Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial.

INTRODUCTION: We evaluated the clinical profile of the orexin receptor antagonist suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia. METHODS: Randomized, double-blind, 4-week trial of suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4. RESULTS: Of 285 participants randomized (suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of suvorexant-treated patients and 1.4% of placebo-treated patients. DISCUSSION: Suvorexant improved TST in patients with probable AD dementia and insomnia.

Assessment of sigma-1 receptor occupancy in mice with non-radiolabelled FTC-146 as a tracer.

The use of liquid chromatography coupled with mass spectrometry (LC-MS/MS) is advantageous in in-vivo receptor occupancy assays at pre-clinical drug developmental stages. Relatively, its application is effective in terms of high throughput, data reproducibility, sensitivity, and sample processing. In this perspective, we have evaluated the use of FTC-146 as a non-radiolabelled tracer to determine the sigma-1 receptor occupancy of test drugs in mice brain. Further, the brain and plasma exposures of test drug were determined at their corresponding occupancies. In this occupancy method, the optimized tracer treatment (sacrification) time after intravenous administration was 30 min. The tracer dose was 3 µg/kg and specific brain regions of interest were frontal cortex, pons and midbrain. Mice were pretreated orally with SA4503, fluspidine, haloperidol, and donepezil followed by tracer treatment. Among the test drugs, SA4503 was used as positive control group at its highest test dose (7 mg/kg, intraperitoneal). There was a dose-dependent decrease in brain regional FTC-146 binding in pretreated mice. From the occupancy curves of SA4503, fluspidine, haloperidol, and donepezil the effective dose (ED50) value ranges are 0.74-1.45, 0.09-0.11, 0.11-0.12, and 0.07-0.09 mg/kg, respectively. Their corresponding brain effective concentration (EC50) values are 74.3-132.5, 3.4-3.7, 122.5-139.5, and 8.8-11.0 ng/g and plasma EC50 values are 34.3-53.7, 0.08-0.10, 7.8-9.5, and 0.6-0.7 ng/mL. Brain regional distribution and binding inhibition upon pretreatment were comparable with data reported with labeled [18F]FTC-146. Drug exposures were simultaneously determined and correlated with sigma-1 occupancy from the same experiment. Wide category drugs can be assayed for sigma-1 receptor engagement and their correlation with exposures aid in clinical development.

Preparation and evaluation of novel chitosan: gelrite ocular system containing besifloxacin for topical treatment of bacterial conjunctivitis: scintigraphy, ocular irritation and retention assessment.

This study was aimed to prepare, characterize and evaluate in situ gel formulations based on a blend of chitosan (CS), polyvinyl alcohol (PVA) and gellan gum (Gelrite™) for a sustained ocular delivery of besifloxacin (BSF). The developed formulations were evaluated for physicochemical properties, gelation time (Tsol-gel), rheological behaviour, antimicrobial efficacy, pharmacokinetic assessment, gamma scintigraphy study and ocular irritation. The results showed BSF sol-gel system were found to be sensitive enough which underwent instantaneous phase transition upon getting physiological stimulation. The ex vivo permeation experiments indicated that the developed formulation was able to enhance the retention of BSF at corneal surface. The HET-CAM confirmed the non-irritancy of developed formulation and also demonstrated the ability of ocular protection against strongly irritant substances. The results of gamma scintigraphy study revealed the higher concentration of drug retains at the corneal surface. In addition, optimized BSF sol-gel system showed enhanced anti-bacterial activity compared to BSF suspension.

Assessment of the Abuse Potential of the Orexin Receptor Antagonist, Suvorexant, Compared With Zolpidem in a Randomized Crossover Study.

Suvorexant is a dual orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia at a maximum dose of 20 mg. This randomized double-blind crossover study evaluated the abuse potential of suvorexant in 36 healthy recreational polydrug users with a history of sedative and psychedelic drug use. Single doses of suvorexant (40, 80, and 150 mg: 2-7.5 × maximum dose), zolpidem (15 and 30 mg: 1.5-3 × maximum dose), and placebo were administered, with a 10-day washout between treatments. Subjective and objective measures, including visual analog scales (VASs), Addiction Research Center Inventory, and cognitive/psychomotor tests, were evaluated for 24-hour postdose. Suvorexant had significantly greater peak effects on "drug liking" VAS (primary endpoint) than placebo. Although effects of suvorexant on abuse potential measures were generally similar to zolpidem, they remained constant across doses, whereas zolpidem often had greater effects at higher doses. Suvorexant (all doses) had significantly fewer effects than zolpidem 30 mg on secondary measures, such as "high" VAS, Bowdle VAS, and Addiction Research Center Inventory morphine-benzedrine group. The overall incidence of abuse-related adverse events, such as euphoric mood and hallucination, was numerically lower with suvorexant than zolpidem. In agreement with its classification as a schedule IV drug, suvorexant demonstrated abuse potential, compared with placebo. The abuse potential was similar to zolpidem using certain measures, but with a reduced incidence of abuse-related adverse events. Although this suggests that the overall abuse liability of suvorexant may be lower than zolpidem, the actual abuse rates will be assessed with the postmarketing experience.

