the medullary respiratory center, producing faster and deeper breathing. In normal people with therapeutic doses, these effects are usually not seen, but when respiration is compromised, it may be proven. Amphetamine also induces contractions in the bladder sphincter, the muscle that controls the urine, which can cause difficulty urinating. This effect can be useful in treating bedwetting and loss of bladder control. The effects of amphetamines on the gastrointestinal tract are unpredictable. If intestinal activity, amphetamines can reduce gastrointestinal motility (the rate at which the content moves through the digestive system); However, amphetamines can increase motility when smooth muscle of the channel is relaxed. Amphetamine also has little analgesic effect and can increase the opioid pain-relieving effect.
USFDA-assigned studies from 2011 show that in children, young adults, and adults there is no association between serious serious cardiovascular events (sudden death, heart attack, and stroke) and medical use of amphetamines or other ADHD stimulants. However, amphetamine drugs are contraindicated in individuals with cardiovascular disease.
Psychological
In normal therapeutic doses, the most common psychological side effects of amphetamines include increased alertness, fear, concentration, initiative, self-confidence, and socialization, mood swings (joyful mood followed by a slightly depressed mood), insomnia or awake, and decreased fatigue. Less common side effects include anxiety, libido changes, grandiosity, irritability, repetitive or obsessive behavior, and anxiety; this effect depends on the user's personality and current mental state. Amphetamine psychosis (eg, delusions and paranoia) can occur in heavy users. Although very rare, this psychosis can also occur in therapeutic doses during long-term therapy. According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive or hostile behavior.
Amphetamine has also been shown to result in conditioned place preference in humans using therapeutic doses, which means that individuals get a preference for spending time in places where they have previously used amphetamine.
Overdose
Overdose amphetamine can cause many different symptoms, but is rarely fatal with proper care. The severity of overdose symptoms increases with the dose and decreases with drug tolerance to amphetamines. Individuals who are tolerant have been known to consume as much as 5 grams of amphetamine in a day, which is about 100 times greater than daily therapeutic doses. The symptoms of moderate and very large overdoses are listed below; Fatal amphibamin poisoning usually also involves seizures and coma. In 2013, overdose in amphetamines, methamphetamines, and other compounds involved in "amphetamine use disorders" resulted in about 3,788 deaths worldwide ( 3,425-4,145 deaths, 95% confidence).
Pathological overactivation of the mesolimbic pathway, the dopamine pathway connecting the ventral ventral region to the nucleus accumbens, plays a central role in amphetamine addiction. Individuals who frequently overdose on amphetamines during recreational use have a high risk of developing amphetamine addiction, since recurrent overdose gradually increases the accumbal rate? FosB, a "molecular switch" and "master master protein" for addiction. After the nucleus accumbens? FosB is quite expressed, it begins to increase the severity of addictive behavior (ie, looking for compulsive drugs) with a further increase in its expression. While there is currently no effective cure for treating amphetamine addiction, regularly engaging in sustainable aerobic exercise seems to reduce the risk of developing such addiction. Regular aerobic exercise regularly also appears to be an effective treatment for amphetamine addiction; exercise therapy improves clinical treatment outcomes and can be used as a combination therapy with cognitive behavioral therapy, which is currently the best available clinical care.
Dependency
Addiction is a serious risk with the use of severe recreational amphetamines but may not arise from typical long-term medical use at therapeutic doses. Compared to other amphetamine drugs, lisdexamfetamine may have lesser responsibility for abuse as a recreational drug. Drug tolerance is growing rapidly in the misuse of amphetamine (ie, recreational amphetamine overdoses), so extended periods of use require larger doses of the drug to achieve the same effect.
Biomolecular mechanism
The use of chronic amphetamine in excessive doses leads to alteration of gene expression in the mesocorticolimbic projection, which appears through transcriptional and epigenetic mechanisms. The most important transcription factor that produces this change is? FosB, cAMP element binding protein (CREB), and nuclear factor kappa B (NF-? B). Fosb is the most important biomolecular mechanism in addiction because Fosb's overexpression in middle-spaced neurons of type D1 in the accumbens nucleus is necessary and sufficient for many nerve adaptations and behavioral effects (eg, increased expression dependent on self-administration and reward sensitization drugs) seen in drug addiction. Once? FosB is sufficiently expressed, it induces an addictive state that gets progressively worse with a further increase in the FosB expression. It has been implicated in alcoholism, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and amphetamine substitutions, among others.
? JunD, transcription factors, and G9a, the histone methyltransferase enzyme, both opposed to Fosb's function and inhibited the increase in expression. Simply over-expressed? JunD in nucleus accumbens with viral vectors can actually block many of the nerve changes and behaviors seen in chronic drug abuse (ie, changes mediated by? FosB). Fosb also plays an important role in regulating behavioral responses to natural rewards, such as good food, sex, and exercise. Because both natural rewards and addictive drugs induce expression? FosB (that is, they cause the brain to produce more), this chronic appreciation can result in the same pathological state of addiction. Consequently, Fosb is the most significant factor involved in amphetamine-induced and amphetamine-induced sex addiction, which is compulsive sexual behavior resulting from excessive sexual activity and amphetamine use. This sex addiction is associated with dopamine dysregulation syndrome that occurs in some patients taking dopaminergic drugs.
