H3 receptor inverse agonists( Arena Pharmaceuticals, Inc.)

Narcolepsy is a rare, chronic neurological disorder characterized by a dysregulated sleep-wake cycle, with core clinical features including excessive daytime sleepiness (EDS), cataplexy, hypnopompic/hypnagogic hallucinations, and sleep paralysis. Several treatment options are available for the symptomatic management of narcolepsy, but they have limitations. Comorbidities of narcolepsy further limit the treatment choices. Blocking of histamine 3 (H3) receptors has been demonstrated to be a viable approach for the management of symptoms of narcolepsy. Samelisant (SUVN-G3031) is a new H3 receptor inverse agonist. The efficacy, safety, tolerability, and pharmacokinetics of Samelisant in narcolepsy patients were evaluated in a phase 2, double-blind, placebo-controlled study (ClinicalTrials.gov identifier: NCT04072380). Patients diagnosed with narcolepsy according to the International Classification of Sleep Disorders criteria and having an Epworth Sleepiness Scale (ESS) score of ≥12 and a mean Maintenance of Wakefulness Test (MWT) time of <12 min across the 4 sessions at baseline were enrolled. The total study duration was up to 7 weeks, which included a screening period of 4 weeks, a treatment period of 2 weeks, and a safety follow-up 1 week after the last study drug administration. The primary efficacy measure was the change in total ESS score compared to placebo. Secondary and exploratory assessments included the Clinical Global Impression of Severity, MWT, Clinical Global Impression of Change, Patient Global Impression of Change and cataplexy rate. Safety assessments included monitoring adverse events (AEs) and laboratory assessments. Of the 426 patients screened, 190 were randomized. The safety and intention-to-treat population included 188 and 164 patients, respectively. A statistically significant treatment effect of Samelisant was observed on the primary endpoint, indicating improvements in EDS. The treatment's impact on EDS was also evident on the other patients' and clinicians' perspectives scales. The AEs reported in ≥5 % patients in any treatment groups were insomnia, abnormal dreams, nausea, and hot flush. Global phase 3 studies and long-term safety and efficacy assessments of Samelisant are planned to reaffirm the current findings.

The mechanisms of emergence from general anesthesia remain to be elucidated. Recent studies indicate that the central histaminergic system plays a critical role in maintaining wakefulness. In addition, the neural pathways that regulate the wake-sleep cycle are involved in general anesthesia. In this study, we determined the role of the central histaminergic system in emergence from propofol anesthesia using microinjections and single-unit recordings in rats.

All rats were implanted with unilateral guide cannulae or bilateral cannulae. Return of righting reflex could be used as an index of recovery of consciousness in rats. Neuronal activity was collected. The placement of the injection cannulae and/or microelectrodes was verified in coronal sections (10 µm) cut with a cryostat microtome. Animals with incorrect placements were removed from this study. The neuronal activity was subjected to an off-line clustering analysis (K-means) using the Plexon Off-line Sorter to identify one or more individual units recorded from the same electrode from each other and noise.

We found intracerebroventricular (icv) microinjections of histamine decreased the emergence time in a dose-dependent manner and had an excitatory effect on the firing activity of medial prefrontal cortex (mPFC) neurons, while the decrease of emergence time was completely reversed by the pre-treatment with triprolidine (80 µg/5 µL) but not cimetidine (100 µg/5 µL). Moreover, the presumed histaminergic neurons fired in a state-dependent manner, and there was a dramatic increase in firing activity before regain of righting reflex. Furthermore, bidirectional manipulations of emergence were achieved through the microinjection of gamma-aminobutyric acid (GABA) (10 µg/side) and a potent H3 receptor inverse agonist ciproxifan (1 µg/side) into the posterior hypothalamus, where the tuberomammillary nucleus (TMN) resides. Combine the behavioral and neurophysiologic evidence, the central histaminergic system promotes emergence from propofol anesthesia in rats.

Our findings suggest an important role of the central histaminergic system in a broader field of state transitions, such as emergence from propofol anesthesia.