Receptor Antagonist Research Articles

GLP-1 enhances β-cell response to protein ingestion and bariatric surgery amplifies it.

The glycemic-independent actions of glucagon-like peptide-1 (GLP-1) in the prandial state in humans are unknown. We examined the contribution of GLP-1 to β-cell secretory response (primary endpoint) and glucose metabolism during protein ingestion under basal glycemia, as well as whether these responses are affected by rerouted gut after gastric bypass (GB) or sleeve gastrectomy (SG). Insulin secretion rate (ISR) and glucose fluxes during a 50-g oral protein load were compared among 10 nondiabetic individuals with GB, 9 with SG, and 7 non-operated controls (CN), with and without intravenous infusion of exendin(9-39) (Ex-9), a GLP-1 receptor (GLP-1R) antagonist. Blocking GLP-1R increased glucose before and after protein ingestion and decreased β-cell sensitivity to glucose in the first 30 min of protein ingestion in all three groups (p < 0.05). Reduction in the premeal ISR by Ex-9 infusion was only observed in CN, whereas diminished prandial ISR3h by GLP-1R blockade was only observed in GB and SG (p < 0.05 for interaction). GLP-1R blockade enhanced post-protein insulin action in GB and SG, but not in CN, and exaggerated endogenous glucose production only GB (p < 0.05 for interaction). These findings are consistent with both pancreatic and extra-pancreatic roles for GLP-1 during protein ingestion in humans that are exaggerated by bariatric surgery.

Consistent evidence that brain serotonin 2A receptor binding is positively associated with personality-based risk markers of depression.

Using [18F]altanserin, a serotonin 2A receptor (5-HT2AR) antagonist Positron Emission Tomography (PET) tracer, a positive association between cortical 5-HT2AR binding and the inward-directed facets of neuroticism has been demonstrated in healthy individuals. Psilocybin, a 5-HT2AR agonist, shows promise for the treatment of depression, reducing neuroticism and mood symptoms potentially via hypothalamic-pituitary-adrenal (HPA) modulation. 5-HT2AR and neuroticism are both modulated by HPA axis function. In this study, we examined whether the association between 5-HT2AR binding and the inward facets of neuroticism can be replicated in an independent healthy cohort using the new 5-HT2AR agonist tracer [11C]Cimbi-36, and if their association is moderated by cortisol awakening response (CAR), an index of HPA axis function. If so, this could advance mechanistic insights into interventions that target the 5-HT2AR and reduce neuroticism. Eighty healthy volunteers underwent [11C]Cimbi-36 PET scans and completed the NEO personality inventory (NEO-PI-R) for the assessment of neuroticism. Salivary samples were available for determination of CAR in 70 of the participants. Using linear latent variable models, we evaluated the association between 5-HT2AR binding and inward facets of neuroticism, namely depression, anxiety, self-consciousness and vulnerability to stress, and whether CAR moderated this association. The study confirms the positive association between 5-HT2AR binding and the inward facets of neuroticism (β = 0.01, 95% CI = [0.0005: 0.02], P = 0.04), and this association is independent of CAR (P = 0.33). The findings prompt consideration of whether novel interventions such as psilocybin that actively targets 5-HT2AR and causes changes in personality could be particularly beneficial if implemented as a targeted approach based on neuroticism profiles.

Direct modulation of CRH nerve terminal function by noradrenaline and corticosterone.

