Adrafinil, sold under the brand name Olmifon, is a

wakefulness-promoting Eugeroics (originally "eugrégorique" or "eugregoric"), also known as wakefulness-promoting agents and wakefulness-promoting drugs, are a class of drugs that promote wakefulness and alertness. They are medically indicated for the treatment of cer ...

medication that was formerly used in

France France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...

to improve

alertness Alertness is the state of active attention by high sensory awareness such as being watchful and prompt to meet danger or emergency, or being quick to perceive and act. It is related for psychology . A lack of alertness is a symptom of a ...

attention Attention is the behavioral and cognitive process of selectively concentrating on a discrete aspect of information, whether considered subjective or objective, while ignoring other perceivable information. William James (1890) wrote that "Atte ...

wakefulness Wakefulness is a daily recurring Human brain, brain state and state of consciousness in which an individual is conscious and engages in coherent cognition, cognitive and behavioral responses to the external world. Being awake is the opposite of ...

, and mood, particularly in the elderly. It was also used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although m ...

by individuals who wished to avoid

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

, such as night workers or others who needed to stay awake and alert for long periods of time. Additionally, the medication has been used non-medically as a

nootropic Nootropics ( , or ) (colloquial: smart drugs and cognitive enhancers, similar to adaptogens) are a wide range of natural or synthetic supplements or drugs and other substances that are claimed to improve cognitive function or to promote re ...

. Adrafinil is a

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

; it is primarily

metabolize Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

d ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' to

modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant medication used to treat sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea. While it has seen off-label ...

, resulting in very similar

pharmacological Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...

effects. Unlike modafinil, however, it takes time for the

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

to accumulate to active levels in the bloodstream. Effects usually are apparent within 45–60 minutes when taken orally on an empty

stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...

. Adrafinil was marketed in France until September 2011 when it was voluntarily discontinued due to an unfavorable

risk–benefit ratio A risk–benefit ratio (or benefit-risk ratio) is the ratio of the risk of an action to its potential benefits. Risk–benefit analysis (or benefit-risk analysis) is analysis that seeks to quantify the risk and benefits and hence their ratio. A ...

Medical uses

Adrafinil is a

wakefulness-promoting agent Eugeroics (originally "eugrégorique" or "eugregoric"), also known as wakefulness-promoting agents and wakefulness-promoting drugs, are a class of drugs that promote wakefulness and alertness. They are medically indicated for the treatment of cer ...

and was used to promote alertness, attention, wakefulness, and mood. It was particularly used in the elderly.

Available forms

Adrafinil was available in the form of 300mg

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or oral ...

tablet Tablet may refer to: Medicine * Tablet (pharmacy), a mixture of pharmacological substances pressed into a small cake or bar, colloquially called a "pill" Computing * Tablet computer, a mobile computer that is primarily operated by touching the s ...

Side effects

There is a

case report In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrence ...

of two patients that adrafinil may increase interest in sex. A

of adrafinil-induced

orofacial dyskinesia Meige's syndrome is a type of dystonia. It is also known as Brueghel's syndrome and oral facial dystonia. It is actually a combination of two forms of dystonia, blepharospasm and oromandibular dystonia (OMD). When OMD is combined with blephar ...

exists. Reports of this side effect also exist for modafinil.

Pharmacology

Pharmacodynamics

Because α₁-adrenergic receptor

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

s were found to block effects of adrafinil and modafinil in animals, "most investigators assume that adrafinil and modafinil both serve as α₁-adrenergic receptor agonists." However, adrafinil and modafinil have not been found to bind to the α₁-adrenergic receptor and they lack

peripheral A peripheral or peripheral device is an auxiliary device used to put information into and get information out of a computer. The term ''peripheral device'' refers to all hardware components that are attached to a computer and are controlled by the ...

sympathomimetic Sympathomimetic drugs (also known as adrenergic drugs and adrenergic amines) are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in hea ...

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s associated with activation of this receptor; hence, the evidence in support of this hypothesis is weak, and other mechanisms are probable. Modafinil was subsequently screened at a variety of targets in 2009 and was found to act as a weak, atypical blocker of the

dopamine transporter The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopam ...

(and hence as a

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopa ...

), and this action may explain some or all of its pharmacological effects. Relative to adrafinil, modafinil possesses greater specificity in its action, lacking or having a reduced incidence of many of the common side effects of the former (including stomach pain,

skin irritation Irritation, in biology and physiology, is a state of inflammation or painful reaction to allergy or cell-lining damage. A stimulus or agent which induces the state of irritation is an irritant. Irritants are typically thought of as chemical age ...

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

, and elevated

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s with prolonged use).

Pharmacokinetics

In addition to modafinil, adrafinil also produces

modafinil acid Modafinil acid (code name CRL-40467), also known as modafinilic acid or modafinil carboxylate, is one of the two major metabolites of modafinil – the other being modafinil sulfone. Modafinil acid is also a metabolite of the modafinil prodrug, a ...

