Receptor Antagonist Research Articles

Blood Pressure Management Strategies and Podocyte Health.

Hypertension (HTN) is one of the key global cardiovascular risk factors, which is tightly linked to kidney health and disease development. Podocytes, glomerular epithelial cells that play a pivotal role in maintenance of the renal filtration barrier, are significantly affected by increased glomerular capillary pressure in HTN. Damage or loss of these cells causes proteinuria, which marks the initiation of the HTN-driven renal damage. It goes without saying that effective blood pressure (BP) management should not only mitigate cardiovascular risks but also preserve renal function by protecting podocyte integrity. This review offers a comprehensive examination of current BP management strategies and their implications for podocyte structure and function and emphasizes strategies for the reduction of proteinuria in HTN. We explore primary and secondary antihypertensive agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics, as well as newer therapies (sodium-glucose cotransporter-2 blocking and endothelin receptor antagonism), emphasizing their mechanistic roles in safeguarding podocytes and curtailing proteinuria.

Redefining Ketamine Pharmacology for Antidepressant Action: Synergistic NMDA and Opioid Receptor Interactions?

Ketamine is a racemic compound and medication comprised of (S)-ketamine and (R)-ketamine enantiomers and its metabolites. It has been used for decades as a dissociative anesthetic, analgesic, and recreational drug. More recently, ketamine, its enantiomers, and its metabolites have been used or are being investigated for the treatment of refractory depression, as well as for comorbid disorders such as anxiety, obsessive-compulsive, and opioid use disorders. Despite its complex pharmacology, ketamine is referred to as an N-methyl-d-aspartate (NMDA) receptor antagonist. In this review, the authors argue that ketamine's pharmacology should be redefined to include opioid receptors and the endogenous opioid system. They also highlight a potential mechanism of action of ketamine for depression that is attributed to bifunctional, synergistic interactions involving NMDA and opioid receptors.

Glucagon Can Increase Force of Contraction via Glucagon Receptors in the Isolated Human Atrium.

Glucagon can increase the force of contraction (FOC) in, for example, canine hearts. Currently, whether glucagon can also increase the FOC via cAMP-increasing receptors in the human atrium is controversial discussed. Glucagon alone did not (up to 1 µM) raise the FOC in human right atrial preparations (HAP). Only in the additional presence of the phosphodiesterase (PDE) 3 inhibitor cilostamide (1 µM) or 1 nM isoprenaline did glucagon raise the FOC, starting at 1 µM. The positive inotropic effects of glucagon in HAP were attenuated by a glucagon receptor antagonist (1 µM SC203972), but not by 100 nM exendin(9-39), a glucagon-like peptide-1 receptor (GLP-1R) antagonist. Glucagon (in the presence of cilostamide) demonstrated a reduced efficacy in elevating the FOC in HAP when compared with isoprenaline. In contrast to glucagon, exenatide alone, a GLP-1R agonist, starting at 1 nM, increased the FOC and was more potent and effective than glucagon in raising the FOC in HAP. The effects of exenatide on the FOC were attenuated by exendin(9-39). Hence, glucagon and GLP-1R agonists act functionally via different receptors in the human right atrium. Clinically, these data suggest that endogenous or exogenous glucagon can stimulate glucagon receptors in the human atrium, but only in the presence of PDE inhibitors.

Kisspeptin and Neurokinin B: roles in reproductive health.