Nerve terminals are the final point of regulation before neurosecretion. As such, neuromodulators acting on nerve terminals can exert significant influence on neural signalling. Hypothalamic corticotropin-releasing hormone (CRH) neurons send axonal projections to the median eminence where CRH is secreted to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline and corticosterone are two of the most important neuromodulators of HPA axis function; noradrenaline excites CRH neurons and corticosterone inhibits CRH neurons by negative feedback. Here, we used GCaMP6f Ca2+ imaging and measurement of nerve terminal CRH secretion using sniffer cells to determine whether these neuromodulators act directly on CRH nerve terminals in male mice. Contrary to expectations, noradrenaline inhibited action potential-dependent Ca2+ elevations in CRH nerve terminals and suppressed evoked CRH secretion. This inhibitory effect was blocked by α2-adrenoreceptor antagonism. Corticosterone also suppressed evoked CRH peptide secretion from nerve terminals, independent of action potential-dependent Ca2+ levels. This inhibition was prevented by the glucocorticoid receptor antagonist, RU486, and indicates that CRH nerve terminals may be a site of fast glucocorticoid negative feedback. Together these findings establish median eminence nerve terminals as a key site for regulation of the HPA axis.Significance Statement Corticotropin-releasing hormone (CRH) neurons control the stress axis. Noradrenaline and corticosterone are two signalling molecules that control CRH neuron cell body excitability. However, their effect on CRH nerve terminal function is unknown. To examine this, we performed live Ca2+ imaging and measured CRH secretion. We found that noradrenaline suppressed nerve terminal Ca2+ levels and inhibited nerve terminal CRH secretion. Corticosterone had no effect on nerve terminal Ca2+, but inhibited nerve terminal CRH secretion. This suggests that CRH nerve terminals may be a site of fast corticosteroid negative feedback. Together, these data demonstrate that CRH nerve terminals are a critical point of regulation in the control of the stress axis.

Agmatine diminishes behavioral and endocrine alterations in a rat model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD), is a severe anxiety disorder characterized by associative fear conditioning. Single prolonged stress (SPS) is a widely accepted reliable animal model to stimulate PTSD. Agmatine is an endogenous neuromodulator of stress; however, its effect on PTSD remains to be investigated. This study explored the role of agmatine in Conditioned Fear Response (CFR) in PTSD and highlighted how imidazoline receptors contribute to effect of agmatine. Intra-cerebroventricular (icv) surgery was done in order to facilitate drug administration. Animals were subjected to SPS. Agmatine and the involvement of Imidazoline receptors (I1 and I2) were assessed for their effect in fear conditioning apparatus. During weeks 1, 2, and 3, in CFR, agmatine (40 µg/rat, icv) showed significantly decreased freezing time as compared to other doses of agmatine (10 and 20 µg/rat, icv). Imidazoline (I1 and I2) receptor agonists Moxonidine (25 µg/rat, icv) and 2-BFI, (10 µg/rat, icv) respectively, at their sub-effective doses, with a submaximal dose of agmatine (20 µg/rat, icv) significantly decreased the altered freezing time during weeks 1, 2 and 3 compared to SPS animals. Moreover, the effective dose of agmatine (40 µg/rat, icv) with imidazoline (I1 and I2) receptor antagonists Efaroxan (10 µg/rat, icv) and Idazoxan (4 µg/rat, icv) respectively does not show a significant effect on freezing. Agmatine and its combination with I1 and I2 agonists, normalized the altered freezing behavior due to SPS during CFR projecting its strong therapeutic implication for CFR in SPS induced-PTSD.

Piriform cortex is an ictogenic trigger zone in the primate brain.

Area tempestas, a functionally defined region in the anterior piriform cortex, was identified as a crucial ictogenic trigger zone in the rat brain in the 1980s. However, whether the primate piriform cortex can trigger seizures remains unknown. Here, in a nonhuman primate model, we aimed to localize a similar trigger zone in the piriform cortex and, subsequently, evaluated the ability of focal inhibition of the substantia nigra pars reticulata (SNpr) to suppress the evoked seizures. Focal microinjection of the γ-aminobutyric acid type A (GABAA) antagonist bicuculline methiodide into the piriform cortex was performed, in macaque monkeys, on a within-subject basis to map the ictogenic regions within this area. Glutamate antagonists were used to characterize the local circuit pharmacology. Focal inhibition of the substantia nigra by infusion of the GABAA agonist muscimol suppressed seizures evoked from piriform cortex. We documented a well-defined region highly susceptible to bicuculline-induced seizures in the piriform cortex, just posterior to the junction of the frontal and temporal lobes, indicating that a functional homolog to the rodent area tempestas is present in the primate brain. Focal infusion of glutamate receptor antagonists into the area tempestas revealed that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated, but not N-methyl-D-aspartate-mediated, neurotransmission was necessary for the expression of seizures. Pharmacological inhibition of the SNpr robustly suppressed area tempestas-evoked seizures. Together, these data point to the area tempestas as a potent ictogenic zone in the primate brain and underscore the antiseizure effects of inhibition of the SNpr. Building on decades of studies in rodents, our present findings emphasize the relevance of these targets to the primate brain and provide further rationale for exploring these targets for clinical use.

