Modafinil , sold under the trademark Provigil among others, is an awareness-raising drug used for the treatment of disorders such as narcolepsy, sleep-shift dysfunction, idiopathic hypersomnia, and excessive sleepiness daytime is associated with obstructive sleep apnea. It has also seen widespread use of off-label as a recognized cognitive enhancer. In the United States modified modafinil as IV controlled substances and limited in availability and use, due to concerns about the possibility of potential addiction. In most other countries it is prescription drugs but not legally restricted.
Modafinil acts as an atypical, selective, and weak dopamine reuptake inhibitor that indirectly activates the release of orexin neuropeptide and histamine from the lateral hypothalamus and tuberomammary nucleus, respectively, by unknown mechanisms, all of which contribute to increased arousal.
Video Modafinil
Usage
Medical
Modafinil is an eugeroic used for the treatment of narcolepsy, sleep shift work disturbances, and excessive daytime sleepiness associated with obstructive sleep apnea.
Due to the risk of skin development or serious adverse psychiatric reactions and psychiatric reactions, the European Medicines Agency has recommended that new patient prescriptions should be only to treat drowsiness associated with narcolepsy.
Occupation ok
Armed forces from several countries are known to have expressed interest in modafinil as an alternative to amphetamines - drugs traditionally used in combat situations or long missions in which troops face sleep deprivation. The French government indicated that the Foreign Legion used modafinil during certain covert operations. The British Ministry of Defense commissioned a study of the modafinil of QinetiQ and spent $ 300,000 on an investigation. In 2011, the Indian Air Force announced that modafinil was included in the contingency plan.
In the United States military, modafinil has been approved for use on certain Air Force missions, and is being investigated for other uses. Until November 2012, modafinil is the only drug approved by the Air Force as a "go pill" for fatigue management. The use of dextroamphetamine is no longer approved.
The Canadian Medical Association Journal also reports that modafinil is used by astronauts for long-term missions over the International Space Station. Modafinil is "available for crew to optimize performance when tired" and helps with disruption in circadian rhythms and by reducing the quality of sleep astronaut experience.
Maps Modafinil
Contraindications
Allergies and hypersensitivity are the only contraindications of the drug, but the literature distributed by Cephalon suggests that it is important to consult a physician before using it, as problems may arise for people who are sensitive to constituent tablets, people with cirrhosis (which may damage drug metabolism), and people with various cardiovascular problems.
Adverse effects
According to the documentation distributed by Teva Pharmaceuticals, one-third of participants in clinical trials reported experiencing headaches; 11% reported nausea; Other negative side effects such as nervousness, diarrhea, insomnia, anxiety, dizziness, and gastrointestinal problems are reported by fewer than 10% of participants.
Rare events have been reported to have more serious side effects, including severe skin rashes and other symptoms that may be associated with allergies. From the start date of marketing, December 1998, to January 30, 2007, the US Food and Drug Administration received six cases of severe cutaneous side effects associated with modafinil, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), epidermal toxicity necrolysis (TEN), and DRESS syndrome, involving adult patients and children. The FDA issues a relevant warning. In the same warning, the FDA also notes that angioedema and multi-organ hypersensitivity reactions have also been reported in post-marketing experience. In 2007, the FDA ordered Cephalon to modify Provigil leaflets with bold prints of some serious and potentially fatal conditions associated with the use of modafinil, including TEN, DRESS syndrome, and SJS.
Long-term safety and effectiveness of modafinil has not been determined.
Modafinil may have adverse effects on hormonal contraceptives up to one month after discontinuation.
Dependency and potential dependency
Dependence and dependence of modafinil dependence is very low. It shares a biochemical mechanism with addictive stimulant drugs, and several studies have reported it to have similar properties of mood enhancement, albeit to a lesser extent. Monkeys will self-regulate modafinil if they have previously been trained to manage cocaine themselves. Although modafinil does not produce a reinforcing effect in mice at a dose equivalent to that used therapeutically in humans, it does so at higher doses. Appropriate, although very rare, reports of cases of modafinil abuse exist. Thus, modafinil is classified by the US FDA as a controlled substance of schedule IV, a category for drugs with valid medical use and a low but significant addiction potential.
Psychological dependence on modafinil is only recorded in case reports involving daily overdose in modafinil for long periods of time. The reported withdrawal symptoms include anhedonia, lethargy, anxiety, and insomnia.
Tolerance
Large-scale clinical studies found no evidence of tolerance with modafinil at therapeutic doses even with long-term use (for 40 weeks and for three years).
Psychiatric reactions
Psychiatric reactions related to modafinil have occurred to those with and without pre-existing psychiatric history.
