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20-September-2008 09:55:56 - Modafinil Modafinil Systematic IUPAC name 2-benzhydrylsulfinylethanamide Identifiers CAS number 68693-11-8 ATC code N06BA07 PubChem 4236 DrugBank APRD00534 Chemical data Formula C15H15NO2S Mol. mass 273.351 g/mol SMILES eMolecules PubChem Pharmacokinetic data Bioavailability ? Protein binding 60% Metabolism Hepatic, including CYP3A4 and other pathways Half life 8-18 hours Excretion Urine as metabolites Therapeutic considerations Pregnancy cat. C Legal status Schedule IV US, POM UK Routes Oral Modafinil Provigil is a stimulant-like drug manufactured by Cephalon, and is approved by the FDA for the treatment of narcolepsy, shift work sleep disorder and obstructive sleep apnea.1 Modafinil, like other stimulants, increases the release of monoamines but also elevates hypothalamic histamine levels,2 leading some researchers to consider Modafinil a wakefulness promoting agent rather than a classic amphetamine-like stimulant as evidenced by the difference in c-fos distribution caused by modafinil as compared to amphetamine.3 Modafinil is also indicated, though not approved, in the treatment of Attention-Deficit Hyperactivity Disorder ADHD,4 shift-work sleep disorder,5 depression,6 cocaine addiction,7 Parkinson's Disease,8 schizophrenia,9 and disease-related fatigue.1011 By law, however, Cephalon is not allowed to market Modafinil for conditions other than those officially approved by the FDA.12 Modafinil and its chemical predecessor Adrafinil were developed by Lafon Laboratories, a French company acquired by Cephalon in 2001.13 Modafinil is the primary metabolite of adrafinil, and, while their activity is similar, adrafinil requires a higher dose to achieve equipotent effects. Contents 1 Indications 2 Off-label use 2.1 Doping agent 2.2 Multiple sclerosis 2.3 ADHD 2.4 Other uses 3 Experimental uses 3.1 Cocaine addiction 3.2 Weight loss 3.3 Primary biliary cirrhosis 3.4 Post-chemotherapy cognitive impairment 3.5 Mood elevation 4 Contraindications and warnings 4.1 Severe adverse reactions 5 Side-effects 6 Military use 7 Pharmacology 8 Pharmacokinetics 9 History 9.1 Formulation patent 9.2 Particle size patent 10 Other wakefulness promoting agents 11 Legal status 12 In popular culture 13 See also 14 References 15 External links Indications In the United States, modafinil is approved by the FDA for the treatment of narcolepsy, obstructive sleep apnea/hypopnea and shift work sleep disorder. In some countries, it is also approved for idiopathic hypersomnia all forms of excessive daytime sleepiness where causes can't be established. Off-label use Modafinil is widely used off-label to suppress the need for sleep. It is also used off-label in combating general fatigue unrelated to lack of sleep such as in treating ADHD and as an adjunct to antidepressants particularly in individuals with significant residual fatigue. There is a disagreement whether the cognitive effects modafinil showed in healthy non-sleep-deprived people are sufficient to consider it to be a cognitive enhancer.141516 The researchers agree that modafinil improves some aspects of working memory, such as digit span, digit manipulation and pattern recognition memory, but the results related to spatial memory, executive function and attention are equivocal.14151617 Some of the positive effects of modafinil may be limited to lower-performing17 individuals or to the individuals with lower IQ.18 There is also evidence that it has neuroprotective effects.19 Even though once a prescription drug is approved as safe and effective for a particular use, a physician may prescribe it for a different or off-label use, a drug manufacturer is prohibited from advertising it or promoting it for these off-label uses. Cephalon, the drugmaker of Provigil modafinil negotiated a plea bargain with the US Attorney in Philadelphia, and signed a corporate integrity agreement where it will admit to a misdemeanor violation of the Food, Drug and Cosmetic Act. The admission relates to its sales reps improperly marketing its narcolepsy approved drug as well as some other drugs for off-label uses such as depression and ADHD. Cephalon