Wikipedia

Modafinil

farmaco
Versione del 22 set 2009 alle 12:18 di 93.45.119.21 (discussione) (→Utilizzi sperimetali)
Questa voce o sezione sull'argomento medicina è stata parzialmente tradotta dalla lingua inglese.
Puoi contribuire terminando la traduzione o usando altre fonti. Non usare programmi di traduzione automatica. Usa {{Tradotto da}} quando hai terminato. Se nella pagina di modifica trovi del testo nascosto, controlla che sia aggiornato servendoti dei collegamenti «in altre lingue» in fondo alla colonna di sinistra. Segui i suggerimenti del progetto di riferimento.
Data "ottobre 2008" non riconosciuta. Sintassi: {{T|lingua|argomento|mese anno}}

Template:Disclaimer soccorso Template:Farmaco2-26-45-36/37/39


Il Modafinil (commercializzato col nome di Provigil) è un farmaco stimolante prodotto dalla Cephalon, ed è approvato dal S.S.N. prevalentemente per il trattamento della narcolessia ed i disturbi ad essa correlati[1].[2] Il Modafinil, come per altri stimolanti, aumenta il rilascio di molti neurotrasmettitori specialmente monoamminici ma innalza anche i livelli di istamina nell'ipotalamo,[3] cosa che ha indotto alcuni ricercatori a considerare il Modafinil come un "agente promotore della veglia" piuttosto che uno stimolante assimilabile alle anfetamine (come dalle differenze dimostrate sulla distribuzione dei geni proto-oncogeni C-Fos indotta dal modafinil comparato alle anfetamine).[4] Il modafinil è anche indicato, sebbene non approvato, nel trattamento della Sindrome da deficit di attenzione e iperattività o ADHD,[5] , della depressione,[6] Sindrome da astinenza da cocaina,[7] Morbo di Parkinson,[8] schizofrenia,[9] e disturbi relativi all'affaticamento.[10][11] Negli Stati Uniti tuttavia, per legge, comunque, Cephalon non è autorizzata alla vendita del Modafinil per condizioni non ufficialmente approvate dall'FDA.[12]

Il Modafinil e il suo precursore chimico, l'Adrafinil furono sviluppati nei Lafon Laboratories, una società francese acquisita dalla Cephalon nel 2001.[13] Il Modafinil è il metabolita primario dell'adrafinil e, sebbene la loro azione sia molto simile, l'adrafinil richiede un dosaggio maggiore per ottenere effetti della stessa entità.

Indicazioni terapeutiche

Allo stato attuale, in Italia il farmaco è approvato ufficialmente solo per il trattamento della narcolessia e dei disturbi ad essa correlati.

Utilizzo Off-label

Il Modafinil è largamente utilizzato per sopprimere il bisogno del sonno. È anche utilizzato per trattare l'affaticamento non correlato alla mancanza di sonno, nel trattamento dell'ADHD e come coadiuvante agli antidepressivi (particolarmente negli individui con notevole affaticamento residuo). C'è un acceso dibattito nel quale viene discusso se gli effetti del modafinil mostrati in persone sane e con sonno regolare sono sufficienti per considerarlo un "potenziatore cognitivo"."[14][15][16] I ricercatori concordano che il modafinil potenzia alcuni aspetti della memoria, come il digit span, manipolazione digitale e nella memoria atta al riconoscimento di forme, oggetti, volti, ecc.., ma i risultati relativi alla memoria spaziale, alle funzioni esecutive e all'attenzione sono dubbi.[14][15][16][17] Alcuni degli effetti positivi del modafinil potrebbero essere limitati a individui "poco performanti"[17] o persone con un quoziente d'intelligenza basso.[18] Vi sono anche prove che esso abbia effetti neuroprotettivi[19] Modafinil potrebbe anche essere un efficace e ben tollerato trattamento nei pazienti con disordine affettivo stagionale o depressione invernale. [20]

Agente dopante

Il modafinil ha ricevuto un po' di pubblicità in passato, quando parecchi atleti furono trovati presumibilmente a doping usarlo come agente dopante. Non è chiaro quanto sia diffusa questa pratica. Dal momento che non ci sono stati studi pertinenti a questo tipo di uso del farmaco, resta sconosciuto se il modafinil possa avere un impatto sulle prestazioni dell'atleta. Comunque, c'è una prova "aneddotica" che testimonia che il modafinil incide certamente sulle prestazioni fisiche degli atleti.

Nel 2004 il Modafinil è stato aggiunto nella "Lista Proibita" della World Anti-Doping Agency come stimolante proibito.