Overdose
In mice and rats, the median lethal dose (LD 50 ) of modafinil is approximately or slightly greater than 1250 mg/kg. The reported ORD 50 values ​​for mice ranged from 1000-3400Ã,Âμg/kg. LD intravenously 50 for dogs is 300 mg/kg. Clinical trials in humans involving taking up to 1200 mg/day for 7-21 days and known acute incidence once overdose up to 4500 mg did not seem to cause life-threatening effects, although a number of bad experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremors, palpitations, sleep disorders, nausea, and diarrhea. In 2004, the FDA was not aware of any fatal overdoses involving modafinil alone (compared with some drugs including modafinil).
Interactions
Co-administration with modafinil with opioids such as hydrocodone, oxycodone, and fentanyl, as well as other medications, may decrease plasma concentrations. The reason behind this action is because modafinil is an enzyme CYP3A4 inducer. If not monitored closely, reducing the efficacy or withdrawal symptoms may occur.
Pharmacology
Pharmacodynamics
By 2017, the mechanism of modafinil action therapy for narcolepsy and sleep-wake disorders is still unknown.
Dopamine transporter blocker
The study found that modafinil increases histamine levels in the hypothalamus in animals. The focus of modafinil monoamine action is also the target of the study, with effects identified on dopamine in the striatum and, in particular, nucleus accumbens, norepinephrine in the hypothalamus and the ventrolateral preoptic nucleus, and serotonin in the amygdala and the frontal cortex. Modafinil is filtered in large panels of receptors and transporters in an attempt to explain its pharmacology. Of the sites tested, it was found to significantly affect only the dopamine transporter (DAT), acting as a dopamine reuptake inhibitor (DRI) with an IC value of 50 4Ã? M. Furthermore, it is determined that modafinil binds to the same site on DAT as cocaine, but in a different way. Accordingly, modafinil increases locomotor activity and extracellular dopamine concentrations in animals in a manner similar to selective DRI vanoxerine (GBR-12909), and also inhibits methamphetamine-induced dopamine release (jointly owned from DRIs, as transport DAT facilitates access of methamphetamine to its intracellular target). Thus, "modafinil is very weak, but appears to be highly selective, [DAT] inhibitor". In addition to animal research, human positron emission tomography (PET) imaging studies found that 200A mg and 300A mg of modafinil doses resulted in 51.4% and 56.9% occupancy dats, respectively, which were described as "close to that of methylphenidate". Other human PET imaging studies also found that modafinil occupied DAT and also determined that significantly increased levels of extracellular dopamine in the brain, including the nucleus accumbens.
Modafinil has been described as a "atypical" DAT inhibitor, and shows a profoundly different profile effect from other dopaminergic stimulants. For example, modafinil produces reported consciousness without the need for sleep compensation, and indicates a relatively low potency of abuse, if any. In addition to modafinil, examples of other atypical DAT inhibitors include vanoxerine and benztropine, which have a relatively low potency of abuse similar to modafinil. These drugs appear to interact molecularly with DAT in different ways relative to conventional "DAT" inhibitors such as cocaine and methylphenidate.
DAT-independent activity
Against the hypothesis that modafinil has its effect by acting as DRI, tyrosine hydroxylase (dopamine-depleting) inhibitors fail to block the effects of modafinil in animals. In addition, modafinil fails to reverse the reserpine-induced akinesia, whereas dextroamphetamine, dopamine releasing agent (DRA), is able to do so. In addition, one of the first published activity-related activity-structure studies of modafinil was discovered in 2012 that inhibition of DAT did not correlate with the animal-awakened promotional effects among modafinil analogues, and analogs without significant inhibition of DAT still resulted in awake-promoting effect. Furthermore, "neurochemical [modafinil] and anatomic activation patterns of brain areas differ from typical psychostimulants and are consistent with their beneficial effects on cognitive performance processes such as attention, learning, and memory", and a study found that modafinil-induced elevations of locomotor activity in animal dependent on the release of histamine and can be eliminated by the depletion of histamine neuronal, while those of methylphenidate are not and can not. Thus, although it is determined that modafinil is a clinically significant DRI, the complete pharmacology remains unclear and may be more complex than this single property (ie, it may also include DAT-independent measures, such as "activation of orexin systems").
