5-HT2A receptor antagonists(Korea Research Institute of Chemical Technology)

Diabetes mellitus affects the functions of large and small vessels, leading to complications broadly classified as macro-vascular complications, including peripheral arterial disease, heart disease, and stroke, and microvascular complications, including neuropathy, retinopathy, and nephropathy. Moreover, vascular dysfunction, including abnormal reactivity to endogenous substances, is often observed in patients with diabetes mellitus. Among various vasoactive substances, serotonin (5-hydroxytryptamine; 5-HT), which was first isolated from peripheral blood >70 years ago, plays a pivotal role in the vascular system. However, the role of 5-HT-mediated vascular function, including vasoconstriction, in diabetes mellitus-associated vascular complications remains unclear. In addition to the abnormal 5-HT responsiveness observed in patients with diabetes mellitus, 5-HT also contributes to diabetes-associated vasculopathy through its role in vascular wall remodeling. In this review, we first summarize the altered responses and downstream signaling pathways induced by 5-HT in large and small vessels in animal models of diabetes mellitus and in patients based on evidence from the past 30 years. We also discuss the effects of sarpogrelate, a 5-HT_2A receptor antagonist, on vascular function in diabetes mellitus and highlight the importance of blocking vascular 5-HT_2A receptors as an approach to mitigate diabetes-associated vascular dysfunction. Our overarching aim is to emphasize the importance of controlling 5-HT-mediated signaling in the vasculature to prevent and treat diabetes-associated vascular complications.

Serotonin syndrome (toxicity), resulting from an excessive accumulation of serotonin in the central nervous system, it can occur due to various factors such as the initiation of medication, overdose or drug interactions. Diagnosing serotonin toxicity presents challenges as there are no definitive criteria. This review delves into the pathophysiology, incidence, clinical assessment and management of serotonin toxicity, stressing the significance of promptly recognizing and managing severe cases. Diagnosis relies primarily relies on clinical assessment due to the absence of specific laboratory tests. The Hunter Serotonin Toxicity criteria are commonly utilized but have only been validated in the overdose setting. Assessing the severity of toxicity is crucial for guiding management decisions. Supportive care, discontinuation of causative agents and symptomatic treatment are prioritized in management. Mild toxicity often requires withdrawal or reduction of the serotonergic agent, while more severe toxicity requires more aggressive resuscitative and supportive care. Severe serotonin toxicity characterized by hyperthermia and rigidity requires aggressive supportive measures, including benzodiazepines, intubation, paralysis and active cooling. Animal studies suggest potential benefits of 5‐HT2A receptor antagonists in preventing hyperthermia and fatalities, but only at high doses. Their clinical effectiveness remains uncertain, and evidence is predominately from case series and case reports. Although commonly used, serotonin antagonists like cyproheptadine lack conclusive evidence of efficacy. Other serotonin antagonists such as chlorpromazine and olanzapine have been explored but evidence is limited to case reports. Hence, the cornerstone of treating severe cases does not lie in ‘antidote’ administration or even diagnosis but in effective early resuscitative and supportive care.