also had to pay a $425 million penalty.20 Doping agent Modafinil has received some publicity in the past when several athletes were discovered allegedly using it as a doping agent. It is not clear how widespread this practice is. Since there are no studies pertaining to this sort of use, it is unknown whether modafinil can have any impact on an athlete's performance. However, anecdotal evidence indicates that modafinil does indeed enhance physical performance. Modafinil was added to the World Anti-Doping Agency Prohibited List in 2004 as a prohibited stimulant. In December 2007, professional poker player Paul Phillips claimed that the use of modafinil and other medications prescribed to him for ADHD treatment made him a much better player and helped him earn more than $2.3 million in poker. The drugs improved his concentration during high-stakes tournaments, he said, allowing him to better track all the action at his table.21 In poker there are currently no rules prohibiting the use of stimulants. Multiple sclerosis Modafinil has been used to allay symptoms of the neurological fatigue reported by some with multiple sclerosis. Patients follow either the standard usage or take a single dose of 100-200 mg at the start of days self-assessed as being potentially excessively fatiguing. In 2000, Cephalon conducted a study to evaluate modafinil as a potential treatment for MS-related fatigue. A group of 72 people with MS of varying degrees of severity tested two different doses of modafinil and an inactive placebo over nine weeks. Fatigue levels were self-evaluated on standardized scales. Participants taking a lower dose of modafinil reported feeling less fatigued and there was a statistically significant difference in fatigue scores for the lower dose versus the placebo. The higher dose of modafinil was not reported to be effective.22 ADHD As of February 2007, there are at least seven English-language articles on randomized clinical trials in humans in the Medline database addressing the use of modafinil for the treatment of attention deficit/hyperactivity disorder ADHD. Some studies have shown the use of modafinil in the treatment of ADHD is associated with significant improvements in primary outcome measures. Cognitive function in ADHD patients was also found to improve following modafinil treatment, in some studies. Studies for ADHD report insomnia and headache were the most common adverse effects, seen in approximately 20% of treated individuals. These studies were not adequate to demonstrate that the beneficial effects of modafinil are maintained with chronic administration. Additional large, long-term studies using flexible titration methods to establish safety and efficacy and head-to-head comparisons between modafinil and stimulants are needed to determine the role of modafinil in the treatment of ADHD.23 In December of 2004, Cephalon submitted a supplemental new drug application sNDA to market Sparlon, a brand name of tablets containing higher doses of modafinil for the treatment of ADHD in children and adolescents ages 6 through 17. However, in March 2006, the FDA advisory committee voted 12 to 1 against approval, citing concerns about a number of reported cases of skin rash reactions in a 1000-patient trial, including one which was thought to be likely a case of Stevens-Johnson syndrome.2425 Final rejection occurred in August 2006, although subsequent follow-up indicated that the skin rash reaction was not Stevens-Johnson syndrome.citation needed Cephalon then decided to discontinue development of the Sparlon product for use in pediatric cases, though there is potential for use in treating Adult ADHD. Modafinil is relatively contraindicated for patients with a history of cardiac events. However, one 2005 case report26 positively describes transitioning a 78 year old with significant cardiac comorbidity from methylphenidate 5 mg b.i.d. to modafinil; however, this was in the setting of severe treatment resistant depression, not ADHD. Thus, Modafinil's physiologic and political advantages over conventional ADHD therapies should not be dismissed out of hand, but rather discussed individually with a physician, neurologist