However, there is still considerable evidence to suggest that modafinil produces at least some of the promotional effects that are maintained by acting as DRIs, or at least through the activation of dopaminergic systems. To support modafinil acting as a dopaminergic agent, its awareness-raising effect was eliminated in DAT knockout mice (although it is important to note that DAT knockout mice show D 1 and D 2 receptors and compensatory abnormalities norepinephrine, which may confound these findings), is reduced by the receptor antagonists D 1 and D 2 (although conflicting reports exist), and are completely blocked by simultaneous inactivation of D receptors 1 and D 2 . Accordingly, modafinil showed generalization of full stimulus for other DAT inhibitors including cocaine, methylphenidate, and vanoxerine, and discrimination was blocked by administration of both ecopipam (SCH-39166), D 1 and haloperidol receptor antagonists. , receptor antagonist D 2 . Partial substitution is seen with dextroamphetamine DRA and receptor agonists D 2 PNU-91356A, as well as nicotine (which indirectly increases dopamine levels through activation of nicotinic acetylcholine receptors).
Modafinil may have an additional mechanism of action. Both modafinil and its metabolites, modafinil sulfon, have anticonvulsant properties in animals, and modafinil sulfafil is almost as strong as modafinil in producing this effect. However, modafinil sulfaf has no effect of raising awareness in animals, suggesting that different mechanisms may play a role in the anticonvulsant effects of both compounds.
D 2 partial agonist receptor
The ( R ) - (-) - enantiomers of modafinil, known as armodafinil, are also subsequently found to act as receptors D 2 High agonist partial, with K i 16 nM, 48% intrinsic activity, and EC 50 120 nM, on mouse striatal tissue. The ( S ) - enantiomer is not active against the receptor D 2 . Modafinil has been found to directly inhibit the firing of central brain dopaminergic neurons in the ventral tegmental area and mouse substantia nigra through the activation of D 2 receptors.
Miscellaneous
Modafinil's efficacy in increasing strength and well-being in the subject of sleep deprivation depends on the status of the catechol-O-methyl transferase (COMT). Research shows that individuals with the Val/Val genotype experience a remarkable increase in their cognitive function, while those with Met/Met alleles have slightly increased.
Pharmacokinetics
Modafinil induces cytochrome P450 CYP1A2, CYP3A4, and CYP2B6 enzymes, and inhibits CYP2C9 and CYP2C19 in vitro . It can also induce P-glycoprotein (Pgp), which can affect drugs transported by Pgp, such as digoxin. Modafinil bioavailability is greater than 80% of the given dose. In vitro measurements show that 60% of modafinil are bound to plasma proteins in clinical drug concentrations. This percentage is actually very little changed when the concentration varies. C max (peak level) occurs about 2-3 hours after administration. Food slows absorption, but does not affect the total AUC (AUC - area under the curve - meaning, food can slow down absorption, but the total amount of chemicals will be absorbed with or without food). The half-life is generally within the range of 10-12 hours, depending on the genotype difference of CYP, liver function and kidney function. It is metabolized in the liver, and its inactive metabolites are excreted in the urine. The excretion of urine from the unchanged drug ranges from 0% to as high as 18.7%, depending on various factors.
The two main metabolites circulating from modafinil are modafinil acid (CRL-40467) and modafinil sulfon (CRL-41056). Both of these metabolites have been described as inactive, and do not appear to contribute to the maintained promotional effect of modafinil. However, modafinil sulfone appears to have anticonvulsant effects, and this is a property shared with modafinil.
Chemistry
Measurements in body fluids
Modafinil and/or its major metabolites, modafinil acids, can be quantified in plasma, serum or urine to monitor doses in those who receive the drug therapeutically, to confirm the diagnosis of poisoning in the inpatient or to assist in vehicle forensic traffic investigation. violation. Instrumental techniques involving gas or liquid chromatography are usually used for this purpose. In 2011, it was not specifically tested for by common drug screens (except for anti-doping screens) and was unlikely to cause false positives for other unrelated chemicals such as substituted amphetamines.
Reagent testing can be used to screen the presence of modafinil in the sample.
Analog structural
Modafinil is a highly studied compound, with many derivatives made and studied, some examples and their differences between dopamine, serotonin & amp; norepinephrine effects are given in the bundled table below.
History
Modafinil was originally developed in France by neurophysiologists and professor of experimental medicine emeritus Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 1970s discovery of a series of benzydryl sulphinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is a major adrafinil metabolite, having no polar-OH group on its terminals. amide, and has similar activity to the parent drug but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil.
In 1998, modafinil was approved by the US Food and Drug Administration for the treatment of narcolepsy and in 2003 for sleep shift and obstructive sleep apnea/hypopnea disorders although caffeine and amphetamines proved to increase awareness at Stanford Sleepiness Test Score from modafinil.
It was approved for use in the UK in December 2002. Modafinil was marketed in the US by Cephalon Inc., which initially leased rights from Lafon, but eventually bought the company in 2001.