Sclerosi multipla

Il Modafinil è stato usato per alleviare i sintomi della "fatica neurologica" riportata da alcuni pazienti affetti da sclerosi multipla. I pazienti seguono o la prescrizione standard o prendono una singola dose di 100-200mg all'inizio dei giorni stimati come potenzialmente troppo "affaticanti". Nel 2000, Cephalon ha condotto uno studio per valutare se il modafinil potesse essere un potenziale trattamento per l'affaticamento correlato alla sclerosi multipla. Un gruppo di 72 persone affette da tale patologia a vari livelli di gravità, provarono due differenti dosi di modafinil e una di placebo in un periodo di più di nove settimane. I livelli di affaticamento furono autovalutati su una scala standardizzata. I partecipanti che prendevano una dose inferiore di modafinil, riportarono una sensazione di affaticamento minore a c'è stata una differenza statisticamente rilevante tra coloro che assumevano il farmaco e coloro trattati con placebo. Dosi maggiori di modafinil non hanno sortito effetti rilevanti.[21]

ADHD o Sindrome da deficit di attenzione e iperattività

Fino al Febbraio 2007, ci sono almeno sette articoli in lingua inglese su sperimentazioni cliniche casuali nel database Medline che indicano l'uso del modafinil per il trattamento dell'ADHD. Alcuni studi hanno evidenziato come l'uso del modafinil nel trattamento del'ADHD sia associato con un significativo miglioramento dei sintomi primari. In altri studi, le funzioni cognitive in pazienti affetti da ADHD sono stati evidenziati miglioramenti con l'uso del modafinil. Studi sull'ADHD riportano insonnia e cefalea come effetti indesiderati più comuni, visti in circa il 20% degli individui trattati. Questi studi non furono adeguati per determinare se i benefici apportati dal modafinil erano mantenuti con una somministrazione cronica. Ulteriori studi a lungo termine, usando metodi flessibili per stabilire sicurezza, efficacia e un confronto diretto con altri stimolanti sono necessari per determinare il ruolo del modafinil nel trattamento dell'ADHD.[22]

Nel Dicembre 2004, Cephalon presentò un nuovo farmaco al mercato col nome Sparlon, nome commerciale di pillole contenenti una quantità maggiore di modafinil per il trattamento dell'ADHD in bambini e adolescenti dai 6 ai 17 anni. Comunque, nel Marzo 2006, in una consultazione l'FDA votò 12 a 1 contro l'approvazione, citando casi riportati di rash cutaneo in una sperimentazione su 1000 pazienti, fra i quali uno era sospettato di aver sviluppato addirittura una Sindrome di Stevens-Johnson.[23][24] La disapprovazione finale avvenne nell'Agosto 2006, sebbene successivi sviluppi nelle ricerche indicarono che il rash cutaneo non era la sindrome di Stevens-Johnson.[senza fonte] Cephalon decise quindi di interrompere lo sviluppo dello Sparlon per uso pediatrico, anche se ci sono possibilità di utilizzarlo per il trattamento dell'ADHD negli adulti.

Il Modafinil ha controindicazioni relative in pazienti con storia di precedenti eventi cardiovascolari. Comunque, un case report del 2005[25] descrive positivamente il passaggio di terapia da Metilfenidato (5 mg 2/die) a Modafinil in un uomo di 78 anni con "comorbidità cardiaca significativa", anche se nel trattamento di una depressione di grado severo e non nell' ADHD. Perciò, vantaggi terapeutici nel trattamento convenzionale della Sindrome da deficit di attenzione e iperattività rispetto ai trattamenti tradizionali, non devono essere dati per scontati, ma al contrario valutati attentamente con il proprio medico, un neurologo od uno psichiatra.

Altri utilizzi

Il Modafinil è usato anche Off-Label per il trattamento di sedazione ed affaticamento nella depressione,[26][27] nella distrofia miotonica,[28] nella sonnolenza indotta da oppioidi,[29] nella paralisi cerebrale infantile,[30] e nel Morbo di Parkinson.[31] Incrementa l'umore soggettivo e l' amichevolezza, quanto meno negli studi effettuati su lavoratori turnisti di notte.[32]

Utilizzi sperimentali

Dipendenza da Cocaina

Uno studio di 8 settimane in Doppio cieco sul Modafinil nella dipendenza da Cocaina ha prodotto risultati inconcludenti. Il numero di campioni di urina positivi per la cocaina era significativamente più basso nel gruppo in trattamento con Modafinil se comparato al gruppo Placebo a metà dello studio, ma alla fine delle 8 settimane la differenza smetteva di essere significativa. Oltretutto già da prima che lo studio iniziasse, il gruppo Modafinil aveva già mostrato un consumo di cocaina più basso, confondendo i risultati ulteriormente. Se comparato al placebo, il Modafinil non riduce il desiderio di cocaina od il consumo dichiarato dai pazienti, ed i risultati raccolti dagli stessi medici sono insignificantemente migliori.[33] Dan Umanoff, della National Association for the Advancement and Advocacy of Addicts, ha criticato gli autori dello studio per aver lasciato i risultati negativi fuori della discussione nella pubblicazione.[34][35]

Weight loss

Studies on modafinil (even those on healthy weight individuals) indicate that it has an appetite reducing/weight loss effect.[36][32][37][38][39] All studies on modafinil in the Medline database that are for one month or longer which report weight changes find that modafinil users experience weight loss compared to placebo.[40]

However, the prescribing information for Provigil notes that "There were no clinically significant differences in body weight change in patients treated with PROVIGIL compared to placebo-treated patients in the placebo-controlled clinical trials." [41]

In experimental studies, the appetite reducing effect of modafinil appears to be similar to that of amphetamines, but, unlike amphetamines, the dose of modafinil that is effective at decreasing food intake does not significantly increase heart rate.