The effects of amphetamine on gene regulation are both dose-dependent and route-dependent. Most studies of gene regulation and addiction are based on animal studies with intravenous administration of amphetamines at very high doses. Several studies that have used the equivalent dose of human therapy (adjusted weight) and oral administration suggest that these changes, if they occur, are relatively small. This suggests that the medical use of amphetamines does not significantly affect gene regulation.
Pharmacological treatments
In 2015, there is no effective pharmacotherapy for amphetamine addiction. Reviews from 2015 and 2016 show that TAAR1 selective agonists have significant therapeutic potential as a treatment for psychostimulary addiction; however, in February 2016, the only compound known to function as a TAAR1 selective agonist was an experimental drug. Amphetamine addiction is largely mediated through increased activation of dopamine receptors and NMDA co-localization receptors NMDA in nucleus accumbens; magnesium ions inhibit NMDA receptors by blocking the calcium channel of the receptor. One review suggested that, based on animal testing, the use of pathological psychostimulants (which trigger addiction) significantly reduces the level of intracellular magnesium throughout the brain. Additional magnesium treatment has been shown to reduce amphetamine self-administration (ie, self-administered dose) in humans, but it is not an effective monotherapy for amphetamine addiction.
Treatment behavior
Current cognitive behavioral therapy is the most effective clinical treatment for psychostimulary addiction. In addition, research on the neurobiological effects of physical exercise shows that daily aerobic exercise, especially endurance exercises (eg, marathon run), prevents the development of drug addiction and is an effective additional therapy (ie, additional treatment) for amphetamine addiction. Exercise leads to better treatment outcomes when used as an adjunct treatment, especially for psychostimulant addiction. Specifically, aerobic exercise decreases the administration of psychostimulant self-administration, reduces recovery (ie, relapsing) of drug-seeking, and induces increased dopamine receptor D 2 (DRD2) density in the striatum. This is the opposite of the use of pathological stimulation, which induces decreased striatal DRD2 density. One review noted that exercise can also prevent the development of drug addiction by altering the immunoreactivity of FosB or c-Fos in the striatum or other parts of the reward system.
Dependence and tethering
According to other Cochrane Collaboration reviews about withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users suddenly discontinue amphetamine use, many reports of limited-time withdrawal syndrome occur within 24 hours of their last dose." This review notes that withdrawal symptoms in chronic high-dose users is common, occurs in about 88% of cases, and persists for 3-4 weeks with the "stuck" phase marked during the first week. Symptoms of withdrawal of amphetamines may include anxiety, drug cravings, depression, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or drowsiness, and lucid dreams. This review shows that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence. Symptoms of mild withdrawal from cessation of amphetamine treatment at therapeutic doses can be avoided by reducing the dose.
Toxicity
In rodents and primates, high doses of amphetamines cause dopaminergic neurotoxicity, or damage to dopamine neurons, characterized by terminal dopamine degeneration and reduced transporter and receptor function. There is no evidence that amphetamines are directly neurotoxic in humans. However, large doses of amphetamines indirectly can cause dopaminergic neurotoxicity as a result of hyperpyrexia, excessive reactive oxygen species formation, and increased dopamine autoxidation. Animal models of neurotoxicity from high doses of amphetamine exposure suggest that the occurrence of hyperpyrexia (ie, core body temperature> = Ã, 40Ã,  ° C) is required for the development of amphetamine-induced neurotoxicity. A rise in brain temperature over 40Ã, ° C probably promotes the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting the function of cellular proteins, and temporarily increasing the permeability of blood brain barrier.
Psychosis
Severe amphetamine overdose can cause stimulatory psychosis that may involve multiple symptoms, such as delusions and paranoia. A Cochrane Collaboration review on treatment for amphetamines, dextroamphetamine, and methamphetamine psychosis states that about 5-15% users fail to recover completely. According to the same review, there is at least one trial that suggests an effective antipsychotic drug resolves the symptoms of acute amphetamine psychosis. Psychosis very rarely arises from therapeutic use.
Interactions
- Acidifying agents: Urinary acidic drugs, such as ascorbic acid, increase urinary dextroamphetamine excretion, thereby reducing dextroamphetamine half-life in the body.
- Alkalinizing Substances: Drugs that anesthetize urine, such as sodium bicarbonate, decrease urinary dextroamphetamine excretion, thereby increasing dextroamphetamine half-life in the body.
- Oxidase Monoamine Inhibitors: Use of MAOI and central nervous system stimulants such as lisdexamfetamine can cause hypertensive crises.
Pharmacology
Action mechanism
Lisdexamfetamine is an inactive altered prodrug in the body to dextroamphetamine, the pharmacologically active compound responsible for drug activity. After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L -sysine, a natural essential amino acid, and dextroamphetamine. The conversion of lisdexamfetamine to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by changes in normal gastrointestinal transit times.
