GIP receptor agonism blocks chemotherapy-induced nausea and vomiting.

OBJECTIVE: Nausea and vomiting remain life-threatening obstacles to successful treatment of chronic diseases, despite a cadre of available antiemetic medications. Our inability to effectively control chemotherapy-induced nausea and vomiting (CINV) highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that block CINV. METHODS: Behavioral pharmacology assays of nausea and emesis in 3 different mammalian species were combined with histological and unbiased transcriptomic analyses to investigate the beneficial effects of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism on CINV. RESULTS: Single-nuclei transcriptomics and histological approaches in rats revealed a topographical, molecularly distinct, GABA-ergic neuronal population in the dorsal vagal complex (DVC) that is modulated by chemotherapy but rescued by GIPR agonism. Activation of DVCGIPR neurons substantially decreased behaviors indicative of malaise in cisplatin-treated rats. Strikingly, GIPR agonism blocks cisplatin-induced emesis in both ferrets and shrews. CONCLUSION: Our multispecies study defines a peptidergic system that represents a novel therapeutic target for the management of CINV, and potentially other drivers of nausea/emesis.

Screening study of anti-emetics to improve GDF15-induced malaise and anorexia: Implications for emesis control.

Considerable preclinical and clinical attention has focused on the food intake and body weight suppressive effects of growth differentiation factor 15 (GDF15) and its elevated blood levels as a consequence of disease states and disease treatment therapeutics. We have previously reported that exogenous administration of GDF15 induces anorexia through nausea and emesis in multiple species. Importantly, GDF15 signaling as a meditator of chemotherapy-induced anorexia and emesis has recently been demonstrated in both murine and nonhuman primate models. The mechanism, however, by which GDF15 induces malaise and the utility of existing therapeutic targets to counteract its effects remain largely unknown. Using a dose of GDF15 that mimics stimulated levels following chemotherapy administration and reliably induces malaise, we sought to screen anti-emetics that represent distinct pharmacotherapeutic classes hypothesized to reduce GDF15-induced effects in rats. Strikingly, our results showed that none of the tested compounds were effective at preventing GDF15-induced malaise. These results illustrate the complexity of GDF15 signaling mechanism and may have important implications for medical conditions characterized by elevated GDF15 levels and incomplete symptom control, such as chemotherapy-induced nausea and vomiting.

Dilemmas of growth hormone treatment for GH deficiency and idiopathic short stature: defining, distinguishing, and deciding.

Worrisome growth can be a sign of underlying pathology but usually reflects healthy variation. It is often recognized through short stature, which is defined by arbitrarily separating height, a physical trait on a continuum, into "normal" and "abnormal." In some cases of worrisome growth, recombinant human growth hormone (rhGH) treatment is indicated to hasten growth/increase height. This review addresses the two most frequently treated indications for rhGH, growth hormone deficiency (GHD) and idiopathic short stature (ISS). A review of worrisome growth itself, of the history of GH treatment, of the blurry line between partial GHD and ISS, of the GH stakeholders, and of the outside pressures involved in these cases demonstrates the ambiguous platform upon which treatment decisions are made. The rhGH treatment decision process can be examined further by considering the three most impactful factors on parental height-related medical decision-making: treatment characteristics, child health, and psychosocial function. While it is important to note that treatment for classical GHD is uncontroversial and supported, treatment decisions for partial GHD and ISS are more complicated and require careful evaluation of both patient needs and the supporting evidence. As the rhGH community grows, physicians, parents, and patients are encouraged to engage in a shared decision-making process to navigate the many challenges facing the GH field. Although this review addresses GHD and ISS specifically, the issues discussed are often applicable to pediatrics as a whole.