Also, an article published in the Annals of Clinical Psychiatry, presented the case of a 280 pound patient (BMI=35.52) who lost 40 pounds over the course of a year on Modafinil (to 30.44 BMI). After three years, his weight stabilized at a 50 pound weight loss (29.59 BMI). The authors conclude that placebo controlled studies should be conducted on using Modafinil as a weight loss agent.[36]

Conversely, a U.S. patent (#6,455,588) on using modafinil as an appetite stimulating agent has been filed by Cephalon in 2000.

Primary biliary cirrhosis

Modafinil has been shown to improve excessive daytime somnolence and fatigue in primary biliary cirrhosis. After two months of treatment significant improvement was observed in symptoms of fatigue using the Epworth Sleepiness Scale.[42]

Post-chemotherapy cognitive impairment

Modafinil has been used off-label in trials with people with symptoms of Post-chemotherapy cognitive impairment, also known as "chemobrain".[43] A University of Rochester study of 68 subjects had significant results. "We knew from previous studies that modafinil does alleviate problems with memory and attention, and were hoping it would do the same for breast-cancer patients experiencing chemo-brain, which it did," related the study's lead author Sadhna Kohli, Ph.D, a research assistant professor at the University of Rochester's James P. Wilmot Cancer Center.[44]

Mood elevation

Modafinil used in a randomized double-blind study showed that normal healthy volunteers between the ages of 30-44 showed general improvement in alertness as well as mood. In the three-day study, counterbalanced, randomized, crossover, inpatient trial of modafinil 400 mg was administered as well as a placebo to the control group. The conclusion demonstrated that modafinil may have general mood-elevating effects in particular for the adjunctive use in treatment-resistant depression.[42]

Contraindications and warnings

Literature distributed by maker Cephalon advises that it is important to consult with your physician before using Modafinil, particularly for those with:

  • Hypersensitivity to the drug or other constituents of the tablets, or
  • Previous cardiovascular problems, particularly while using other stimulants, or
  • Cardiac conditions, particularly:

Although it is not discussed in the literature, the standard binders used for Modafinil contain wheat gluten[senza fonte], and so persons who have Coeliac Disease (Celiac Disease) should avoid the drug.

Severe adverse reactions

Modafinil may induce severe dermatologic reactions requiring hospitalization. From the date of initial marketing, December 1998, to January 30 2007, FDA received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) involving adult and pediatric patients. The FDA issued a relevant alert. In the same alert, the FDA also noted that angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experience. Modafinil (marketed as Provigil): Serious Skin Reactions, su fda.gov, FDA, Fall, 2007.

See the ADHD section for discussion of transitions to Modafinil from high dose stimulant regimens.

Patients with severe anxiety should be carefully supervised, as modafinil may exacerbate their condition. It may be necessary to coadminister an anxiolytic. High blood pressure should be stabilized before initiating treatment with modafinil or any other stimulant.

The patient should inform the prescribing physician of any other drugs they are currently taking, as modafinil may interact with a great number of drugs.

Relatively little is known regarding safety of modafinil during pregnancy or breastfeeding. Studies on pregnant rats and rabbits suggest that high doses of modafinil during pregnancy may increase the likelihood of birth defects. There are no adequate and well controlled trials with modafinil in pregnant women. Modafinil should only be used in pregnancy if the potential benefit for the mother justifies the potential risk to the fetus.

It is not known if modafinil or its metabolites are excreted in human milk. Caution should be exercised when modafinil is administered to a nursing woman.

Modafinil may reduce the effectiveness of contraceptives.

Alcohol and similar depressants should be avoided if at all possible while taking Modafinil.

Side-effects

The most common side-effects observed with modafinil, as compared to placebo, when prescribed in the recommended doses for the approved indications, are as follows:

Additionally, gastrointestinal distress, which may be alleviated by taking the drug after a meal, aggressiveness and skin irritation have been reported, but are rare.

Most side-effects subside after a few weeks without reducing the dose. Only headaches and anxiety have been shown to be proportional to dose, and these may benefit from a temporary reduction or dividing the dose.

