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Pronunciation | /pɪˈtɒlɪsənt/ pi-TOL-i-sənt |
Trade names | Wakix, Ozawade |
Other names | Tiprolisant; Ciproxidine; BF2.649 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a619055 |
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Routes of administration | By mouth |
Drug class | Histamine H3 receptor inverse agonist |
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Elimination half-life | 10–12 hours |
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Chemical and physical data | |
Formula | C17H26ClNO |
Molar mass | 295.85 g·mol−1 |
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Pitolisant, sold under the brand name Wakix among others, is a medication used for the treatment of excessive daytime sleepiness in adults with narcolepsy. [3] It is an inverse agonist of the histamine 3 (H3) receptor (an antihistamine drug specific to that kind of receptors). [3] It represents the first commercially available medication in its class, so that the U.S. Food and Drug Administration (FDA) declares it a first-in-class medication. [7] [8] Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness. [9] It was approved by the European Medicines Agency (EMA) in March 2016 for narcolepsy with or without cataplexy, and for excessive daytime sleepiness by the FDA in August 2019. [10] The most common side effects include difficulty sleeping, nausea, and feeling worried. [11]
Pitolisant is indicated in adults for the treatment of narcolepsy. [3] [4] Narcolepsy is a chronic sleep disorder that causes overwhelming daytime drowsiness. [4] Pitolisant is also indicated to improve alertness and reduce excessive daytime sleepiness in adults with obstructive sleep apnea. [5]
The most common side effects include insomnia, headache, nausea, anxiety, irritability, dizziness, depression, tremor, sleep disorders, tiredness, vomiting, vertigo, dyspepsia, and heartburn. [4] Rare but serious side effects are abnormal weight loss and spontaneous abortion. [4]
Pitolisant is an inverse agonist of the histamine 3 (H3) autoreceptor. The H3 autoreceptors regulate histaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting histamine synthesis and release upon binding to endogenous histamine. [12] By preventing the binding of endogenous histamine at the H3, as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain. [13]
Pitolisant is a drug that belongs to the class of CNS stimulants. [14] [15] [16] [17] Pitolisant is also considered a medication of class "eugeroic", which means that it promotes wakefulness and alertness. Eugeroics are different from traditional CNS stimulants such as amphetamine in that they have fewer side effects and lower abuse potential. Pitolisant is the first eugeroic drug that acts by blocking the histamine 3 (H3) autoreceptor, which increases the activity of histamine neurons in the brain. Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy. [18] [19] [20]
Pharmacokinetics
Pitolisant is readily absorbed when taken by mouth and reaches peak blood concentrations approximately 3 hours after administration. The biological half-life of Pitolisant ranges from 10 to 12 hours. [13]
Pitolisant is marketed in the European Union by Bioprojet Pharma. [4] It was approved for medical use in the European Union in March 2016 by the European Medicines Agency (EMA). [10] [4]
The U.S. Food and Drug Administration (FDA) approved pitolisant for excessive daytime sleepiness in participants with narcolepsy based primarily on evidence from two trials (Trial 1/NCT01067222, Trial 2/NCT01638403). [11] An additional trial (Trial 3/NCT01800045), in which participants with a different type of narcolepsy were exposed to the same dose of pitolisant, was used to add data for evaluation of side effects. [11] The trials were conducted in Europe and South America. [11]
The two primary trials enrolled adults with narcolepsy and excessive daytime sleepiness. [11] Participants received pitolisant, placebo, or an approved drug for narcolepsy for eight weeks. [11] For participants receiving pitolisant, the dose could be increased during the first three weeks but had to remain the same for the next five weeks. [11] Neither the participants nor the healthcare providers knew which treatment was being given during the trial. [11]
The benefit of pitolisant was evaluated by comparing changes in daytime sleepiness during the trial between pitolisant- and placebo-treated participants. [11] To measure the daytime sleepiness, the investigators used a scale called the Epworth Sleepiness Scale (ESS). [11] The ESS asks participants to rate the likelihood that they would fall asleep while doing eight daily activities (such as sitting and reading or watching television). [11] Participants rate each item from zero (would never doze) to three (high chance of dozing). [11]
Pitolisant was approved by the FDA in August 2019. [10] [11] It was granted orphan drug designation for the treatment of narcolepsy, [21] fast track designation for the treatment of excessive daytime sleepiness and cataplexy in people with narcolepsy, and breakthrough therapy designation for the treatment of cataplexy in people with narcolepsy. [22]
Pitolisant is approved in the European Union and the United States to treat narcolepsy, and is not a controlled substance in these countries.[ failed verification ] Still, long-term studies comparing the effectiveness and tolerability of pitolisant with modafinil or sodium oxybate are lacking.[ failed verification ] Pitolisant, the only non-controlled anti-narcoleptic drug in the US, [20] has shown minimal abuse risk in studies. [20] [23]
Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.