or psychiatrist. Other uses Modafinil is also used off-label to treat sedation and fatigue in depression,2728 myotonic dystrophy,29 opioid-induced sleepiness,30 spastic cerebral palsy,31 and Parkinson's disease.32 It increases subjective mood and friendliness, at least among shift workers.33 Experimental uses Cocaine addiction A single 8-week double-blind study of modafinil for cocaine dependence produced inconclusive results. The number of cocaine-positive urine samples was significantly lower in the modafinil group as compared to the placebo group in the middle of the trial, but by the end of the 8 weeks the difference stopped being significant. Even before the treatment began, the modafinil group had had lower cocaine consumption further confounding the results. As compared to placebo, modafinil did not reduce cocaine craving or self-reported cocaine use, and the physicians ratings were only insignificantly better.34 In the polemics with the authors of the study, Dan Umanoff, of the National Association for the Advancement and Advocacy of Addicts, criticized them for leaving the negative results out of the discussion part and the abstract of the article.3536 Weight loss Studies on modafinil even those on healthy weight individuals indicate that it has an appetite reducing/weight loss effect.3733383940 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.41 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. 42 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.37 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.43 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.44 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.45 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.43 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: Left ventricular hypertrophy, or Mitral valve prolapse. Asymptomatic MVP is not uncommon, but neither is it prominently discussed in Modafinil's context. Although it is not discussed in the literature, the standard binders used for Modafinil contain wheat glutencitation needed, 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. 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: Common Headache 34% vs 23% Nausea 11% vs 3% Uncommon Nervousness 7% vs 3% Insomnia 5% vs 1% Anxiety 5% vs 1% Anorexia 4% vs 1% Dry mouth 4% vs 2% Rare Chest pain 3% vs 1% Hypertension 3% vs 1% Tachycardia 2% vs 1% Vasodilation 2% vs 0% Dizziness 5% vs 4% Paresthesia 2% vs 0% Pharyngitis 4% vs 2% 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.46 Modafinil may have an adverse effect on hormonal contraceptives, lasting for a month after cessation of dosage.47 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.48 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 Modafinil49 and spent £300,000 on one investigation.50 In the United States military, Modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses.51One 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.52However, 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.53 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.54 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,5556 noradrenalin in the hypothalamus and ventrolateral preoptic nucleus,5758 and serotonin in the amygdala and frontal cortex.59 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.60 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.61 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. 61 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.62 Formulation patent A U.S. Patent 4,927,855 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 U.S. Patent 5,618,845 , 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.63 However, a settlement in which Cephalon apparently paid out US$ 200 million to four generic drug manufacturers64 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. 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.65 Legal status 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.66 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.67 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: Canada not listed in the Controlled Drugs and Substances Act, but it is a Schedule F prescription drug68, so it is subject to seizure by Canada Customs Mexico69 United Kingdom not listed in the Misuse of Drugs Act and is available by prescription without legal restrictions70 Australia listed as a Schedule 4 prescription drug In Germany the classification has been changed from controlled substance BtM to prescription drug RP effective since March 1, 2008. 