A single case of premature ventricular contractions appeared causally linked to administration of modafinil.[45]

Modafinil may have an adverse effect on hormonal contraceptives, lasting for a month after cessation of dosage.[46]

Modafinil toxicity levels vary widely among species. In mice and rats, the median lethal dose LD50 of modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD50 values reported for rats range from 1000 mg/kg to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. In clinical trials on humans, taking up to 1200 mg/day for 7 to 21 days or one-time doses up to 4500 mg did not appear to cause life-threatening effects, although a number of adverse experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, and diarrhea. As of 2004, FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs, including modafinil).[47] Consequently, oral LD50 of modafinil in humans is not known exactly. However, it appears to be higher than oral LD50 of caffeine.

Military use

Militaries of several countries are known to have expressed interest in Modafinil as an alternative for amphetamine—the drug traditionally employed in sleep deprivation situations.

The French government indicated that the Foreign Legion used modafinil during certain covert operations. The United Kingdom's Ministry of Defence has admitted conducting ongoing research into Modafinil[48] and spent £300,000 on one investigation.[49]

In the United States military, Modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses.[50]One study on helicopter pilots suggested that 600 mg of modafinil given in three doses can be used to keep pilots alert and maintain their accuracy at pre-deprivation levels for 40 hours without sleep.[51]However, significant levels of nausea and vertigo were observed. Another study of fighter pilots showed that modafinil given in three divided 100 mg doses sustained the flight control accuracy of sleep-deprived F-117 pilots to within about 27 percent of baseline levels for 37 hours, without any considerable side effects.[52] In an 88-hour sleep loss study of simulated military grounds operations, 400 mg/day doses were mildly helpful at maintaining alertness and performance of subjects compared to placebo, but the researchers concluded that this dose was not high enough to compensate for most of the effects of complete sleep loss.[53]

Pharmacology

The exact mechanism of action of Modafinil is unclear, although numerous in vitro studies have shown it to increase the levels of various monoamines, namely; dopamine in the striatum and nucleus accumbens,[54][55] noradrenalin in the hypothalamus and ventrolateral preoptic nucleus,[56][57] and serotonin in the amygdala and frontal cortex.[58] While the co-administration of a dopamine antagonist is known to decrease the stimulant effect of amphetamine, it does not negate the wakefulness-promoting actions of modafinil. Modafinil activates glutamatergic circuits while inhibiting GABAergic neurotransmission. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects.

The central stimulating effect of modafinil shows dose and time-related features. The effect tends to be enhanced by chlorination but reduced by methylation. Modafinil blocks the reuptake of norepinephrine by the noradrenergic terminals on sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.

Modafinil has a binding coefficient (Ki) of about 4,000 nmol/L for the dopamine reuptake transporter, and in excess of 10,000 nmol/L for the norepinephrine reuptake transporter.

A newly proposed mechanism of action involves brain peptides called orexins, also known as hypocretins. Orexin neurons are found in the hypothalamus but project to many different parts of the brain, including several areas that regulate wakefulness. Activation of these neurons increases dopamine and norepinephrine in these areas, and excite histaminergic tuberomammillary neurons increasing histamine levels there. There are two receptors for hypocretins, namely hcrt1 and hcrt2. Animal studies have shown that animals with defective orexin systems show signs and symptoms similar to narcolepsy. Modafinil seems to activate these orexin neurons thus promoting wakefulness. However, a study of genetically modified dogs lacking orexin receptors showed that modafinil still promoted wakefulness in these animals, suggesting that orexin activation is not required for the effects of modafinil.

It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine and norepinephrine reuptake, as well as orexin activation.

It has been shown in rats that modafinil increases histamine release in the brain, and this may be a possible mechanism of action in humans.[59]

Armodafinil a single R-enantiomer of modafinil was approved by the FDA for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome and shift work sleep disorder.

Pharmacokinetics

Modafinil induces the cytochrome P450 enzymes CYP1A2, CYP2B6 and CYP3A4, as well as inhibiting CYP2C9 and CYP2C19 in vitro. It may also induce P-glycoprotein, which may affect drugs transported by Pgp, such as digoxin.

The bioavailability of Modafinil is greater than 80% of the administered dose. In vitro measurements indicate that 60% of Modafinil is bound to plasma proteins at clinical concentrations of the drug. This percentage actually changes very little when the concentration is varied.[60]

Cmax occurs approximately 2–3 hours after administration. Food will slow absorption, but does not affect the total AUC. Half-life is generally in the 10–12 hour range, subject to differences in CYP genotypes, liver function and renal function. It is metabolized in the liver, and its inactive metabolite is excreted in the urine. Urinary excretion of the unchanged drug ranges from 0% to as high as 18.7%, depending on various factors. [60]

History

Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, also including adrafinil, by scientists working with the French pharmaceutical company Lafon. Adrafinil was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil and has similar activity 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. It was approved for use in the UK in December 2002. Modafinil is marketed in the US by Cephalon Inc., who leased the rights from Lafon. Cephalon eventually purchased Lafon in 2001. In 2005, a petition by a private individual was filed with the FDA requesting over-the-counter sale of modafinil.[61]

Formulation patent

A (EN) US4927855, United States Patent and Trademark Office, Stati Uniti d'America. was granted to Lafon for modafinil in 1990. The FDA granted modafinil orphan drug status in 1993. The formulation patent expired on 30 March, 2006.