Modafinil, sold under the brand name Provigil among others, is a wakefulness-promoting medication used primarily to treat narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and sudden sleep attacks. Modafinil is also approved for stimulating wakefulness in people with sleep apnea and shift work sleep disorder. It is taken by mouth. Modafinil is not approved by the US Food and Drug Administration (FDA) for use in people under 17 years old.
Stimulants are a class of drugs that increase the activity of the brain. They are used for various purposes, such as enhancing alertness, attention, motivation, cognition, mood, and physical performance. Some of the most common stimulants are caffeine, nicotine, amphetamines, cocaine, methylphenidate, and modafinil.
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a primary medication for ADHD ; it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect. For ADHD, the effectiveness of methylphenidate is comparable to atomoxetine but modestly lower than amphetamines, alleviating the executive functioning deficits of sustained attention, inhibition, working memory, reaction time and emotional self-regulation.
Dextroamphetamine (INN:dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Dextroamphetamine reduces the negative symptoms of schizophrenia, and has been shown to enhance the effects of auditory discrimination training. Prescribed dextroamphetamine has also been shown to reduce rates of hospitalisation in patients with schizophrenia, although repeated, elevated doses can provoke psychosis. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine is generally regarded as the prototypical stimulant.
Adderall and Mydayis are trade names for a combination drug containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.
A microsleep is a sudden temporary episode of sleep or drowsiness which may last for a few seconds where an individual fails to respond to some arbitrary sensory input and becomes unconscious. Episodes of microsleep occur when an individual loses and regains awareness after a brief lapse in consciousness, often without warning, or when there are sudden shifts between states of wakefulness and sleep. In behavioural terms, MSs may manifest as droopy eyes, slow eyelid-closure, and head nodding. In electrical terms, microsleeps are often classified as a shift in electroencephalography (EEG) during which 4–7 Hz activity replaces the waking 8–13 Hz background rhythm.
Viloxazine, sold under the brand name Qelbree among others, is a selective norepinephrine reuptake inhibitor medication which is used in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. It was marketed for almost 30 years as an antidepressant for the treatment of depression before being discontinued and subsequently repurposed as a treatment for ADHD. Viloxazine is taken orally. It was used as an antidepressant in an immediate-release form and is used in ADHD in an extended-release form, latterly with comparable effectiveness to atomoxetine and methylphenidate.
Cataplexy is a sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror. Cataplexy is the first symptom to appear in about 10% of cases of narcolepsy, caused by an autoimmune destruction of hypothalamic neurons that produce the neuropeptide hypocretin, which regulates arousal and has a role in stabilization of the transition between wake and sleep states. Cataplexy without narcolepsy is rare and the cause is unknown.
Sodium oxybate, sold under the brand name Xyrem among others, is a medication used to treat symptoms of narcolepsy: sudden muscle weakness and excessive daytime sleepiness. It is used sometimes in France and Italy as an anesthetic given intravenously; it is also approved and used in Italy and in Austria to treat alcohol dependence and alcohol withdrawal syndrome.
Armodafinil (trade name Nuvigil) is the enantiopure compound of the eugeroic modafinil (Provigil). It consists of only the (R)-(−)-enantiomer of the racemic modafinil. Armodafinil is produced by the pharmaceutical company Cephalon Inc. and was approved by the U.S. Food and Drug Administration (FDA) in June 2007. In 2016, the FDA granted Mylan rights for the first generic version of Cephalon's Nuvigil to be marketed in the U.S.
Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours.
Ciproxifan is an extremely potent histamine H3 inverse agonist/antagonist.
An H3 receptor antagonist is a type of antihistaminic drug used to block the action of histamine at H3 receptors.
Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM sleep. The pentad symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep related hallucinations, sleep paralysis, disturbed nocturnal sleep (DNS) and cataplexy. There are two recognized forms of narcolepsy, narcolepsy type 1 and type 2. Narcolepsy type 1 (NT1) can be clinically characterized by symptoms of EDS and cataplexy, and/or will have CSF orexin levels of less than 110 pg/ml. Cataplexy are transient episodes of aberrant tone, most typically loss of tone, that can be associated with strong emotion. In pediatric onset narcolepsy, active motor phenomena are not uncommon. Cataplexy may be mistaken for syncope, tic disorder or seizures. Narcolepsy type 2 (NT2) does not have features of cataplexy and CSF orexin levels are normal. Sleep related hallucinations, also known as hypnogogic and hypnopompic are vivid hallucinations that can be auditory, visual or tactile and may occur independent of or in combination with an inability to move. People with narcolepsy tend to sleep about the same number of hours per day as people without it, but the quality of sleep is typically compromised. Narcolepsy is a clinical syndrome of hypothalamic disorder, but the exact cause of narcolepsy is unknown, with potentially several causes. A leading consideration for the cause of narcolepsy type 1 is that it is an autoimmune disorder. Proposed pathophysiology as an autoimmune disease suggest antigen presentation by DQ0602 to specific CD4+ T cells resulting in CD8+ T-cell activation and consequent injury to orexin producing neurons. Familial trends of narcolepsy are suggested to be higher than previously appreciated. Familial risk of narcolepsy among first degree relatives is high. Relative risk for narcolepsy in a first degree relative has been reported to be 361.8. However, it is important to note that there is a spectrum of symptoms found in this study, including asymptomatic abnormal sleep test findings to significantly symptomatic.
Eugeroics, also known as wakefulness-promoting agents and wakefulness-promoting drugs, are a class of drugs that promote wakefulness and alertness. They are medically indicated for the treatment of certain sleep disorders including excessive daytime sleepiness (EDS) in narcolepsy or obstructive sleep apnea (OSA). Eugeroics are also often prescribed off-label for the treatment of EDS in idiopathic hypersomnia. In contrast to classical psychostimulants, such as methylphenidate and amphetamine, which are also used in the treatment of these disorders, eugeroics typically do not produce marked euphoria, and, consequently, have a lower addictive potential.
Idiopathic hypersomnia(IH) is a neurological disorder which is characterized primarily by excessive sleep and excessive daytime sleepiness (EDS). Idiopathic hypersomnia was first described by Bedrich Roth in 1976, and it can be divided into two forms: polysymptomatic and monosymptomatic. The condition typically becomes evident in early adulthood and most patients diagnosed with IH will have had the disorder for many years prior to their diagnosis. As of August 2021, an FDA-approved medication exists for IH called Xywav, which is oral solution of calcium, magnesium, potassium, and sodium oxybates; in addition to several off-label treatments (primarily FDA-approved narcolepsy medications).
Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults. Suvorexant helps with falling asleep faster, sleeping longer, being awake less in the middle of the night, and having better quality of sleep. Its effectiveness is modest, and is similar to that of other orexin antagonists, but is lower than that of benzodiazepines and Z-drugs. Suvorexant is taken by mouth.
Solriamfetol, sold under the brand name Sunosi, is a wakefulness-promoting medication used in the treatment of excessive sleepiness related to narcolepsy and sleep apnea. It is taken by mouth.
Xywav is a medication used to treat cataplexy or excessive daytime sleepiness. It contains a mixture of the oxybate salts calcium oxybate, magnesium oxybate, potassium oxybate, and sodium oxybate. It is a central nervous system (CNS) depressant and it is taken by mouth.