(CRL-40467) and

modafinil sulfone Modafinil sulfone (code name CRL-41056) is an achiral, oxidized metabolite of modafinil, a wakefulness-promoting agent. It is one of two major circulating metabolites of modafinil, the other being modafinil acid. Modafinil sulfone is also a metab ...

(CRL-41056) as metabolites, which form from metabolic modification of modafinil.

Chemistry

Analogues of adrafinil include

armodafinil Armodafinil (trade name Nuvigil) is the enantiopure compound of the eugeroic modafinil (Provigil). It consists of only the (''R'')-(−)-enantiomer of the racemic modafinil. Armodafinil is produced by the pharmaceutical company Cephalon Inc. an ...

, CRL-40,940,

CRL-40,941 CRL-40,941 (also known as fladrafinil and fluorafinil) is a eugeroic closely related to adrafinil and modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant medication used to t ...

, and

fluorenol Fluorenol, also known as hydrafinil, is an Alcohol (chemistry), alcohol derivative of fluorene. In the most significant isomer, fluoren-9-ol or 9-hydroxyfluorene, the hydroxy group is located on the bridging carbon between the two benzene rings. H ...

History

Adrafinil was discovered in 1974 by two chemists working for the French pharmaceutical company Laboratoires Lafon who were screening compounds in search of

analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...

s. Pharmacological studies of adrafinil instead revealed psychostimulant-like effects such as

hyperactivity Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...

and

in animals. The substance was first tested in humans, specifically for the treatment of narcolepsy, in 1977–1978. Introduced by Lafon (now Cephalon), it reached the market in France in 1984, and for the treatment of narcolepsy in 1985. In 1976, two years after the discovery of adrafinil, modafinil, its

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

, was discovered. Modafinil appeared to be more potent than adrafinil in animal studies, and was selected for further clinical development, with both adrafinil and modafinil eventually reaching the market. Modafinil was first approved in France in 1994, and then in the United States in 1998. Lafon was acquired by

Cephalon Cephalon, Inc. was an American biopharmaceutical company co-founded in 1987 by pharmacologist Frank Baldino, Jr., neuroscientist Michael Lewis, and organic chemist James C. Kauer—all three former scientists with the DuPont Company. Baldino s ...

in 2001. As of September 2011, Cephalon has discontinued Olmifon, its adrafinil product, while modafinil continues to be marketed.

Society and culture

Names

''Adrafinil'' is the generic name of the drug and its and . It is also known by its brand name Olmifon and its developmental code name ''CRL-40028''.

Regulation

Athletic doping

Adrafinil and its

modafinil were added to the list of substances prohibited for athletic competition according to

World Anti-Doping Agency The World Anti-Doping Agency (WADA; french: Agence mondiale antidopage, AMA) is a foundation initiated by the International Olympic Committee based in Canada to promote, coordinate, and monitor the fight against drugs in sports. The agency's key ...

in 2004.

New Zealand

In 2005 a Medical Classification Committee in

New Zealand New Zealand ( mi, Aotearoa ) is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and over 700 smaller islands. It is the sixth-largest island count ...

recommended to MEDSAFE NZ that adrafinil be classified as a

prescription medicine A prescription drug (also prescription medication or prescription medicine) is a pharmaceutical drug that legally requires a medical prescription to be dispensed. In contrast, over-the-counter drugs can be obtained without a prescription. The rea ...

due to risks of it being used as a

party drug Recreational drug use indicates the use of one or more psychoactive drugs to induce an altered state of consciousness either for pleasure or for some other casual purpose or pastime by modifying the perceptions and emotions of the user. When a ...

. At that time adrafinil was not scheduled in New Zealand.MCC Minutes Out of Session Meeting
Medsafe.govt.nz (2013-05-23). Retrieved on 2013-12-18.

Research

In a

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

with the

tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...

clomipramine Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used for the treatment of obsessive–compulsive disorder, panic disorder, major depressive disorder, and chronic pain. It may increase th ...

and

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

as comparators, adrafinil showed efficacy in the treatment of depression. In contrast to clomipramine however, adrafinil was well-tolerated, and showed greater improvement in

psychomotor retardation Psychomotor may refer to: * Psychomotor learning, the relationship between cognitive functions and physical movement * Psychomotor retardation, a slowing-down of thought and a reduction of physical movements in an individual * Psychomotor agitatio ...

in comparison. The authors concluded that further investigation of the potential antidepressant effects of adrafinil were warranted.

References

External links

* * * * {{Monoamine reuptake inhibitors CYP3A4 inducers Dopamine reuptake inhibitors Drugs with unknown mechanisms of action Hydroxamic acids Nootropics Phenyl compounds Prodrugs Stimulants Sulfoxides Withdrawn drugs World Anti-Doping Agency prohibited substances