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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 agonists |
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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 a histamine 3 (H3) receptor antagonist/inverse agonist (an antihistamine drug specific to that kind of receptors). [3] It represents the first commercially available medication in its class, so that the US 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, and dyspepsia (heartburn). [4] Rare but serious side effects are abnormal loss of weight 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]
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 US 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]
Modafinil, sold under the brand name Provigil among others, is a wakefulness-promoting medication used primarily to treat narcolepsy. 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 age 17.
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, and modafinil.
Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a potent 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, commonly ranging from 2-4 hours. For ADHD, the effectiveness of methylphenidate is comparable to atomoxetine but modestly lower than amphetamines.
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.
Histamine H3 receptors are expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons and control histamine turnover by feedback inhibition of histamine synthesis and release. The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin.
Viloxazine, sold under the brand name Qelbree and formerly as Vivalan 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.
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 affects approximately 20% of people who have narcolepsy, and is 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.
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 involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. Narcolepsy paired with cataplexy is evidenced to be an autoimmune disorder. These experiences of cataplexy can be brought on by strong emotions. Less commonly, there may be vivid hallucinations or an inability to move while falling asleep or waking up. People with narcolepsy tend to sleep about the same number of hours per day as people without it, but the quality of sleep tends to be lessened.
GSK-189,254 is a potent and selective H3 histamine receptor inverse agonist developed by GlaxoSmithKline. It has subnanomolar affinity for the H3 receptor (Ki = 0.2nM) and selectivity of over 10,000x for H3 over other histamine receptor subtypes. Animal studies have shown it to possess not only stimulant and nootropic effects, but also analgesic action suggesting a role for H3 receptors in pain processing in the spinal cord. GSK-189,254 and several other related drugs are currently being investigated as a treatment for Alzheimer's disease and other forms of dementia, as well as possible use in the treatment of conditions such as narcolepsy, or neuropathic pain which do not respond well to conventional analgesic drugs.
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.
Jean-Charles Schwartz, born on May 28, 1936, in Paris, is a French neurobiologist, pharmacist and researcher. Husband of Ketty Schwartz, née Gersen (1937–2007) and father of Olivier, Marc and Emmanuelle. He is a member of the Academy of Sciences. He developed pitolisant, the first clinically approved antagonist for H3 receptors.
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.
Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant 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.