Double-blinded, randomized tolerance study of a biologically enhanced Nanogel with endothelin-1 and bradykinin receptor antagonist peptides via intra-articular injection for osteoarthritis treatment in horses

BackgroundOsteoarthritis is a leading cause of pain and retirement in athletic horses. Hydro-expansive functionalized nanogels, acting as Drug Delivery Systems, constitute one of the current therapeutic prospects. These nanogels have the potential to combine mechanical benefits through polymers with the biological effect of prolonged release of bioactive molecules. The purpose of this double-blinded randomized tolerance study versus negative control was to evaluate the response of healthy joints to a single injection of the expected efficient dose (further referred to as the trial dose) and overdose of nanogels composed of chitosan and hyaluronic acid and featuring a type A endothelin receptor antagonist and a type B1 bradykinin receptor antagonist. The metacarpophalangeal joints of 8 healthy horses were randomly injected with 2.4 mL of functionalized nanogels and 2.4 mL of saline as control on the contralateral limb. Injections were repeated twice at one-week intervals, followed by injection of a triple dose of nanogel on week four. Clinical, ultrasonographic and synovial fluid cellular and biochemical follow-ups were performed up to three months following the first injection.ResultsNo change in general clinical parameters, lameness or sensitivity to passive flexion of the fetlocks was noted. Mild to moderate synovitis was noted on the day following injection in the treated group, with a significant difference (p < 0.05) compared to the control group. It spontaneously resolved on day 3 following the injections and did not increase with repeated injections. Similar effects were noted after injection of the triple dose but lasted for a week. Synovial fluid markers of inflammation also showed a transient significant increase in the treated group one week after each injection, but no differences were detected at the end of the study.ConclusionsInjections of the expected therapeutic dose of functionalized nanogel in healthy joints induced a mild transient inflammatory response in the joint. Three injections of the trial dose at one-week intervals and injection of thrice the trial dose induce a mildly greater inflammation without harmful effects on joints. Functionalized nanogels are well tolerated prospects for the treatment of osteoarthritis in horses. Their beneficial effects on arthritic joints have yet to be evaluated to determine their therapeutic potential.

Systematic Review and Meta-Analysis: Role of Proton Pump Inhibitors in Prevention of Upper Gastrointestinal Bleeding in Patients on Dual Antiplatelet Therapy.

Dual antiplatelet therapy (DAPT) with oral P2Y12 inhibitors and aspirin is crucial for patients with acute coronary syndrome (ACS) and postpercutaneous coronary interventions (PCI). Concomitant proton pump inhibitor (PPI) therapy with DAPT can potentially reduce the risk of upper gastrointestinal bleeding (UGIB). We conducted a meta-analysis of randomized controlled trials to evaluate the prevention of UGIB with concomitant use of PPI with DAPT. We reviewed several databases to identify randomized controlled trials comparing the risk of UGIB in patients using DAPT + PPI vs. DAPT with no PPI or DAPT + Histamine 2 receptor antagonists. Our outcomes of interest were UGIB, major cardiovascular adverse events (MACE), myocardial infarction, and all-cause mortality. We calculated pooled risk ratio (RR) with 95% confidence intervals (CI) for all of the outcomes and analyzed data using random effect model. Heterogeneity was assessed using I2 statistic. Seven randomized controlled trials comprising 6708 patients were included. Rate of UGIB was significantly lower in the PPI + DAPT group, RR (95% CI): 0.39 (0.25-0.60). There was no significant difference in the rate of MACE between groups, RR (95% CI): 0.87 (0.69-1.10). Rate of MI was also not significantly different between groups, RR (95% CI): 0.93 (0.75-1.14). Rate of mortality was significantly lower in the PPI + DAPT group, RR (95% CI) 0.46 (0.27-0.80). Our meta-analysis demonstrates that adding PPI therapy to DAPT significantly lowers the risk of UGIB and all-cause mortality, without adversely affecting major cardiovascular outcomes.