Particle size patent

Cephalon filed for (EN) US5618845, United States Patent and Trademark Office, Stati Uniti d'America., covering pharmaceutical compositions of modafinil, in 1994. That patent, granted in 1997, was reissued in 2002 as RE 37,516, which provides Cephalon with patent protection for certain preparations of the drug in the United States until 2014, which is now apparently extended to April 6 2015 after Cephalon received a six-month patent extension from the FDA.[62] However, a settlement in which Cephalon apparently paid out US$ 200 million to four generic drug manufacturers[63] may mean that generic forms of the drug will become available in April 2012 (October 2011 prior to the six month extension).

Some competing pharmaceutical manufacturers have applied to the FDA to market a generic form of modafinil in 2006. At least one withdrew their application after early opposition by Cephalon based on their new patent on particle sizes. There is some question as to whether a particle size patent is sufficient protection against the manufacture of generics. Pertinent questions include whether modafinil may be modified or manufactured to avoid the granularities specified in the new Cephalon patent, and whether patenting particle size is invalid because particles of appropriate sizes are likely to be obvious to practitioners skilled in the art. However, under United States patent law, a patent is entitled to a legal presumption of validity, meaning that in order to invalidate the patent, much more than "pertinent questions" are required. To date, no generic manufacturer has been able to invalidate Cephalon's particle size patent, and, indeed, those that attempted to do so were not successful such that the patent remains in full force and effect.

Other wakefulness promoting agents

As of 2007, Modafinil does not have any significant competition. However, Vanda Pharmaceuticals, Inc. began Phase II clinical trials in 2007 for VSF-173, a drug that also targets excessive sleepiness.[64]

Modafinil is currently classified as a non-narcotic Schedule IV controlled substance under United States federal law; it is illegal to import by anyone other than a DEA-registered importer without a prescription.[65] However, one may legally bring up to 50 dosage units (i.e. pills) of Modafinil to the United States in person from a foreign country, provided that he or she has a prescription for it, and the drug is properly declared at the border crossing.[66] Note that Adrafinil, a drug that is closely related to Modafinil, is currently not classified as a controlled substance, and therefore it is not as severely regulated.

The following countries do not classify Modafinil as a controlled substance:

Currently, use of modafinil is controversial in the sporting world, with high profile cases attracting press coverage as prominent United States athletes have tested positive for the substance. Some athletes who were found to have used modafinil protested that the drug was not on the prohibited list at the time of their offence. However, the World Anti-Doping Agency (WADA) maintains it was related to already banned substances. The agency added modafinil to the list of prohibited substances on August 3, 2004, ten days before the start of the 2004 Summer Olympics.

In the film The Invasion, Nicole Kidman is seen rummaging in a pharmacy for a stimulant. She grabs a bottle of "modifinil" 1 gram dosage. The common dosages for modafinil are 100 mg and 200 mg. The premise of the movie is that an alien virus works its evil during sleep so she needs to stay awake until she finds a cure.

In the television series Stargate SG-1, the season 10 episode "Morpheus" features the Stargate team infected by a disease which apparently caused a town to die in its sleep. The team struggles to stay awake and is provided with a variety of stimulants, as Colonel Mitchell takes out various bottles and reads their labels he finds one and reads "Modia... something", a likely reference to the European branding of Modafinil—Modiodal.

In the television series CSI: Crime Scene Investigation, the season 8 episode "Cockroaches" has CSI Warrick Brown suffering from stress related insomnia due to his divorce. He is shown taking a prescription for 100 mg modafinil to help him stay "alert" at work, but a co-worker becomes concerned that he is taking the pills too often and is taking them in conjunction with a prescription for sleeping pills (which are later referred to as Zolpidem).

In the Legacy of the Aldenata series of science fiction novels, the drug is referred to by the trade name Provigil and is used by military personnel in combination with a powerful stimulant to remain alert.

Nella serie televisiva Dr. House - Medical Division, l'episodio della seconda stagione intitolato "La forza è dentro di noi" termina con una scena in cui Foreman testa la sua memoria provando a ricordare le dosi prescritte di vari farmaci. Dopo essersi fermato per la frustrazione, accorgendosi che Cameron lo guarda, decide di continuare. Uno dei farmaci è il modafinil.