Cephalon began to market the armodafinil R-enantiomer from modafinil in the US in 2007. After protracted litigation and protest negotiations (see below), a generic version of modafinil became available in the US in 2012.
Patent protection and antitrust litigation
US. Patent 4,927,855 was issued to Laboratoire L. Lafon on May 22, 1990, including the modafinil chemical compound. After receiving a temporary extension of 1066 days and a six-month pediatric exclusivity, it ended on October 22, 2010. On October 6, 1994, Cephalon filed an additional patent, which included modafinil in particle size form. The patent, AS. Patent 5,618,845 was issued on April 8, 1997, but reissued in 2002 as RE 37,516, which awarded the patent 5618845. With pediatric exclusivity, the patent expires on April 6, 2015.
On December 24, 2002, anticipating the end of exclusive marketing rights, Mylan, Teva, Barr and Ranbaxy generic drug manufacturers applied to the FDA to market generic forms of modafinil. At least one app pulls after the initial opposition by Cephalon based on '516 patents. There are several questions as to whether the particle size patent is sufficient protection against generic drug preparation. Relevant questions include whether modafinil can be modified or made to avoid the granularity specified in the new Cephalon patent, and whether the size of the patent particle is invalid because particles of the appropriate size tend to be obvious to practitioners skilled in the art. However, under United States patent law, the patent is entitled to the presumption of legal validity, which means that to void the patent, more than "relevant questions" are required.
Starting October 31, 2011, republish US Pat. RE 37.516 has been declared invalid and unenforceable. The District Court for the Eastern District of Pennsylvania ruled that RE 37,516 is invalid because: (1) sold for more than one year before the date of the petition violates 35 U.S.C. section 102 (b); (2) actually found by others (French company Laboratoire L. Lafon); (3) is clear at the time the invention is made for someone who has ordinary skills in this field under 35 U.S.C. section 103 (a); and (4) failed requirements of written description of 35 U.S.C. Section 112. The patent was also found to have no legal force due to Cephalon's unfair conduct during the patent prosecution.
Cephalon made a deal with four major generic manufacturers of Teva, Barr Pharmaceuticals, Ranbaxy Laboratories, and Watson Pharmaceuticals between 2005 and 2006 to delay generic modafinil sales in the US until April 2012 by these companies in exchange for prepayments and royalties. Litigation arising from this agreement is pending including the FTC lawsuit filed in April 2008. Apotex received regulatory approval in Canada despite a lawsuit from Cephalon's Canadian marketing partner Shire Pharmaceuticals. Cephalon has sued Apotex in the US to prevent it releasing generative armodafinil (Nuvigil). Cephalon's 2011 efforts to join Teva have been approved by the FTC in a number of conditions, including granting the US general rights to other companies; Finally, Par Pharmaceutical acquired the US Modafinil rights as well as several others.
In the United Kingdom, Mylan Inc. received regulatory approval to sell generic modafinil produced by Orchid in January 2010; Cephalon was sued to prevent the sale, but lost in a patent trial in November.
Society and culture
Legal status
United States
Modafinil is currently classified as Schedule IV controlled substance under US federal law; it is illegal to import by anyone other than a registered importer of DEA without a prescription. However, a person may legally bring modafinil to the United States personally from a foreign country, provided he has a prescription for it, and the drug is properly stated at the border crossing. US residents are limited to 50 dose units (eg, pills). Under the US Pure Food and Drug Act, drug companies are not allowed to market their drugs for off-label use (conditions other than those officially approved by the FDA); Cephalon was reprimanded in 2002 by the FDA because its promotional material was found to be "wrong, out of balance, or misleading". Cephalon pleaded guilty to criminal offenses and paid several fines, including a $ 50 million and spant of $ 425 million to the US government on in 2008. China
In mainland China, modafinil is strictly controlled as other stimulants, such as amphetamines and methylphenidate, and are not approved for medical use.
Japanese
In Japan, modafinil is a psychotropic drug Schedule I. There are reports of arrests of people importing modafinil for personal use.
Russian
In Russia modafinil is Schedule II controlled substances such as cocaine and morphine. Ownership of some modafinil pills can cause 3-10 years in prison.
Australia
In Australia, modafinil is considered a prescription of Schedule 4 only medication or prescription of veterinary drugs. Schedule 4 is defined as "Substance, use or supply to be by or on the orders of persons permitted by State or Territory laws to prescribe and must be available from pharmacists on prescription."
Other countries
The following countries do not classify modafinil as a controlled substance:
- Canada (not listed in the Drug and Control Laws, but this is prescription drug Schedule F, subject to seizure by the Canadian Border Service Agency)
- In Finland and Sweden modafinil is a prescription drug but not listed as a controlled substance.