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 popular culture 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. In the television series House, the season 2 episode Forever ends with a scene where Dr. Foreman is testing his memory with flash cards containing dosage information for various prescription drugs. After briefly giving up in frustration, he realizes Dr. Cameron saw him and decides to continue. Upon reading the next card, he smiles in triumph; the card is turned over to reveal the drug was modafinil. See also Adrafinil Armodafinil Orexin-A Human reliability Hypopnea syndrome Narcolepsy Seasonal affective disorder SAD Shift work sleep disorder SWSD Sleep apnea Sleep disorder Nootropics References ^ Provigil Modafinil Site. 12/24/1998 1. ^ Ishizuka T, Murakami M, Yamatodani A. Involvement of central histaminergic systems in modafinil-induced but not methylphenidate-induced increases in locomotor activity in rats. European Journal of Pharmacology 2008 Jan 14;5782-3:209-15. Epub 2007 Sep 26. PMID 17920581 ^ 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. Neuroscience Letters 1998 Jan 30;2412-3:95-8. PMID 9507929 ^ Biederman J, Pliszka SR. Modafinil improves symptoms of attention-deficit/hyperactivity disorder across subtypes in children and adolescents. Journal of Pediatrics 2008 Mar;1523:394-9. Epub 2007 Oct 24. PMID 18280848 ^ 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;93:188-94. Full Text ^ IFava 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. Annals of Clinical Psychiatry 2007 Jul-Sep;193:153-9. PMID 17729016 ^ Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology 2005 Jan;301:205-11. PMID 15525998 ^ 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. Behavioral Pharmacology 2006 Sep;175-6:453-62. PMID 16940766 ^ 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. Neuropsychopharmacology 2004 Jul;297:1363-73. PMID 15085092 ^ 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. Journal of Neurology, Neurosurgery, and Psychiatry 2002 Feb;722:179-83. Full Text ^ Rabkin JG, McElhiney MC, Rabkin R, Ferrando SJ. Modafinil treatment for fatigue in HIV+ patients: a pilot study. Journal of Clinical Psychology 2004 Dec;6512:1688-95. PMID 5641875 ^ U.S. Food and Drug Administration. Prescription Drug Marketing Act of 1987 PDMA, PL 100-293. Link ^ News Release Cephalon. Cephalon, Inc. Plans to Acquire France's Group Lafon. WEST CHESTER, Pa., Dec 3, 2001 PR Newswire Link ^ a b Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ 2003. Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology Berl. 165 3: 260-9. doi:10.1007/s00213-002-1250-8. PMID 12417966. ^ a b Randall DC, Viswanath A, Bharania P, Elsabagh SM, Hartley DE, Shneerson JM, File SE 2005. Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived?. J Clin Psychopharmacol 25 2: 175-9. doi:10.1097/01.jcp.0000155816.21467.25. PMID 15738750. ^ a b Baranski JV, Pigeau R, Dinich P, Jacobs I 2004. Effects of modafinil on cognitive and meta-cognitive performance. Hum Psychopharmacol 19 5: 323-32. doi:10.1002/hup.596. PMID 15252824. ^ a b Müller U, Steffenhagen N, Regenthal R, Bublak P 2004. Effects of modafinil on working memory processes in humans. Psychopharmacology Berl. 177 1-2: 161-9. doi:10.1007/s00213-004-1926-3. PMID 15221200. ^ Randall DC, Shneerson JM, File SE 2005. Cognitive effects of modafinil in student volunteers may depend on IQ. Pharmacol. Biochem. Behav. 