Voci correlate

Note

  1. ^ Erman MK, Rosenberg R, For The U S Modafinil Shift Work Sleep Disorder Study Group. "Modafinil for excessive sleepiness associated with chronic shift work sleep disorder: effects on patient functioning and health-related quality of life." Primary Care Companion to the Journal of Clinical Psychiatry 2007;9(3):188-94. Full Text
  2. ^ "Provigil (Modafinil) Site." 12/24/1998 [1].
  3. ^ Ishizuka T, Murakami M, Yamatodani A, Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats, in Eur. J. Pharmacol., vol. 578, n. 2-3, Jan 2008, pp. 209–15, DOI:10.1016/j.ejphar.2007.09.009.
  4. ^ Engber TM, Koury EJ, Dennis SA, Miller MS, Contreras PC, Bhat RV, Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil, in Neurosci. Lett., vol. 241, n. 2-3, Jan 1998, pp. 95–8.
  5. ^ Biederman J, Pliszka SR, Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescents, in J. Pediatr., vol. 152, n. 3, Mar 2008, pp. 394–9, DOI:10.1016/j.jpeds.2007.07.052.
  6. ^ Fava M, Thase ME, DeBattista C, Doghramji K, Arora S, Hughes RJ, Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness, in Ann Clin Psychiatry, vol. 19, n. 3, 2007, pp. 153–9, DOI:10.1080/10401230701464858.
  7. ^ Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP, A double-blind, placebo-controlled trial of modafinil for cocaine dependence, in Neuropsychopharmacology, vol. 30, n. 1, Jan 2005, pp. 205–11, DOI:10.1038/sj.npp.1300600.
  8. ^ van Vliet SA, Vanwersch RA, Jongsma MJ, van der Gugten J, Olivier B, Philippens IH, Neuroprotective effects of modafinil in a marmoset Parkinson model: behavioral and neurochemical aspects, in Behav Pharmacol, vol. 17, n. 5-6, Sep 2006, pp. 453–62.
  9. ^ Turner DC, Clark L, Pomarol-Clotet E, McKenna P, Robbins TW, Sahakian BJ, Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia, in Neuropsychopharmacology, vol. 29, n. 7, Jul 2004, pp. 1363–73, DOI:10.1038/sj.npp.1300457.
  10. ^ Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN, Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study, in J. Neurol. Neurosurg. Psychiatr., vol. 72, n. 2, Feb 2002, pp. 179–83.
  11. ^ Rabkin JG, McElhiney MC, Rabkin R, Ferrando SJ, Modafinil treatment for fatigue in HIV+ patients: a pilot study, in J Clin Psychiatry, vol. 65, n. 12, Dec 2004, pp. 1688–95.
  12. ^ U.S. Food and Drug Administration. Prescription Drug Marketing Act of 1987 (PDMA), PL 100-293. Link
  13. ^ News Release (Cephalon). "Cephalon, Inc. Plans to Acquire France's Group Lafon." WEST CHESTER, Pa., Dec 3, 2001 (PR Newswire) Link
  14. ^ a b Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ, Cognitive enhancing effects of modafinil in healthy volunteers, in Psychopharmacology (Berl.), vol. 165, n. 3, 2003, pp. 260–9, DOI:10.1007/s00213-002-1250-8.
  15. ^ a b Randall DC, Viswanath A, Bharania P, Elsabagh SM, Hartley DE, Shneerson JM, File SE, Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived?, in J Clin Psychopharmacol, vol. 25, n. 2, 2005, pp. 175–9, DOI:10.1097/01.jcp.0000155816.21467.25.
  16. ^ a b Baranski JV, Pigeau R, Dinich P, Jacobs I, Effects of modafinil on cognitive and meta-cognitive performance, in Hum Psychopharmacol, vol. 19, n. 5, 2004, pp. 323–32, DOI:10.1002/hup.596.
  17. ^ a b Müller U, Steffenhagen N, Regenthal R, Bublak P, Effects of modafinil on working memory processes in humans, in Psychopharmacology (Berl.), vol. 177, n. 1-2, 2004, pp. 161–9, DOI:10.1007/s00213-004-1926-3.
  18. ^ Randall DC, Shneerson JM, File SE, Cognitive effects of modafinil in student volunteers may depend on IQ, in Pharmacol. Biochem. Behav., vol. 82, n. 1, 2005, pp. 133–9, DOI:10.1016/j.pbb.2005.07.019.
  19. ^ P Jenner, Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset, in Experimental Brain Research, vol. 133, July 2000, pp. 178–188, DOI:10.1007/s002210000370.
  20. ^ Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study, Journal of affective disorders, 2004 Aug;81(2):173-8.
  21. ^ K W Rammohan, Efficacy and safety of modafinil (Provigil®) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study, in Journal of Neurology Neurosurgery and Psychiatry, vol. 72, 2002, pp. 179–183, DOI:10.1136/jnnp.72.2.179.