In vivo performance of an oral MR matrix tablet formulation in the beagle dog in the fed and fasted state: assessment of mechanical weakness.

PURPOSE: To evaluate the behaviour of an oral matrix modified release formulation in the canine gastrointestinal tract, and establish if a mechanical weakness previously observed in clinical studies would have been identified in the dog model. MATERIALS AND METHODS: In vitro release profiles were obtained for two modified release matrix tablets containing UK-294,315, designed to release over either 6 (formulation A) or 18 (formulation B) hours. Tablets were labelled with (153)samarium and in vivo pharmacoscintigraphy studies were performed in four beagle dogs in the fasted state for both formulations, and following ingestion of an FDA high fat meal for formulation B. RESULTS: The matrix tablet formulations displayed significantly different in vitro release profiles (F (2) < 50), with time to 80% release for formulation A and B of 406 and 987 min respectively. Complete in vivo disintegration occurred at 339 +/- 181 and 229 +/- 171 for formulation A and B respectively in the fasted state, and at 207 +/- 154 min for formulation B in the fed state, in disagreement with in vitro release. CONCLUSION: The fed/fasted dog model would have predicted a lack of physical robustness in the matrix tablet formulation B, however it would not have predicted the clear fed/fasted effects on performance observed previously in man.

[Actigraphic assessment of the effects of hypnotics on the night before surgery in relation with the severity of surgery].

BACKGROUND: Hypnotics have been used to provide adequate sleep on the night before surgery, but these effects have rarely been investigated. We investigated whether the preoperative hypnotic effects are related with the severity of surgery with quantitative evaluation using actigraph. METHODS: Sleep time on the night before surgery was evaluated after the administration of brotizolam 0.25 mg in 40 patients awaiting surgery; 20 patients for cardiovascular surgeries (Group I) and 20 patients for general surgeries (Group II). Sleep and awake state were identified by wrist activity measured with a motion-logger actigraph. Sleep time was assessed in total period from 22:00 to 6:00 and its 4 subdivided 2-hour periods (22:00-24:00, 24:00-2:00, 2:00-4:00, 4:00-6:00). RESULTS: The total sleep time in Group II (448 +/- 22 min) was significantly longer than that in Group I (409 +/- 44 min). Group I showed a significant reduction in sleep time in the period of 4:00-6:00 compared with other periods, whereas Group II did not show any difference among 4 periods. Group I showed significant shorter sleep time in the period of 4:00-6:00 compared with Group II. CONCLUSIONS: An actigraphic assessment of sleep time has demonstrated the possible influence of the severity of surgery on the sleep time on the night before surgery.

[Electroencephalographic assessment of dosage and sleep-profile in a hypnotic Triazolothienodiazepine (author's transl)]. / Elektroenzephalographische Dosis- und Schlafprofilbeurteilung eines Hypnotikums aus der Reihe der Triazolothienodiazepine.

We 941, a Triazolodiazepine, has satisfying hypnotic properties. The optimum dosage lies nearly at 0.3 mg. In this dosage the sleep-begin is shortened, the number of nightly wakeness is decreased and the total sleep-time is extended, while the sleep-profile remains unchanged. A normal cycling can be taken as a sign of qualitative good sleep. The REM-percentage is diminished insignificantly and increases again under the continuated therapy. The percentage of deep sleep increases by 0.3 mg. The subjective presentations confirm the melioration of sleep. In higher dosages troubles occur as decrease of deep-sleep stage and deteriorations of feeling. Remarkable is the withdrawal effect after 1.0 mg with an initial and a dissociated REM. However, such strong disturbances couldn't be observed in the carried on therapy with 0.3 mg.

Clinical assessment of oral meptazinol in postoperative pain.

The pain relieving properties of orally administered meptazinol, a new hexahydroazepine analgesic, were studied in 51 patients recovering from major surgery. In doses of 250, 400 and 500 mg it produced significant analgesia which was maximal at the end of one hour and had a duration of action of approximately four hours. Arterial pressure and heart rate were not affected significantly by meptazinol. Nausea and vomiting were the main side-effects observed in a few patients and there were no abnormal hematological or biochemical findings.