Cardiovascular Disease in Patients with Chronic Kidney Disease: Current Understanding, Preventative Strategies, and Future Directions.

Chronic kidney disease (CKD) presents a significant burden on global health, with cardiovascular disease (CVD) being a leading cause of mortality in this population. Despite advancements in pharmacotherapies, preventing CVD in CKD patients remains challenging due to the intricate interplay of traditional risk factors and novel pathophysiological processes. This review aims to elucidate the current understanding of CVD prevention in CKD, encompassing epidemiology, risk factors, diagnostic considerations, and pharmacological therapeutic strategies. CKD patients exhibit a unique cardiovascular risk profile characterized by traditional risk factors such as hypertension and dyslipidemia, as well as CKD-specific factors including albuminuria, vascular calcification, and valvulopathies. The utility of coronary artery calcium scoring in risk stratification and the efficacy of aspirin, lipid-lowering agents, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, and nonsteroidal mineralocorticoid receptor antagonists in CVD prevention are discussed. Despite promising findings, challenges such as lack of specific guidelines and data gaps persist, highlighting the need for multidisciplinary efforts to address the CVD burden in the CKD population effectively. Further research is warranted to optimize preventative strategies and improve outcomes in this high-risk population.

Risk of respiratory, thoracic, and mediastinal disorders associated with endothelin receptor antagonists and prostacyclin-related drugs in pulmonary hypertension: a disproportionality analysis based on FAERS

ABSTRACT Background Adverse drug events (ADEs) for endothelin receptor antagonists (ERAs) and prostacyclin-related drugs (PRDs) have been reported in clinical trials, but large-scale, real-world evaluations for respiratory, thoracic, and mediastinal disorders (RTMD) remain scarce. Methods A pharmacovigilance analysis of the FAERS database (Q1 2004~Q2 2024) used the reporting odds ratio (ROR) method for disproportionality analysis to assess the adverse drug events (ADEs) of ERAs and PRDs in pulmonary arterial hypertension, focusing on risks related to RTMD. Results Reports of ADEs for ERAs (bosentan, ambrisentan, and macitentan) were 15,286, 36795, and 17,497, respectively, and for PRDs (epoprostenol, treprostinil, iloprost, and selexipag) were 5,477, 57265, 3,247, and 5,504. Females exceeded males, with most cases in adults. The top PTs for ERAs were death, dyspnea, and pneumonia, with bosentan linked to liver impairment. PRDs commonly cause headaches, flushing, hypotension, edema, and fluid retention. Dyspnea was the most reported RTMD risk for all drugs, and nasal congestion was noted for all. Selexipag had the fewest RTMD-related PTs, and iloprost had the strongest signal for hemoptysis. Conclusion The analysis highlights the RTMD risks of ERAs and PRDs in treating PH and underscores the need for careful monitoring of ADEs to ensure their safe and effective use in clinical practice.

Pathophysiology of Angiotensin II-Mediated Hypertension, Cardiac Hypertrophy, and Failure: A Perspective from Macrophages

Heart failure is a complex syndrome characterized by cardiac hypertrophy, fibrosis, and diastolic/systolic dysfunction. These changes share many pathological features with significant inflammatory responses in the myocardium. Among the various regulatory systems that impact on these heterogeneous pathological processes, angiotensin II (Ang II)-activated macrophages play a pivotal role in the induction of subcellular defects and cardiac adverse remodeling during the progression of heart failure. Ang II stimulates macrophages via its AT1 receptor to release oxygen-free radicals, cytokines, chemokines, and other inflammatory mediators in the myocardium, and upregulates the expression of integrin adhesion molecules on both monocytes and endothelial cells, leading to monocyte-endothelial cell-cell interactions. The transendothelial migration of monocyte-derived macrophages exerts significant biological effects on the proliferation of fibroblasts, deposition of extracellular matrix proteins, induction of perivascular/interstitial fibrosis, and development of hypertension, cardiac hypertrophy and heart failure. Inhibition of macrophage activation using Ang II AT1 receptor antagonist or depletion of macrophages from the peripheral circulation has shown significant inhibitory effects on Ang II-induced vascular and myocardial injury. The purpose of this review is to discuss the current understanding in Ang II-induced maladaptive cardiac remodeling and dysfunction, particularly focusing on molecular signaling pathways involved in macrophages-mediated hypertension, cardiac hypertrophy, fibrosis, and failure. In addition, the challenges remained in translating these findings to the treatment of heart failure patients are also addressed.

