Disease relevance of C13302

• Modafinil-associated clozapine toxicity [1].
• A case of premature ventricular contractions with modafinil [2].
• Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea [3].
• Modafinil for excessive daytime sleepiness in myotonic dystrophy [4].
• Pro: modafinil has a role in management of sleep apnea [5].

Psychiatry related information on C13302

• Newer compounds, such as modafinil (non-amphetamine wake-promoting compound for excessive daytime sleepiness) and sodium oxybate (short-acting sedative for fragmented nighttime sleep, cataplexy, excessive daytime sleepiness), are increasingly used [6].
• The brain targets on which modafinil acts to induce wakefulness, however, remain unknown [7].
• Modafinil for social phobia and amphetamine dependence [8].
• We examined whether modafinil induced similar improvements in adults with attention-deficit/hyperactivity disorder [9].
• Modafinil selectively improves neuropsychological task performance in healthy volunteers, possibly through improved inhibitory control [9].
• These data suggest that adjunctive modafinil at doses of 100-200 mg a day may improve depressive symptoms in patients with bipolar disorder [10].

High impact information on C13302

• Moreover, modafinil, an anti-narcoleptic drug with ill-defined mechanisms of action, activates orexin-containing neurons [11].
• Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat [7].
• Cats were sacrificed after a single oral administration of amphetamine, methylphenidate, or modafinil at equivalent doses for wake induction (1, 2.5, or 5 mg/kg, respectively) and brain sections examined for Fos by immunocytochemistry [7].
• In contrast, administration of modafinil resulted in the labeling of few cells in these structures, but did induce marked Fos labeling in neurons of the anterior hypothalamic nucleus and adjacent areas [7].
• The main clinical features of narcolepsy, excessive daytime sleepiness and symptoms of abnormal REM sleep (cataplexy, sleep paralysis, hypnagogic hallucinations) are currently treated using amphetamine-like compounds or modafinil and antidepressants [12].

Chemical compound and disease context of C13302

• To date, the strongest evidence among off-label uses exists for the use of modafinil in attention-deficit disorder, postanesthetic sedation, and cocaine dependence and withdrawal and as an adjunct to antidepressants for depression [13].
• The effects of caffeine, dextroamphetamine, and modafinil on humor appreciation during sleep deprivation [14].
• CONCLUSIONS: Sodium oxybate and modafinil are both effective for treating excessive daytime sleepiness in narcolepsy, producing additive effects when used together [15].
• The effects of modafinil were compared with those of dexamphetamine on three tests that assessed the anxiety level (drugs were used at doses which induced a roughly similar stimulation of locomotor activity) [16].
• We postulated that modafinil enhances wakefulness by modulating dopamine (DAT), norepinephrine (NET), or serotonin (SERT) transporter activities [17].

Biological context of C13302

• During hypoglycaemia, autonomic symptom scores were significantly higher with modafinil (increase at lowest plasma glucose concentration 271.3+/-118.9 vs 211.2+/-80.4/40 min, p=0.019), and the heart rate response was increased (12,928+/-184 vs 6773+/-148 bpm/140 min, p=0.016) [18].
• Does short-term treatment with modafinil affect blood pressure in patients with obstructive sleep apnea [19]?
• Compounds that induce or inhibit CYP activity are unlikely to have major effects on the pharmacokinetics of modafinil [20].
• The present study examined the potential of modafinil as a cognitive enhancer in schizophrenia [21].
• We thus studied the effect of modafinil on the membrane potential and firing rate of VLPO neurons recorded in rat-brain slices [22].

Anatomical context of C13302

• BACKGROUND: Modafinil has been reported to produce a concentration-related induction of CYP3A4/5 activity in vitro in primary cultures of human hepatocytes [23].
• The mechanism of action of modafinil is unknown, but, unlike other stimulants, the drug is highly selective for the central nervous system, has little effect on dopaminergic activity in the striatum, and appears to have a lower abuse potential [24].
• Although modafinil exhibits a small degree of dopaminergic action by blocking the dopamine transporter, the major effect of modafinil may be attributable to neuronal activity in the hypothalamus, particularly pertaining to the recently discovered peptides hypocretin 1 and 2 (also known as orexin A and B) [25].
• The effects of modafinil on glutamatergic and GABAergic transmission in the rat medial preoptic area (MPA) and posterior hypothalamus (PH), are analysed [26].
• Modafinil (1-33 microM) failed to affect [3H]glutamate uptake in hypothalamic synaptosomes and slices [26].

Associations of C13302 with other chemical compounds

• The modafinil (100 mg/kg)-induced increase of glutamate levels was antagonized by local perfusion with bicuculline (1 microM) [26].
• Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization [27].
• Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG [28].
• However, as shown previously in nonhuman primates and in humans, modafinil could possibly have reinforcing effects in cocaine-experienced individuals [29].
• Together these data suggest that, in the frontal cortex, the amygdala, and the dorsal raphe, modafinil is more potent in enhancing extracellular 5-HT levels and presumably 5-HT transmission than in the medial preoptic area and the posterior hypothalamus [30].
• Cocaine significantly increased self-administration, subjective-effect ratings, and cardiovascular measures; modafinil at both doses (200 and 400 mg/day) markedly attenuated these effects [31].

Gene context of C13302

• In vitro, modafinil was observed to produce a reversible inhibition of CYP2C19 in human liver microsomes [20].
• The mean activities of microsomal CYP1A2, CYP2B6, and CYP3A4/5 from modafinil-treated hepatocytes were higher (up to 2-fold) than those in the solvent-treated controls but were less than those produced by reference inducers of these enzymes [32].
• At high concentrations of modafinil (>/=100 microM), the mean activity of CYP2C9 was decreased (up to 60%) relative to that in the solvent controls [32].
• In vitro, modafinil effects in DAT-human embryonic kidney (HEK), NET-HEK, and SERT-HEK cells were investigated alone or combined with the TA1 receptor [17].
• In vitro, modafinil inhibited [(3)H]dopamine (IC(50) = 6.4 muM), [(3)H]norepinephrine (IC(50) = 35.6 muM), and [(3)H]serotonin (IC(50) > 500 muM) transport via the human DAT, NET, and SERT [17].

Analytical, diagnostic and therapeutic context of C13302

• Thirty sleep apneics receiving effective CPAP therapy (objective use, 6.5 +/- 1.1 h/night) received daily single doses of 400 mg modafinil or placebo for 2 wk in a double-blind randomized crossover design [33].
• Modafinil may be a useful adjunct treatment for the management of residual daytime sleepiness in patients with obstructive sleep apnea/hypopnea syndrome who are regular users of nasal continuous positive airway pressure therapy [3].
• An electroencephalographic (EEG) study on the rhesus monkey, primate model of human sleep, showed the significant wakening effect of a new psychostimulant, Modafinil [34].
• Modafinil is a unique wake-promoting agent for oral administration [20].
• METHODS: Subjects with narcolepsy enrolled in a nine-week, placebo-controlled, double-blind study and were randomized to placebo, modafinil 200 mg, or modafinil 400 mg [35].

References