Application of armodafinil-loaded microneedle patches against the negative influence induced by sleep deprivation.

Cognition maintenance is essential for healthy and safe life if sleep deprivation happens. Armodafinil is a wake-promoting agent against sleep deprivation related disorders. However, only the tablet formulation is available, which may limit its potential in some circumstances. Here, we report the synthesis of a new formulation of armodafinil, microneedle patches, which can be conveniently used by any individual and removed in time if not wanted. To produce the needles of higher mechanical strength and higher drug loading, polyvinylpyrrolidone (PVP) K90 was used to fabricate armodafinil-loaded microneedles by applying the mold casting method after dissolving in methanol and drying. The higher mechanical strength was validated by COMSOL Multiphysics® software stimulation and universal mechanical testing machines. The obtained armodafinil microneedles can withstand a force of 70 N and penetrate the skin to a depth of 230 µm, and quickly released the drug within 1.5 h in vitro. The pharmacokinetic analysis showed that microneedle administration can maintain a more lasting and stable blood concentration as compared to oral administration. After the treatment of sleep deprived mice with microneedles, the in vivo pharmacodynamics study clearly demonstrated that armodafinil microneedles could eliminate the effects of sleep deprivation and improve the cognitive functions of sleep-deprived mice. A self-administered, high drug-loaded microneedle patch were prepared successfully, which appeared to be highly promising in preserving cognition by transdermal administration.

Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling.

Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 and 6, is metabolized mainly by cytochrome P450 (CYP)3A4. Clinical studies were performed to assess the impact of strong inhibitor (clarithromycin) and inducer (rifampin) on the exposure of abemaciclib and active metabolites. A physiologically based pharmacokinetic (PBPK) model incorporating the metabolites was developed to predict the effect of other strong and moderate CYP3A4 inhibitors and inducers. Clarithromycin increased the area under the plasma concentration-time curve (AUC) of abemaciclib and potency-adjusted unbound active species 3.4-fold and 2.5-fold, respectively. Rifampin decreased corresponding exposures 95% and 77%, respectively. These changes influenced the fraction metabolized via CYP3A4 in the model. An absolute bioavailability study informed the hepatic and gastric availability. In vitro data and a human radiolabel study determined the fraction and rate of formation of the active metabolites as well as absorption-related parameters. The predicted AUC ratios of potency-adjusted unbound active species with rifampin and clarithromycin were within 0.7- and 1.25-fold of those observed. The PBPK model predicted 3.78- and 7.15-fold increases in the AUC of the potency-adjusted unbound active species with strong CYP3A4 inhibitors itraconazole and ketoconazole, respectively; and 1.62- and 2.37-fold increases with the concomitant use of moderate CYP3A4 inhibitors verapamil and diltiazem, respectively. The model predicted modafinil, bosentan, and efavirenz would decrease the AUC of the potency-adjusted unbound active species by 29%, 42%, and 52%, respectively. The current PBPK model, which considers changes in unbound potency-adjusted active species, can be used to inform dosing recommendations when abemaciclib is coadministered with CYP3A4 perpetrators.

Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters.

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the S-configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by in silico, in vitro, and in vivo studies that have demonstrated both safety and efficacy profile of this compound class.

Central nervous system effects of the histamine-3 receptor antagonist CEP-26401, in comparison with modafinil and donepezil, after a single dose in a cross-over study in healthy volunteers.

AIMS: In previous studies, the histamine-3 receptor antagonist CEP-26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 µg), and a dose-dependent disruption of sleep. In the current study, 3 low-dose levels of CEP-26401 were compared with modafinil and donepezil. METHODS: In this double-blind, placebo- and positive-controlled, randomized, partial 6-way cross-over study, 40 healthy subjects received single doses of placebo, CEP-26401 (5, 25 or 125 µg) or modafinil 200 mg or donepezil 10 mg. Pharmacokinetic and pharmacodynamic measurements were performed predose and at designated time points postdose. RESULTS: The main endpoint between-errors of the spatial working memory-10-boxes task only improved for the 125 µg dose of CEP-26401 with a difference of 2.92 (confidence interval [CI] -1.21 to 7.05), 3.24 (CI -1.57 to 8.04) and 7.45 (CI 2.72 to 12.19) for respectively the 5, 25 and 125 µg dose of CEP-26401, -1.65 (CI -0.572 to 1.96) for modafinil and - 3.55 (CI -7.13 to 0.03) for donepezil. CEP-26401 induced an improvement of adaptive tracking, saccadic peak velocity and reaction time during N-back, but a dose-related inhibition of sleep and slight worsening of several cognitive parameters at the highest dose. CEP-26401 significantly changed several subjective visual analogue scales, which was strongest at 25 µg, causing the same energizing and happy feeling as modafinil, but with a more relaxed undertone. DISCUSSION: Of the doses tested, the 25 µg dose of CEP-26401 had the most optimal balance between favourable subjective effects and sleep inhibition. Whether CEP-26401 can have beneficial effects in clinical practice remains to be studied.

Modafinil and orexin system: interactions and medico-legal considerations.

Modafinil (Mo) is increasingly being used as an enhancement drug rather than for its therapeutic effects. The effects of this drug have been examined in attention deficit disorders, depression, mental fatigue, and in enhancing concentration. The drug possesses wakefulness-promoting properties which are mediated through the interaction of orexinergic system with the activated sympathetic nervous system. Mo exerts a synergistic effect on the orexin system, controls energy expenditure and strengthens the ability of the individual to exercise. Some view Mo as a drug that enhances sports performance, since it induces a prolonged wakefulness and decreasing the sense of fatigue. These characteristics being similar to conventional stimulants have allowed Mo to emerge as a novel stimulant requiring medico-legal considerations. However, more studies are needed to better understand the mid and long-term effects of the drug on user/abuser.

Evaluating Transfer of Modafinil Into Human Milk During Lactation: A Case Report.

ABSTRACT: We present a case of a 27-year-old woman in whom idiopathic hypersomnolence was diagnosed in adolescence with adequate symptomatic control on daily dosage of 250 mg of modafinil. She maintained this dosage throughout her pregnancy and during the peripartum period, but did not breastfeed her newborn because of a lack of information on the transmission of modafinil in human breast milk. Samples of her breast milk were obtained at various times over a 24-hour period and analyzed using liquid chromatography mass spectrometry. The relative infant dose was calculated to be 5.3%, below the threshold of concern for drug passage via breast milk. This is the first reported case of modafinil transfer into human breast milk. Given the drug's use in a variety of sleep disorders, the results of this case can be used to advise breastfeeding mothers prescribed modafinil.

Acute hypertensive crisis and severe headache after concurrent use of armodafinil and tranylcypromine: Case report and review of the literature.

Concurrent use of modafinil or armodafinil with monoamine oxidase inhibitors (MAOIs) is contraindicated due to a theoretical risk of drug synergism and acute hypertensive episodes. However, few data are available to substantiate that risk, and several case studies have suggested that the combination is safe. To our knowledge, we present the first case of a patient treated concurrently with armodafinil and tranylcypromine. The patient developed an acute hypertensive crisis with severe headache, nausea, blurry vision, and neck stiffness. Her symptoms corresponded with the predicted pharmacokinetic and pharmacodynamic response. She was also taking brexpiprazole, which could have contributed to her underlying symptoms. However, limited data suggest that the single combination of brexpiprazole with armodafinil or MAOIs would be safe. Upon review of the literature, two out of seven patients, including our own, treated concurrently with modafinil or armodafinil and an MAOI developed an adverse reaction. Physicians should exercise caution if using these classes of drugs together.