  22. ^ Lindsay SE, Gudelsky GA, Heaton PC, Use of modafinil for the treatment of attention deficit/hyperactivity disorder, in Ann Pharmacother, vol. 40, n. 10, Oct 2006, pp. 1829–33, DOI:10.1345/aph.1H024.
  23. ^ Psychopharmacologic Drugs Advisory Committee (transcript), su fda.gov, FDA, 23 marzo 2006.
  24. ^ Modafinil (CEP-1538) Tablets Supplemental NDA 20-717/S-019 ADHD Indication Briefing Document for Psychopharmacologic Drugs Advisory Committee Meeting (PDF), su fda.gov, FDA, 23 marzo 2006. URL consultato il 21 luglio 2007.
  25. ^ Glen L. Xiong, M.D., Eric J. Christopher, M.D., and Jason Goebel, M.D., Modafinil as an Alternative to Methylphenidate as Augmentation for Depression Treatment, in Psychosomatics, vol. 46, Academy of Psychosomatic http://it.wikipedia.org/w/index.php?title=Physician&action=edit&redlink=1Medicine, 2005, pp. 578–579, DOI:10.1176/appi.psy.46.6.578.
  26. ^ MA Menza, Modafinil augmentation of antidepressant treatment in depression, in J Clin Psychiatry, vol. 61, 2000, pp. 378–381.
  27. ^ C DeBattista, A prospective trial of modafinil as an adjunctive treatment of major depression, in J Clin Psychopharmacol, vol. 24, 2004, pp. 87–90, DOI:10.1097/01.jcp.0000104910.75206.b9.
  28. ^ JR MacDonald, Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy, in Neurology, vol. 59, 2002, pp. 1876–1880.
  29. ^ L Webster, Modafinil treatment of opioid-induced sedation, in Pain Med, vol. 4, June 2003, pp. 135–140, DOI:10.1046/j.1526-4637.2003.03014.x.
  30. ^ DL Hurst, Use of modafinil in cerebral palsy, in J Child Neurology, vol. 17, March 2002, pp. 169–172, DOI:10.1177/088307380201700303.
  31. ^ AV Nieves, Treatment of excessive daytime sleepiness in patients with Parkinson’s disease with modafinil, in Clin. Neuropharmacol., vol. 25, March 2002, pp. 111–114, DOI:10.1097/00002826-200203000-00010.
  32. ^ a b Hart CL, Haney M, Vosburg SK, Comer SD, Gunderson E, Foltin RW, Modafinil attenuates disruptions in cognitive performance during simulated night-shift work, in Neuropsychopharmacology, vol. 31, n. 7, Jul 2006, pp. 1526–36, DOI:10.1038/sj.npp.1300991.
  33. ^ Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP, A double-blind, placebo-controlled trial of modafinil for cocaine dependence, in Neuropsychopharmacology, vol. 30, n. 1, 2005, pp. 205–11, DOI:10.1038/sj.npp.1300600.
  34. ^ Umanoff DF, Trial of modafinil for cocaine dependence, in Neuropsychopharmacology, vol. 30, n. 12, 2005, pp. 2298; author reply 2299–300, DOI:10.1038/sj.npp.1300866.
  35. ^ Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP, Reply: Do Self-Reports Reliably Assess Abstinence in Cocaine-Dependent Patients?, in Neuropsychopharmacology, vol. 30, n. 12, 2005, pp. 2299–300, DOI:10.1038/sj.npp.1300867.
  36. ^ a b David Henderson, Modafinil-Associated Weight Loss in a Clozapine-Treated Schizoaffective Disorder Patient, in Annals of Clinical Psychiatry;, vol. 17, n. 2, April–June 2005, pp. 95–97, DOI:10.1080/10401230590932407.
  37. ^ Efficacy and Safety of Modafinil Film-Coated Tablets in Children and Adolescents
  38. ^ Vaishnavi S, Gadde K, Alamy S, Zhang W, Connor K, Davidson JR, Modafinil for atypical depression: effects of open-label and double-blind discontinuation treatment, in J Clin Psychopharmacol, vol. 26, n. 4, Aug 2006, pp. 373–8, DOI:10.1097/01.jcp.0000227700.263.75.39.
  39. ^ Thase ME, Fava M, DeBattista C, Arora S, Hughes RJ, Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: a 12-week, open-label, extension study, in CNS Spectr, vol. 11, n. 2, Feb 2006, pp. 93–102.
  40. ^ Makris AP, Rush CR, Frederich RC, Kelly TH, Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity, in Appetite, vol. 42, n. 2, Apr 2004, pp. 185–95, DOI:10.1016/j.appet.2003.11.003.
  41. ^ 11613_Provigil_PI_4pgr_lo4.indd
  42. ^ a b Bonaventure P, Letavic M, Dugovic C, et al, Histamine H3 receptor antagonists: from target identification to drug leads, in Biochem. Pharmacol., vol. 73, n. 8, Apr 2007, pp. 1084–96, DOI:10.1016/j.bcp.2006.10.031.
  43. ^ "Doctors are finding it harder to deny 'Chemobrain'", The Virginian-Pilot, © October 2, 2007.
  44. ^ Modafinil Relieves Cognitive Chemotherapy Side Effects Psychiatric News, Stephanie Whyche, August 3, 2007 Volume 42 Number 15, page 31
