A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

Abstract

There is currently no pharmacotherapy for OSA, but there is no principled a-priori reason why there shouldn’t be one. This review identifies a rational decision-making strategy with the necessary logical underpinnings that any reasonable approach would be expected to navigate to develop a viable pharmacotherapy for OSA. The process first involves phenotyping an individual to quantify and characterize the critical predisposing factor(s) to their OSA pathogenesis and identify, a-priori, if the patient is likely to benefit from a pharmacotherapy that targets those factors. We then identify rational strategies to manipulate those critical predisposing factor(s), and the barriers that have to be overcome for success of any OSA pharmacotherapy. A new analysis then identifies candidate drug targets to manipulate the upper airway motor circuitry for OSA pharmacotherapy. The first conclusion is that there are two general pharmacological approaches for OSA treatment that are of most potential benefit and are practically realistic, one being fairly intuitive but the second perhaps less so. The second conclusion is that after identifying the critical physiological obstacles to OSA pharmacotherapy, there are current therapeutic targets of high interest for future development. The final analysis provides a tabulated resource of “druggable” targets that are relatively restricted to the circuitry controlling the upper airway musculature, with these candidate targets being of high priority for screening and further study. We also emphasize that a pharmacotherapy may not cure OSA per se, but may still be a useful adjunct to improve the effectiveness of, and adherence to, other treatment mainstays.

Postural preinspiratory cortical activity, genioglossus activity and fluid shift in awake obstructive sleep apnoea patients

“…Indeed, in normal individuals, small inspiratory loads are known to induce PIPs less often than large inspiratory loads (Hudson, Niérat, Raux, & Similowski, , Raux et al., ; Tremoureux, Raux, Jutand, & Similowski, ). Although it is generally considered that all OSA patients present anatomical abnormalities of the upper airways, it is also accepted that the extent of these abnormalities varies from one patient to another, which contributes, among other factors, to various OSA phenotypes (Horner, Grace, & Wellman, ). The results of the present study indicate that the preinspiratory activation of cortical resources in OSA patients also probably varies from one patient to another.…”

Year in review 2017: Interstitial lung disease, pulmonary vascular disease and sleep

“…This phenotypic approach to OSA holds the possibility of altering our assessment and treatment paradigm and fits in well with the P4 approach to personalized health care (Fig. ) …”

“…Phenotyping an individual aids in determining whether a therapy is likely to be effective and opens the way for developing newer targeted therapies . This is particularly relevant for pharmacological approaches to OSA which, to date, have been uniformly unsuccessful . However, some promising results using phenotyping‐based pharmacotherapy are emerging .…”

“…However, some promising results using phenotyping‐based pharmacotherapy are emerging . Nonetheless, for physiological phenotyping to be clinically feasible, simple non‐invasive methods are needed with validity across a range of clinical populations . Some progress has been made in this area with surrogate measures of physiological traits discernible from awake breathing measures, PSG data and therapeutic CPAP levels .…”

Update in respiratory sleep disorders: Epilogue to a modern review series

“… Drug therapy for OSA: Advances in our understanding of the neuropharmacology of brainstem control have enabled targeted approaches to therapy . A medication that could be used to augment hypoglossal motor output during sleep, or stabilize the ventilator control or perhaps mitigate OSA complications (e.g.…”