- Mexico (Not listed as controlled substances, in the National Health Act)
- South Africa Schedule V
- United Kingdom (not registered in Drug Abuse so ownership is not illegal, but recipes are required)
Brand name
Modafinil is sold under a variety of brand names worldwide, including Alertec, Alertex, Altasomil, Aspendos, Forcilin, Intensit, Mentix, Modafinil, Modafinilo, Modalert, Modanil, Modigliil, Modvigil, Modiodake, Modiwake, Movigil, Provigil, Resotyl, Stavigile, Vigia, Vigicer, Vigil, Vigimax, Wakelert and Zalux.
Doping agent
Sports
Modafinil regulation as a doping agent has been a controversy in the sporting world, with high profile cases attracting press coverage as some famous American athletes have tested positive for substance. Some athletes found to have used modafinil protested that the drug was not on the forbidden list at the time of their offense. However, the World Anti-Doping Agency (WADA) declared that it was related to prohibited substances. The agency added modafinil to the list of illegal substances on August 3, 2004, ten days before the start of the 2004 Summer Olympics.
Modafinil has received some publicity in the past when several athletes (such as the Kelli White sprinter in 2004, cyclist David Clinger and basketball player Diana Taurasi in 2010, and oarsman Timothy Grant in 2015) were found suspected of using it as a performance enhancement doping agent. (Taurasi and other players, Monique Coker, tested in the same lab, then cleansed.) It is unclear how extensive this practice is. The BALCO scandal reveals an unproven (but widely publicized) major lead-to-date report played by Barry League's back run home, including modafinil in addition to anabolic steroids and human growth hormone. Modafinil has been shown to extend training time to exhaustion while doing 85% VO 2max and also reduces the perceptions of effort required to maintain this threshold. Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a forbidden stimulant (see Modafinil Legal Status).
Nootropic
Modafinil has been used non-medically as a "smart drug" by students, office workers, soldiers and transhumanists. This is often compared to the fictional drug NZT-48 described in Unlimited and is sometimes called "Unlimited 'pills."
Research
ADHD
In the United States, applications to market modafinil for pediatric ADHD are submitted to the FDA, but approval is denied because of major concerns over the occurrence of Stevens-Johnson Syndrome in clinical trials.
Schizophrenia
Modafinil and armodafinil have been studied as a complement to antipsychotic drugs in the treatment of schizophrenia. They have been consistently shown to have no effect on positive symptoms or cognitive performance. A 2015 meta-analysis found that modafinil and armodafinil can slightly reduce the negative symptoms in people with acute schizophrenia, although it appears to be useless for people with stable conditions, with high negative symptoms scores. Among the drugs proven effective for reducing negative symptoms in combination with anti-psychotic, modafinil and armodafinil is one of the smallest effect sizes.
Weight
The decisive information for Provigil noted that "There was no clinically significant difference in weight change in patients treated with Provigil compared with placebo-treated patients in placebo-controlled clinical trials."
Cognitive Improvement
A review of 2015 from clinical studies of possible nootropic effects on healthy individuals was found: "... while most studies using basic testing paradigms show that modafinil intake improves executive function... half shows increased attention and learning and memory, and some even report disorder in different creative thinking.On the contrary, when more complex judgments are used, modafinil seems to consistently lead to increased attention, executive function, and learning. Importantly, we do not observe any additional factors for side effects or mood swings. " > Post-chemotherapy cognitive damage
Modafinil has been used off-label in trials with people with symptoms of post-chemotherapy cognitive impairment, also known as "chemobrain", but a 2011 review found that it was no better than placebo. In 2015 it has been studied for use in multiple sclerosis-related fatigue, but the resulting evidence is weak and unconvincing.
See also
- Adrafinil
- Armodafinil
- Caffeine
- CRL-40,940
- CRL-40,941
- Fluorenol
References
Further reading
- Minzenberg MJ, Carter CS (June 2008). "Modafinil: review of neurochemical actions and effects on cognition". Neuropsychopharmacology . 33 (7): 1477-502. doi: 10.1038/sj.npp.1301534. PMID 17712350.
- "Stay Awake Pill May Get Wider Approval". ABC News . October 9, 2006.
External links
- PROVIGIL - the official website
- Treatment Guide for Patients
- Complete Prescribing Information
- RxList Patient Information for modafinil users
- "Mayo Clinic Proceedings Published NUVIGIL Study on Patients with Working Disorders Shifting"
- US. National Library of Medicine: Drug Information Portal - Modafinil
Source of the article : Wikipedia
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