Optical isomers of amphetamines, ie dextroamphetamine and levoamphetamine, are TAAR1 agonists and inhibitors of vesicular monoamine transporters 2 that can enter monoamine neurons; this allows them to release the monoamine neurotransmitters (dopamine, norepinephrine, and serotonin, among others) from their containers in presinaptic neurons, as well as prevent the reuptake of these neurotransmitters from the synaptic cleft.
Lisdexamfetamine was developed with the aim of providing consistent duration of effects throughout the day, with a low potential for abuse. The attachment of the lysine amino acid slows the relative amount of dextroamphetamine available for blood flow. Since there is no free dextroamphetamine in the lisdexamfetamine capsule, dextroamphetamine is not available through mechanical manipulation, such as crushing or simple extraction. A sophisticated biochemical process is needed to produce dextroamphetamine from lisdexamfetamine. In contrast to Adderall, which contains nearly equal parts of rasemic amphetamine and dextroamphetamine salts, lisdexamfetamine is a single enantiomer dextroamphetamine formula. Studies have shown that lisdexamfetamine dimesylate may have less abuse potential than dextroamphetamine and a profile of abuse similar to diethylpropion at FDA-approved doses for ADHD treatment, but still has a high potential for abuse when this dose is exceeded by more than 100%.
Pharmacokinetics
Oral amphetamine oral bioavailability varies with gastrointestinal pH; it is well absorbed from the intestine, and bioavailability is usually over 75% for dextroamphetamine. Amphetamine is a weak base with p K a 9.9; consequently, when the pH is basic, more drugs are in the lipid-soluble base form, and are more absorbed through the lipid-rich cell membrane of the intestinal epithelium. In contrast, acidic pH means the drug is mainly in the form of cationic (salt) that is soluble in water, and less absorbed. About 15-40% of amphetamines circulating in the bloodstream are bound by plasma proteins. After absorption, amphetamines are readily distributed to most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.
The half-life of amphetamine enantiomers is different and varies with urinary pH. At normal urinary pH, half of dextroamphetamine and levoamphetamine life respectively 9-11 and clock 11-14 . Extremely acidic urine will reduce the half-life of the enantiomers up to 7 hours; Highly alkaline urine will increase the half-life to 34 hours. The release of direct and extended releases of salts from both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively. Amphetamines are removed through the kidney, with <30% -40% of the excreted drug unchanged at normal urine pH. When the basic urine pH, amphetamine is in its free base form, so less is excreted. When the urine pH is abnormal, urinary recovery of amphetamines can range from a low of 1% to a high of 75%, depending on whether the urine is too basic or acidic, respectively. After oral administration, amphetamines appear in the urine within 3 hours. About 90% of the digestible amphetamines are removed 3 days after the last oral dose
The prodrug lisdexamfetamine is not sensitive to pH as amphetamine when it is absorbed in the gastrointestinal tract; after absorption into the bloodstream, it is altered by enzymes associated with red blood cells to dextroamphetamine through hydrolysis. The elimination half-life of lisdexamfetamine is generally less than 1 hour.
CYP2D6, dopamine? -hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butat-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are enzymes known to metabolize their amphetamines or metabolites in humans. Amphetamines have a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hypuratic acid and norephedrine. , and phenylacetone. Among these metabolites, active sympathomimetics are 4-hydroxyamphetamine , 4-hydroxynorephedrine , and norephedrine. The main metabolic pathway involves aromatic hydroxylation, aliphatic alpha and beta hydroxylation, N-oxidation, N-dealkylation, and deamination. Known metabolic pathways, detectable metabolites, and human metabolic enzymes include the following:
Chemistry
Lisdexamfetamine dimesylate is a water-soluble powder (792 mg/mL) with white to off-white color.
Comparison with other formulas
Lisdexamfetamine dimesylate is one of the marketed formulations that produces dextroamphetamine. The following table compares this drug with other amphetamine drugs.
History, society and culture
Lisdexamfetamine was developed by New River Pharmaceuticals, purchased by Shire Pharmaceuticals shortly before lisdexamfetamine began to be marketed. It was developed for the purpose of creating a more durable and less abusive version of dextroamphetamine, since the need for conversion to dextroamphetamine via enzymes in red blood cells delayed its onset of action, regardless of the consumption route.
On April 23, 2008, Vyvanse received FDA approval for the adult population. On February 19, 2009, Health Canada approved 30 mg and 50 mg lisdexametamine capsules for the treatment of ADHD.
In January 2015, lisdexamfetamine was approved by the US Food and Drug Administration for the treatment of eating disorders in adults.
Brand name
In July 2014 lisdexamfetamine was sold under the following brands: Elvanse, Samexid, Tyvense, Venvanse, and Vyvanse.
Research
Depression
Several clinical trials using lisdexametamine as adjunctive therapy with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) for treatment-resistant depression suggest that this is no more effective than SSRI or SNRI use. alone. Other studies have shown that psychostimulants potentiate antidepressants, and are less prescribed for drug-resistant depression. In the study, patients showed significant improvement in energy activity, mood, and psychomotor. In February 2014, Shire announced that two end-stage clinical trials have shown that Vyvanse is not an effective treatment for depression.
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Reference notes
References
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