82 1: 133-9. doi:10.1016/j.pbb.2005.07.019. PMID 16140369. ^ Jenner, P July 2000, Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset, Experimental Brain Research 1332: 178-188, doi:10.1007/s002210000370, http://www.springerlink.com/content/x38bd13amf33cd5u/ ^ http://www.fiercepharma.com/story/cephalon-pay-425m-settlement/2007-11-09fiercepharma.com Cephalon pay 425 m settlement Nov 9, 2007 accessed Dec 11, 2007 ^ Drugs to build up that mental muscle - Los Angeles Times ^ Rammohan, K W 2002, Efficacy and safety of modafinil Provigil® for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study, Journal of Neurology Neurosurgery and Psychiatry 722: 179-183, doi:10.1136/jnnp.72.2.179, PMID 11796766, http://jnnp.bmj.com/cgi/content/abstract/72/2/179 ^ Lindsay, SE; Gudelsky GA, Heaton PC October 2006. Use of modafinil for the treatment of attention deficit/hyperactivity disorder. The Annals of Pharmacotherapy 40 10. Retrieved on 2006-12-07. ^ Psychopharmacologic Drugs Advisory Committee transcript. FDA 2006-03-23. ^ Modafinil CEP-1538 Tablets Supplemental NDA 20-717/S-019 ADHD Indication Briefing Document for Psychopharmacologic Drugs Advisory Committee Meeting PDF. FDA 2006-03-23. Retrieved on 2007-07-21. ^ Xiong, M.D., Glen L.; Eric J. Christopher, M.D., and Jason Goebel, M.D. 2005. Modafinil as an Alternative to Methylphenidate as Augmentation for Depression Treatment. Psychosomatics 46: 578-579. Academy of Psychosomatic Medicine. doi:10.1176/appi.psy.46.6.578. PMID 16288139. Case report: Modafinil 200 mg daily replacing Methylphenidate 5 mg b.i.d in 78 year old cardiac patient ^ Menza, MA 2000, Modafinil augmentation of antidepressant treatment in depression, J Clin Psychiatry 6111: 378-381, http://bjsm.bmj.com/cgi/external_ref?access_num=10847314link_type=MED ^ DeBattista, C 2004, A prospective trial of modafinil as an adjunctive treatment of major depression, J Clin Psychopharmacol 241: 87-90, doi:10.1097/01.jcp.0000104910.75206.b9, http://bjsm.bmj.com/cgi/external_ref?access_num=14709953link_type=MED ^ MacDonald, JR 2002, Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy, Neurology 59: 1876-1880, PMID 12499477, http://bjsm.bmj.com/cgi/ijlink?linkType=ABSTjournalCode=neurologyresid=59/12/1876 ^ Webster, L June 2003, Modafinil treatment of opioid-induced sedation, Pain Med 42: 135-140, doi:10.1046/j.1526-4637.2003.03014.x, http://bjsm.bmj.com/cgi/external_ref?access_num=12873263link_type=MED ^ Hurst, DL March 2002, Use of modafinil in cerebral palsy, J Child Neurology 173: 169-172, doi:10.1177/088307380201700303, PMID 12026230, http://bjsm.bmj.com/cgi/external_ref?access_num=12026230link_type=MED ^ Nieves, AV March 2002, Treatment of excessive daytime sleepiness in patients with Parkinson's disease with modafinil, Clin. Neuropharmacol. 252: 111-114, doi:10.1097/00002826-200203000-00010, http://bjsm.bmj.com/cgi/external_ref?access_num=11981239link_type=MED ^ a b Hart, Carl 2006, Modafinil attenuates disruptions in cognitive performance during simulated night-shift work., Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 317: 1526-1536, doi:10.1038/sj.npp.1300991, http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmedCmd=ShowDetailViewTermToSearch=16395298 ^ Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP 2005. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology 30 1: 205-11. doi:10.1038/sj.npp.1300600. PMID 15525998. ^ Umanoff DF 2005. Trial of modafinil for cocaine dependence. Neuropsychopharmacology 30 12: 2298; author reply 2299-300. doi:10.1038/sj.npp.1300866. PMID 16294193. ^ Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O'Brien CP 2005. Reply: Do Self-Reports Reliably Assess Abstinence in Cocaine-Dependent Patients?. Neuropsychopharmacology 30 12: 2299-300. doi:10.1038/sj.npp.1300867. ^ a b Henderson, David April-June 2005, Modafinil-Associated Weight Loss in a Clozapine-Treated Schizoaffective Disorder Patient, Annals of Clinical Psychiatry; 172: 95-97, doi:10.1080/10401230590932407 ^ Efficacy and Safety of Modafinil Film-Coated Tablets in Children and Adolescents ^ Vaishnavi, Sandeep 2006, Modafinil for atypical depression: effects of open-label and double-blind discontinuation treatment., Journal of clinical psychopharmacology 264: 373-378, http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmedCmd=ShowDetailViewTermToSearch=16855454 ^ Michael, Thase 2006, Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: a 12-week, open-label extension study, CNS Spectrums 112: 93-101, http://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMedCmd=ShowDetailViewTermToSearch=16520686ordinalpos=2itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum ^ Makris, Angela April 2004, Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity, Appetite 422: 185, doi:10.1016/j.appet.2003.11.003, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrievedb=PubMedlist_uids=15010183dopt=Abstract ^ 11613_Provigil_PI_4pgr_lo4.indd ^ a b Bonaventure, P., Letavic, M., Dugovich, C., Wilson, S., Alusio, L., Pudiak, C., et al. 2007, April 15. Histamine H3 receptor antagonists: From target identification to drug leads. Biochemical Pharmocology, 732007 Apr 15; Vol. 73 8, pp. 1084-96, 1084-96. Abstract retrieved April 2, 2007, from Medline database. ^ Doctors are finding it harder to deny 'Chemobrain', The Virginian-Pilot, © October 2, 2007. ^ Modafinil Relieves Cognitive Chemotherapy Side Effects Psychiatric News, Stephanie Whyche, August 3, 2007 Volume 42 Number 15, page 31 ^ Oskooilar, Nader October 2005. A Case of Premature Ventricular Contractions With Modafinil. American Journal of Psychiatry 162: 1983-a-1984. doi:10.1176/appi.ajp.162.10.1983-a. PMID 16199853. ^ MedlinePlus Drug Information: Modafinil. NIH 2005-07-01. Retrieved on 2007-07-21. ^ FDA Approved Labeling Text for Provigil PDF. FDA 2004-01-23. ^ BBC report on MoD research into Modafinil ^ MoD's secret pep pill to keep forces awake ^ Modafinil and Management of Aircrew Fatigue - United States Air Force memo ^ The Effects of Modafinil on Aviator Performance During 40 Hours of Continuous Wakefulness ^ The efficacy of Modafinil for sustaining alertness and simulator flight performance in F-117 pilots during 37 hours of continuous wakefulness ^ http://stinet.dtic.mil/cgi-bin/GetTRDoc?AD=ADA454558Location=U2doc=GetTRDoc.pdf A Double-Blind Placebo-Controlled Investigation of the Efficacy of Modafinil for Maintaining Alertness and Performance in Sustained Military Ground Operations ^ Dopheide MM, Morgan RE, Rodvelt KR, Schachtman TR, Miller DK. Modafinil evokes striatal 3Hdopamine release and alters the subjective properties of stimulants. European Journal of Pharmacology 2007 Jul 30;5681-3:112-23. Epub 2007 Apr 5. PMID: 17477916 ^ 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. Behavioral Brain Research 2007 Jan 25;1762:353-7. Epub 2006 Nov 13. PMID: 17098298. ^ 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. Neuroreport 2001 Nov 16;1216:3533-7. PMID: 11733706. ^ 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. Sleep 2004 Feb 1;271:19-25. PMID: 14998233. ^ 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. Journal of Neuroscience Research 2002 Apr 1;681:107-12. PMID: 11933055. ^ Ishizuka, T; Sakamoto Y, Sakurai T, Yamatodani A 2003. Modafinil increases histamine release in the anterior hypothalamus of rats. Neuroscience Letters 339 2: 143-6. doi:10.1016/S0304-39400300006-5. PMID 12614915. ^ a b Hardman, Joel and Limbird, Lee. 2001. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. ion 10. pp 1984t. New York: McGraw-Hill. ^ Dockets Entered On December 26, 2006. FDA 2006-12-26. Retrieved on 2007-07-21. 2005P-0265 Over-the Counter Sale of Modafinil ^ Cephalon gets six-month Provigil patent extension, Philadelphia Business Journal 2006-03-28. Retrieved on 2007-07-21. ^ Pringle, Evelyn 2006-03-20. Sparlon: Just What Kids Need - Another ADHD Drug. Retrieved on 2007-07-21. ^ www.vandapharma.com/development.html. ^ Is It Illegal to Obtain Controlled Substances From the Internet?. United States Drug Enforcement Administration. Retrieved on 2007-07-21. ^ USC 201 Section 1301.26 Exemptions from import or export requirements for personal medical use. United States Department of Justice 1997-03-24. ^ Regulations Amending the Food and Drug Regulations 1184 - Modafinil 2006-10-04. Canada Gazette 140 20. ^ Estupefacientes y Psicotrópicos in Spanish. Comisión Federal para la Protección contra Riesgos Sanitarios. Retrieved on 2007-07-21. ^ Julia Llewellyn Smith 2004-01-06. The 44-hour day, The Telegraph. External links Provigil corporate website Wake Up, Little Susie article and reporter's diary on taking modafinil from March 7, 2003 Slate magazine Get ready for 24-hour living from 18 February 2006 New Scientist RxList Patient Information for modafinil users Minzenberg, Michael J.; Cameron