The Prognostic Role of RDW in Hospitalized Heart Failure Patients with and Without Chronic Kidney Disease

Background: Chronic kidney disease (CKD) and heart failure (HF) are interrelated conditions that exacerbate each other through mechanisms like fluid retention, neurohormonal activation, and inflammation. Red blood cell distribution width (RDW), a measure of red blood cell size variability, has emerged as a potential prognostic marker in HF. This study aimed to assess the prognostic value of RDW in HF patients, both with and without CKD, focusing on all-cause mortality and HF rehospitalizations. Methods: This observational retrospective study included 171 patients hospitalized for acute decompensated HF in a tertiary university hospital in Greece. Patients were divided into two groups based on their estimated glomerular filtration rate (eGFR), as Group 1 (eGFR &lt; 60 mL/min/1.73 m2) and Group 2 (eGFR ≥ 60 mL/min/1.73 m2). RDW was measured upon admission, and outcomes of interest were all-cause mortality and HF rehospitalizations over a median follow-up period of 6.1 months. Statistical analyses included Kaplan–Meier survival curves, whereas the discrimination traits of RDW were evaluated by constructing receiver operating characteristic (ROC) curves and by calculating the area under the ROC curve (AUC). A p-value &lt;0.05 was indicative of a statistically important result. Results: Patients in Group 1 (eGFR &lt; 60 mL/min/1.73 m2) were older (80 (73–86) vs. 75 (62–83)) and manifested higher median RDW values (16.6 (15.0–18.8) vs. 15.6 (14.1–17.8)) and received less frequent (57.9% vs. 75%) mineralocorticoid receptor antagonists (MRAs) as compared to those in Group 2 (eGFR ≥ 60 mL/min/1.73 m2). RDW demonstrated better prognostic value in predicting combined mortality and rehospitalization outcomes in Group 2 patients (area under the curve: 0.70; 95% CI (0.62–0.80)) compared to those in Group 1 (area under the curve: 0.53; 95% CI (0.35–0.72)). No statistically significant differences (p = 0.579) were observed in survival between patients with high (≥15%) and low (&lt;15%) RDW values in the overall population, though trends favored worse outcomes with elevated RDW. Similarly, no significant differences (p = 0.374) were observed in survival between patients with high (Group 2) and low (Group 1) eGFR values. Conclusions: RDW appears to be a meaningful prognostic biomarker for HF patients, particularly in those without CKD. Further multicenter studies are needed to validate its clinical utility and potential for guiding treatment in this high-risk population.

Pharmacological targeting of dopamine D1 or D2 receptors evokes a rapid-onset parkinsonian motor phenotype in mice.

Dopaminergic nigrostriatal denervation in Parkinson's disease (PD) disrupts the functional balance between striatal projecting neurons, leading to aberrant activity in the cortico-basal ganglia circuit and characteristic motor symptoms. While genetic and toxin-based animal models are commonly used to mimic PD pathology and behaviour, they have limitations when combined with circuit manipulation tools. This highlights the need for complementary approaches, particularly when combined with viral-based circuit targeting of specific neuronal subpopulations involved in PD circuit dysfunction. Here, we pursue a pharmacological approach targeting dopamine D1 or D2 receptors to induce dopamine deprivation and to replicate key motor symptoms in PD. We demonstrate a clear dose-dependent induction of parkinsonian motor behaviour by both a dopamine D1 receptor antagonist (SCH23390) and a D2 receptor antagonist (haloperidol). The motor phenotype is evaluated by considering relevant motor metrics in an open-field maze platform. The proposed parkinsonian pharmacological model constitutes an acute, flexible approach, which allows parallel brain circuit manipulations.

Losartan attenuates sex-dependent hypertension, neuroinflammation, and cognitive impairment in the aging male sprague-dawley rat.

