rdd page

RATIONAL DRUG DISCOVERY
FOR TREATING SLEEP DISORDERS

Pharmacologic Treatments for Sleep Apnea
David W. Carley, Principal Investigator (BTG International)
Abstract

Pathogenesis and Treatment of Sleep Apnea: Serotonergic Mechanisms
David W. Carley, Principal Investigator (Organon, NV)
Abstract

Pharmacologic Treatments for Sleep Apnea
Over the past decade, Professors Carley and Radulovacki have characterized and validated an animal model of central sleep-related breathing disorder in laboratory rats (abstract). We used this model system to screen a panel of drugs that influence the actions of serotonin, an important endogenous neuromodulator. Our preliminary studies demonstrated that serotonin antagonists acting in the peripheral nervous system had the potential to reduce disordered breathing during REM sleep. Conversely, serotonin promoting drugs such as fluoxetine had a modest potential to reduce disordered breathing during NREM sleep, presumably by acting in the brain. This study will examine the impact of combined administration of a peripherally acting serotonin antagonist with a centrally acting serotonin reuptake inhibitor. A systematic approach will be taken to optimizing both the ratio of the two active agents and the total dose needed to control sleep disordered breathing in the animal model.

Pathogenesis and Treatment of Sleep Apnea: Serotonergic Mechanisms
Over the past decade, Professors Carley and Radulovacki have characterized and validated an animal model of central sleep-related breathing disorder in laboratory rats (abstract). We used this model system to screen a panel of drugs that influence the actions of serotonin, an important endogenous neuromodulator. Our preliminary studies demonstrated that serotonin antagonists acting in the peripheral nervous system had the potential to reduce disordered breathing during REM sleep. Conversely, serotonin promoting drugs such as fluoxetine had a modest potential to reduce disordered breathing during NREM sleep, presumably by acting in the brain. Among the compounds tested, mirtazapine was in many ways the most intriguing. Mirtazapine is a mixed profile serotonergic drug that blocks serotonin type 2 and type 3 receptors with high potency and also promotes serotonin release selectively within the brain. In the animal model system, mirtazapine unique in effectively reducing disordered respiration during both REM and NREM sleep for at least 6 hours following a single dose (abstract). Because they posess distinct stereo-chemistry, this present study will examine the effects of the two separate stereo-isomers of mirtazapine alone and in various combinations. These studies will demonstrate the optimal isomeric ratio and total dose for controlling sleep disordered breathing in the animal model.