concentration over time with the relationship between the concentration at the effect site and the intensity of the observed response, while considering multiple covariables.19 While the precise clinical indications for S-ketamine films remain undefined, our research primarily centers on evaluating its analgesic efficacy and its profile of side effects. It is conceivable that this thin film formulation may eventually find application as a potential treatment for therapy-resistant depression, akin to its intranasal counterpart. In Chapter 4, we compare the respiratory effects of oliceridine, a muopioid receptor agonist with biased characteristics, to morphine, a prototypical mu-opioid receptor agonist. The concept of biased agonism, or functional selectivity, underscores the origins of these distinctive characteristics.20 The respiratory effects of opioids are exerted via mu-opioid receptors in important brainstem respiratory centers. Upon binding to the mu-opioid receptor, opioids trigger the activation of distinct intracellular pathways. Earlier studies pointed towards the role of beta-arrestin recruitment in adverse effects of opioids, including respiratory depression.21 This understanding paved the way for the development of oliceridine, a mu-opioid receptor agonist exhibiting a pronounced bias in favor of G-protein signaling.22 The resultant net effect is an opioid that mitigates the extent of respiratory depression, offering a potential therapeutic advantage. Finally, in Chapter 5, we explore the effect of type 2 diabetes and hyperinsulinemia on ventilatory control. Only recently, a link between metabolic disorders and changes in ventilatory control has been established in animal and preclinical studies.23,24,25 These changes comprise changes in chemoreflex sensitivity, modifications in breathing patterns, and adjustments in carotid-body mediated sympathetic outflow.26,27,28 Given the increased incidence, morbidity, and mortality associated with SARS-COV-2 among individuals with type 2 diabetes, our particular interest was the ventilatory effect of hypoxia in this group of patients. The hypoxic ventilatory response is crucial in determining an individual’s predisposition to hypoxia-related pathologies. Therefore, this response was obtained in individuals with type 2 diabetes and compared to healthy controls, both during fasting conditions and under the influence of a hyperinsulinemic-euglycemic clamp. This study provides insight into the effects of metabolic dysregulation on ventilatory control. Given the large increase in patients with type 2 diabetes worldwide, this is an important study that may guide our approach to type 2 diabetics, particularly under conditions of changes in ventilatory control, such as those encountered perioperatively or following opioid administration. 4
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