The prevalence of hypertension increases with age and is the leading modifiable risk factor for cognitive impairment and dementia. At present, the neural mechanisms promoting hypertension across the lifespan are incompletely understood. Using the Sprague-Dawley (SD) rat as a model of normal aging, we hypothesized (1) blood brain barrier (BBB) disruption and neuroinflammation in the paraventricular nucleus (PVN) of the hypothalamus enhances sympathetic tone and contributes to age-dependent hypertension, (2) age-dependent hypertension is associated with cognitive impairment, and (3) lowering blood pressure in aged rats with established hypertension improves cognitive function. We found male, but not female, rats develop age-dependent hypertension with enhanced sympathetic tone, BBB disruption, and neuroinflammation in the PVN. Aged hypertensive male rats also showed impairments in recognition and spatial memory. Utilizing pharmacological interventions, blood pressure was lowered in male rats with established hypertension using either losartan (LOS) or hydrochlorothiazide. However, only losartan improved recognition memory. Further, LOS reduced BBB disruption, microglial activation, astrocyte reactivity, and proinflammatory cytokine expression in the PVN which we speculate contributes to a decrease in blood pressure. These data show SD rats develop age-dependent hypertension and cognitive impairment in a sex-dependent manner. However, not all antihypertensive agents improve cognitive function equally as only losartan, an angiotensin II type 1 receptor antagonist (AT1R) improved recognition memory. Thus, AT1R antagonists represent a potential therapeutic approach for treating cognitive decline in the aging population.

TRPM8′s Role in the Shift Between Opioid and Cannabinoid Pathways in Electroacupuncture for Inflammatory Pain in Mice

The TRPM8 channel, a temperature-sensitive ion channel, plays a crucial role in various physiological processes, particularly in the modulation of inflammation and nociception. Although electroacupuncture (EA) is a recognized analgesic treatment for pain conditions, its interaction with TRPM8 remains underexplored. This study aims to determine TRPM8′s role in EA-induced analgesia using a murine model of inflammatory pain. Mechanical allodynia, evidenced by a reduced paw withdrawal threshold (PWT), was induced in both wild-type and Trpm8−/− mice through CFA injection. EA applied at the GB34 and LR3 acupoints significantly alleviated mechanical allodynia in both groups. In wild-type mice, the analgesic effects of EA were partially reversed by naloxone (an opioid receptor antagonist) or AM251 (a CB1 receptor antagonist) and fully reversed by their combination. In contrast, only AM251 reversed EA-induced analgesia in Trpm8−/− or TRPM8-inhibited wild-type mice (via AMTB treatment, a TRPM8 antagonist), indicating no involvement of the opioid pathway. Additionally, the combination of menthol, a partial TRPM8 agonist, and EA enhanced analgesia in wild-type mice. In Trpm8−/− or AMTB-pretreated mice, the CB1 receptor agonist WIN 55,212-2 (WIN) exhibited stronger analgesic effects compared to wild-type controls. These findings suggest that EA at LR3 and GB34 mediates analgesia through both opioid and endocannabinoid pathways. TRPM8 is critical for EA to activate the opioid pathway, while its inhibition or deletion shifts the analgesic mechanism towards reliance on the cannabinoid system. Understanding this mechanistic shift may help optimize EA treatment strategies and improve pain management outcomes.

Adenosine signaling in tumor-associated macrophages and targeting adenosine signaling for cancer therapy.

This review examined the critical role of adenosine signaling in modulating the behavior of tumor-associated macrophages (TAMs), a key determinant of the tumor microenvironment (TME). Adenosine is an immunosuppressive metabolite that is highly enriched in the TME due to elevated expression of adenosine triphosphatase (ATPase). Adenosine influences polarization of TAMs through A2A and A2B receptors, which drives a phenotype that supports tumor progression and immune evasion. The adenosine-mediated regulation of TAMs significantly suppresses the TME, dampening the efficacy of current immunotherapies. Targeting the adenosine pathway has shown potential in preclinical studies through reversal of the immunosuppressive microenvironment and antitumor immune response enhancement. Clinical trials are currently underway to determine the impact of A2A receptor antagonists, and CD39 and CD73 inhibition, enzymes that are pivotal in adenosine production, in various cancers. The current understanding of the CD39-CD73-adenosine axis in TAM regulation and the emerging strategies targeting adenosine signaling pathway for therapeutic intervention are the subjects of this review. The current clinical trials focusing on adenosine pathway inhibitors in combination with existing therapies to improve clinical outcomes are summarized and the need for continued research to refine these approaches for cancer treatment is emphasized.