S. Carter 2008. Modafinil: A Review of Neurochemical Actions and Effects on Cognition. Neuropsychopharmacology 33: 1477-502. doi:10.1038/sj.npp.1301534. v d e Stimulants Alkylamines Cyclopentamine Geranamine Isometheptene Octodrine Propylhexedrine Tuamine Alphapyrrolidinylalkiophenones α-PPP MDPPP MDPV MPBP MPHP MPPP MOPPP Pyrovalerone Cholinergics ABT-089 ABT-418 Anabasine Arecoline Cotinine Cytisine Dianicline Epibatidine Epiboxidine GTS-21 Ispronicline Nicotine Rivanicline Tebanicline Varenicline Convulsants Bicuculline DMCM Gabazine Pentetrazol Picrotoxin Strychnine Thujone Eugeroics Adrafinil Armodafinil Carphedon Modafinil Phenethylamines 4-Bromomethcathinone 4-Fluoroamphetamine 4-Fluoromethamphetamine 4-Fluoromethcathinone 4-Methylmethcathinone 4-MTA Aletamine Amfepentorex Amphechloral Amphetamine Dextroamphetamine, Adderall Amphetaminil Benzphetamine Bupropion Cathinone Chlorphentermine Clenbuterol Clobenzorex Clortermine Diethylpropion Dimethoxyamphetamine Dimethylamphetamine Dimethylcathinone Ephedrine Epinephrine Ethcathinone Ethylamphetamine Fenethylline Fenfluramine Fenproporex Fludorex Furfenorex Levomethamphetamine Lisdexamfetamine MDMA Mefenorex Methamphetamine Methcathinone Methoxyphedrine Methylone Octopamine Ortetamine Parahydroxyamphetamine PCA PIA PMA PMEA PMMA PPAP Phendimetrazine Phenmetrazine Phentermine Phenylephrine Phenylpropanolamine Propylamphetamine Pseudoephedrine Selegiline Synephrine Tiflorex Xylopropamine Phenylaminooxazoles 4-Methyl-aminorex Aminorex Clominorex Fenozolone Fluminorex Pemoline Thozalinone Piperazines 2C-B-BZP BZP GBR-12783 GBR-12935 GBR-13069 GBR-13098 GBR-13119 MeOPP MBZP Vanoxerine Piperidines 2-Benzylpiperidine Desoxypipradrol Diphemethoxidine Ethylphenidate HDMP-28 --Methyl-1-methyl-4β-2-naphthylpiperidine-3β-carboxylate Methylphenidate Dexmethylphenidate Nocaine Phacetoperane Pipradrol Tropanes 3α-Bis-4-fluorophenylmethoxytropane 3α-4-Chlorophenylphenylmethoxytropane 3-Pseudotropyl-4-fluorobenzoate Altropane IACFT Brasofensine CFT WIN 35,428 β-CIT RTI-55 Cocaethylene Cocaine β-CPPIT Dichloropane RTI-111 Difluoropine FE-β-CPPIT FP-β-CPPIT PIT PTT RTI-31 RTI-32 RTI-51 RTI-112 RTI-113 RTI-121 IPCIT RTI-126 RTI-150 RTI-171 RTI-177 RTI-336 Tesofensine Troparil β-CPT, WIN 35,065-2 WF-23 WF-33 WF-60 Xanthines Aminophylline Caffeine Dimethazan Paraxanthine Theobromine Theophylline Others Amineptine Bemegride Benzydamine BPAP Bromantane BTQ Clofenciclan Cypenamine Cyprodenate Diclofensine Dimethocaine Diphenyl prolinol Ethamivan Fencamfamine Feprosidnine Gilutensin GYKI-52895 Hexacyclonate Indanorex Indatraline LR-5182 Mazindol Mesocarb Naphthylisopropylamine Nikethamide Nomifensine Phthalimidopropiophenone Prolintane Sibutramine Yohimbine Zylofuramine See also Sympathomimetic amines v d e Psychoanaleptics: psychostimulants, agents used for ADHD and nootropics N06B Centrally acting sympathomimetics Amphetamine - Amphetaminil - Atomoxetine - Dextroamphetamine - Dextromethamphetamine - Fencamfamin - Fenozolone - Fenetylline - Methylphenidate - Mesocarb - Pemoline - Pipradrol - Prolintane Xanthine derivatives Caffeine - Propentofylline Glutamate receptor Racetams Aniracetam - Nefiracetam - Oxiracetam - Phenylpiracetam - Piracetam - Pramiracetam Ampakines CX-516 - CX-546 - CX-614 - CX-691 - CX-717 - IDRA-21 - LY-503,430 - PEPA Eugeroics / Benzhydryl compounds Adrafinil - Armodafinil - Modafinil Histamine H3 receptor antagonists ABT-239 - Ciproxifan Other psychostimulants and nootropics Acetylcarnitine - Citicoline - Cyprodenate - Idebenone - Ispronicline - Deanol - Dimebon - Fipexide - Linopirdine - Meclofenoxate - Nizofenone - Pirisudanol - Pyritinol - Sulbutiamine - Taltirelin - Tricyanoaminopropene - Vinpocetine Retrieved from http://en..org/wiki/Modafinil Categories: Nootropics | Stimulants | SulfoxidesHidden categories: All articles with statements | Articles with statements since February 2007 | Articles with statements since April 2008 Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Español Français Galego עברית Nederlands 日本語 Polski Português Suomi Svenska 中文 This page was last modified on 14 August 2008, at 20:02
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