  45. ^ Nader Oskooilar, A Case of Premature Ventricular Contractions With Modafinil, in American Journal of Psychiatry, vol. 162, October 2005, pp. 1983-a-1984, DOI:10.1176/appi.ajp.162.10.1983-a.
  46. ^ MedlinePlus Drug Information: Modafinil, su nlm.nih.gov, NIH, 1º luglio 2005. URL consultato il 21 luglio 2007.
  47. ^ FDA Approved Labeling Text for Provigil (PDF), su fda.gov, FDA, 23 gennaio 2004.
  48. ^ BBC report on MoD research into Modafinil
  49. ^ MoD's secret pep pill to keep forces awake
  50. ^ Modafinil and Management of Aircrew Fatigue - United States Air Force memo
  51. ^ The Effects of Modafinil on Aviator Performance During 40 Hours of Continuous Wakefulness
  52. ^ The efficacy of Modafinil for sustaining alertness and simulator flight performance in F-117 pilots during 37 hours of continuous wakefulness
  53. ^ http://stinet.dtic.mil/cgi-bin/GetTRDoc?AD=ADA454558&Location=U2&doc=GetTRDoc.pdf A Double-Blind Placebo-Controlled Investigation of the Efficacy of Modafinil for Maintaining Alertness and Performance in Sustained Military Ground Operations
  54. ^ Dopheide MM, Morgan RE, Rodvelt KR, Schachtman TR, Miller DK, Modafinil evokes striatal [(3)H]dopamine release and alters the subjective properties of stimulants, in Eur. J. Pharmacol., vol. 568, n. 1-3, Jul 2007, pp. 112–23, DOI:10.1016/j.ejphar.2007.03.044.
  55. ^ Murillo-Rodríguez E, Haro R, Palomero-Rivero M, Millán-Aldaco D, Drucker-Colín R, Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats, in Behav. Brain Res., vol. 176, n. 2, Jan 2007, pp. 353–7, DOI:10.1016/j.bbr.2006.10.016.
  56. ^ de Saint Hilaire Z, Orosco M, Rouch C, Blanc G, Nicolaidis S, Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats, in Neuroreport, vol. 12, n. 16, Nov 2001, pp. 3533–7.
  57. ^ Gallopin T, Luppi PH, Rambert FA, Frydman A, Fort P, Effect of the wake-promoting agent modafinil on sleep-promoting neurons from the ventrolateral preoptic nucleus: an in vitro pharmacologic study, in Sleep, vol. 27, n. 1, Feb 2004, pp. 19–25.
  58. ^ Ferraro L, Fuxe K, Tanganelli S, Tomasini MC, Rambert FA, Antonelli T, Differential enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression, in J. Neurosci. Res., vol. 68, n. 1, Apr 2002, pp. 107–12, DOI:10.1002/jnr.10196.
  59. ^ Ishizuka T, Sakamoto Y, Sakurai T, Yamatodani A, Modafinil increases histamine release in the anterior hypothalamus of rats, in Neurosci. Lett., vol. 339, n. 2, Mar 2003, pp. 143–6, DOI:10.1016/S0304-3940(03)00006-5.
  60. ^ a b Hardman, Joel and Limbird, Lee. 2001. "Goodman and Gilman’s: The Pharmacological Basis of Therapeutics." Edition 10. pp 1984t. New York: McGraw-Hill.
  61. ^ Dockets Entered On December 26, 2006, su google.fda.gov, FDA, 26 dicembre 2006. URL consultato il 21 luglio 2007.
    «2005P-0265 Over-the Counter Sale of Modafinil»
  62. ^ Cephalon gets six-month Provigil patent extension, Philadelphia Business Journal, 28 marzo 2006. URL consultato il 21 luglio 2007.
  63. ^ Evelyn Pringle, Sparlon: Just What Kids Need - Another ADHD Drug, su lawyersandsettlements.com, 20 marzo 2006. URL consultato il 21 luglio 2007.
  64. ^ www.vandapharma.com/development.html, su vandapharma.com.
  65. ^ Is It Illegal to Obtain Controlled Substances From the Internet?, su usdoj.gov, United States Drug Enforcement Administration. URL consultato il 21 luglio 2007.
  66. ^ USC 201 Section 1301.26 Exemptions from import or export requirements for personal medical use, su deadiversion.usdoj.gov, United States Department of Justice, 24 marzo 1997.
  67. ^ Regulations Amending the Food and Drug Regulations (1184 — Modafinil), in Canada Gazette, vol. 140, n. 20, 4 ottobre 2006.
  68. ^ (Spanish) Estupefacientes y Psicotrópicos, su cofepris.gob.mx, Comisión Federal para la Protección contra Riesgos Sanitarios. URL consultato il 21 luglio 2007. Lingua sconosciuta: Spanish (aiuto)
  69. ^ Julia Llewellyn Smith, The 44-hour day (XML), The Telegraph, 6 gennaio 2004.

Collegamenti esterni

  Portale Medicina: accedi alle voci di Wikipedia che trattano di medicina
Estratto da "https://it.wikipedia.org/w/index.php?title=Modafinil&oldid=26871864"