Efficacy and safety of the glucagon receptor antagonist volagidemab in type-1 diabetes: A systematic review and meta-analysis.

The glucagon receptor antagonist (GRA) volagidemab is the first-in-class fully human monoclonal antibody that inhibits glucagon receptor. GRA can improve glycemia by reducing endogenous glucose production and reduce risks of diabetic ketoacidosis by suppressing ketogenesis. This systematic review and meta-analysis analyzed the efficacy and safety of volagidemab in type-1 diabetes (T1D). Electronic databases were searched for randomized controlled trials (RCTs) involving T1D patients receiving volagidemab. The primary outcome was to evaluate changes in total daily dose (TDD) of insulin. The secondary outcomes were to evaluate changes in measures of glycemia, hypoglycemia, and adverse events. Data from 3 RCTs (98 patients) were analyzed. Volagidemab (70mg/week) was associated with a significant reduction in TDD of insulin requirement (mean difference [MD]: -8.45 units/day (95% confidence interval [CI]: [-12.09, -4.81]); I2=83%; p<0.01) and average blood glucose (MD: -21.42mg/dL (95% CI: [-37.10, -5.74]); I2=88%; p<0.01), compared to placebo. Volagidemab use was associated with a significant increase in time in range (blood glucose: 70-180mg/dL) (MD: 10.93% (95% CI: [6.69, 15.17]); I2=55%; p<0.01) and significant reduction in time above range (blood glucose >180mg/dL) (MD: -11.93% (95% CI: [-14.71, -9.15]); I2=6%; p<0.01) without any impact on time below range (blood glucose <70mg/dL) (MD: 0.14% (95% CI: [-0.56, 0.84]); I2=0%; p=0.70), compared to placebo. Occurrence of treatment-emergent adverse events (odds ratio [OR]: 0.96 (95% CI: [0.36, 2.56]); I2=8%; p=0.94) and hypoglycemia (OR: 0.56 (95% CI: [0.11, 2.89]); I2=0%; p=0.49) were similar among volagidemab users as compared to placebo. Short-term volagidemab use was associated with significant reduction in insulin requirement along with improvement in glycemia.

Assessment of the Utilization of Sodium–Glucose Cotransporter-2 Inhibitors in Patients Without Diabetes

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2Is) have demonstrated effects beyond glucose-lowering, leading to their approval for treating chronic heart failure (HF) in Japan. This study examines prescription trends for SGLT2Is in patients with diabetes versus those without diabetes, focusing on their backgrounds and HF treatment status of patients without diabetes who received SGLT2I after an HF diagnosis. Methods: Using data from DeSC Healthcare Inc., we analyzed patients aged 65 and above who received their first SGLT2I prescription between October 2014 and February 2023. Patients were classified into SGLT2I-treated diabetic and non-diabetic groups. We analyzed the annual prescription trends and compared the characteristics of both groups who started SGLT2I between 2022 and 2023. Additionally, we assessed the timing of SGLT2I initiation and the use of concomitant HF treatment in patients without diabetes after HF diagnosis. Results: The proportion of patients without diabetes receiving their first SGLT2I prescription has increased since 2021. Patients without diabetes receiving SGLT2Is were older, likely owing to aging-related diseases. In patients without a confirmed diabetes diagnosis, SGLT2I was most frequently initiated at the time of HF diagnosis. Mineralocorticoid receptor antagonists (MRAs) are the most common concomitant HF medications. The increase in SGLT2I prescriptions for patients without diabetes receiving SGLT2I since 2021, particularly in older individuals, suggests that SGLT2I is being initiated either at the time of HF diagnosis or in a stepwise manner. Conclusion: In Japan, MRA is commonly used as a concomitant medication in patients without diabetes receiving SGLT2I.

Orexants, Orexin Receptor Antagonists: Novel Therapeutic Agents for Insomnia Disorder

Insomnia is when a person feels difficulty falling asleep or staying asleep, often associated with complications, such as fatigue, sleepiness, etc. Insomnia may cause disruptions in daytime physical and mental abilities. Orexins or hypocretins are the neuropeptides secreted from the lateral hypothalamus and play a major role in the sleep-wake cycle through a complex interplay between wake-promoting and sleep-promoting neuronal systems. Orexin receptor antagonists (Orexants) are the new treatment options for insomnia disorder, narcolepsy, and other sleep disturbances. There are two classes of Orexants, namely those that bind selectively to a specific orexin receptor are selective orexin receptor antagonists (SORA), and the others that bind to both the orexin receptors are dual orexin receptor antagonists (DORA). The first DORA was almorexant but restricted in use and the other three approved DORAs, such as suvorexant, lemborexant, and daridorexant were approved by the FDA, and several other DORAs and SORAs are under various stages of discovery and clinical investigation. Among the labeled limitations, the currently approved Orexants are contraindicated in people with narcolepsy and are controlled substances owing to their misuse liability. The present review discussed the sleep-wake cycle, phases of a sleep cycle, orexins, and Orexants, and summarized the pharmacology of the three approved DORAs, a type of Orexants and their potential advantages and limitations of their use in pharmacotherapy of insomnia disorder.

The Syndrome of Inappropriate Antidiuresis

Abstract The syndrome of inappropriate antidiuresis (SIAD)–the most frequent cause of hypotonic hyponatremia–is mediated by nonosmotic release of arginine vasopressin (AVP), which promotes water retention by activating renal vasopressin type 2 (V2) receptors. There are numerous causes of SIAD, including malignancy, pulmonary and central nervous system diseases and medications. Rare activating mutations of the V2 receptor can also cause SIAD Determination of the etiology of SIAD is important because removal of the stimulus for inappropriate AVP secretion offers the most effective therapy. Treatment of SIAD is guided by symptoms and their severity as well as the level of plasma sodium. In the absence of severe symptoms which require urgent intervention, many clinicians focus on fluid restriction as a first-line treatment. Second-line therapeutic options include loop diuretics and salt tablets, urea, and V2 receptor antagonists.

The Prostaglandin EP4 Antagonist Vorbipiprant Combined with PD-1 Blockade for Refractory Microsatellite Stable Metastatic Colorectal Cancer: A Phase 1b/2a Trial.

Novel combinations are required to overcome resistance to immune checkpoint inhibitors (ICIs) in proficient mismatch repair (pMMR) or microsatellite stable (MSS) metastatic colorectal cancer (mCRC). We aimed to determine whether vorbipiprant, a prostaglandin EP4 receptor antagonist, can convert immune-resistant mCRC into a tumor responsive to anti-PD-1 inhibition. This phase 1b/2a prospective, open-label, single-arm trial followed a 3 + 3 dose escalation and dose optimization design. A total of 28 patients with chemorefractory pMMR/MSS mCRC were given dose-escalated oral vorbipiprant (30, 90, or 180 mg twice daily), along with biweekly intravenous balstilimab (3 mg/kg), an anti-PD-1 antibody. The primary endpoints included safety and the disease control rate (DCR). Secondary endpoints were the objective response rate (ORR), duration of response, progression-free survival (PFS) and overall survival (OS). No dose-limiting toxicities were observed. Out of the 28 patients, seven (25%) experienced serious adverse events, but only one was attributed to vorbipiprant and one to balstilimab. The trial achieved a DCR of 50% observed across the entire cohort. In the subgroup of patients with liver metastases (n = 12) DCR was 25%. The ORR was 11%, with three patients showing a partial response (median duration of response: 7.4 months). Median PFS was 2.6 months and median OS was 14.2 months. Translational exploratory analyses suggested that vorbipiprant may boost response to anti-PD-1 in patients with immunogenic tumors. The combination of vorbipiprant and a PD-1 inhibitor (balstilimab) yielded sufficient activity in refractory pMMR/MSS mCRC, worth of confirmation in future clinical trials in biomarker-enriched populations.