Kisspeptin and neurokinin B (NKB) play a key role in several physiological processes including in puberty, adult reproductive function including the menstrual cycle, as well as mediating the symptoms of menopause. Infundibular kisspeptin neurons, which co-express NKB, regulate the activity of gonadotropin releasing hormone (GnRH) neurons, and thus the physiological pulsatile secretion of GnRH from the hypothalamus. Outside of their hypothalamic reproductive roles, these peptides are implicated in several physiological functions including sexual behavior and attraction, placental function, and bone health. Over the last two decades, research findings have considerably enhanced our understanding of the physiological regulation of the hypothalamic-pituitary-gonadal (HPG) axis and identified potential therapeutic applications. For example, recognition of the role of kisspeptin as the natural inductor of ovulation has led to research investigating its use as a safer, more physiological trigger of oocyte maturation in <em>in vitro</em> fertilization (IVF) treatment. Moreover, the key role of NKB in the pathophysiology of menopausal hot flashes has led to the development of pharmacological antagonism of this pathway. Indeed, Fezolinetant, a neurokinin 3 receptor antagonist, has recently received Food and Drug Administration (FDA) approval for clinical use to treat menopausal vasomotor symptoms. Herein, we discuss the roles of kisspeptin and NKB in human physiology, including in the regulation of puberty, menstrual cyclicity, reproductive behavior, pregnancy, menopause, and bone homeostasis. We describe how perturbations of these key physiological processes can result in disease states and consider how kisspeptin and NKB could be exploited diagnostically, as well as therapeutically to treat reproductive disorders.

Case report: Tocilizumab for hypersensitivity reaction after oxaliplatin in a patient with NK/T-cell lymphoma

Oxaliplatin-induced hypersensitivity reactions (HSRs) are commonly encountered in first-line therapies for various malignancies. Recent research indicates that these reactions can include cytokine release reactions (CRRs), which are characterized by a marked increase in interleukin-6 (IL-6) levels, sometimes rising as much as 40-fold. Standard management strategies for HSRs typically involve desensitization protocols and routine treatments. However, these conventional approaches may be insufficient for managing CRRs. Preliminary studies suggest that tocilizumab, an IL-6 receptor (IL-6R) antagonist, may play a crucial role in mitigating CRRs. In our case, a 65-year-old male with stage IV extranodal NK/T-cell lymphoma developed a severe HSR on day 1 following the infusion of oxaliplatin during his fourth chemotherapy cycle. This reaction was marked by a substantial increase in IL-6 levels. Despite the administration of standard treatments, including epinephrine and corticosteroids, the patient required ventilatory support and vasopressors on day 1. On day 2, tocilizumab was administered, resulting in a rapid and significant reduction in IL-6 levels. Subsequently, the patient’s symptoms, including fever, dyspnea, and hypotension, resolved, and he was discharged on day 5. This case demonstrates that tocilizumab can be an effective intervention in managing severe HSRs associated with CRRs. To our knowledge, this is the first reported instance of tocilizumab successfully salvaging a patient experiencing oxaliplatin-induced HSR. Nevertheless, further research is required to validate the efficacy of tocilizumab in treating oxaliplatin-induced HSRs.

A retrospective study on potential drug‒drug interactions in patients with severe asthma receiving biological therapy: a single-center experience

BackgroundPrevalence of potential drug-drug interactions (pDDIs) in adult patients with severe asthma on biological therapy and their clinical significance have not been fully addressed, thus the aim of this study was to investigate them.MethodsIn this retrospective observational study, patients who were diagnosed with severe asthma and to whom biological therapy was prescribed between September 2015 and December 2020, were enrolled. The study was conducted at the Department of Allergic and Obstructive Pulmonary Diseases, Clinic for Lung Diseases Jordanovac, Clinical Hospital Center Zagreb. Data on demographic characteristics as well as concomitant medication were collected. The analysis of pDDIs was conducted via Lexicomp® online software. Interactions of significance levels A and B were only recorded, while those of levels C, D and X were further analysed. The collected data was processed via Microsoft Excel 365 software.Results60 adult patients, 60% female and 40% male, with median age of 56.2 years, were enrolled. The incidence of pDDIs was 86.67%. Total number of pDDIs detected was 518, out of which 43.24%, 45%, 4.44% and 7.3% of clinical significance B, C, D and X. Interactions of level C, D and X were recorded in, as follows: 83.33%, 25% and 33.33% patients with an average of 4.66, 1.53 and 1.9 interactions per patient. Only 13.33% of the patients had none of the potential clinically significant DDI. Most drug pairs contained at least one antiasthmatic drug. Muscarinic receptor antagonists, oral corticosteroids, β2 agonists and methylxanthines showed potential of entering into clinically significant DDIs, while leukotriene antagonists and biologicals showed no potential for the above.ConclusionPrevalence of potential drug-drug interactions in patients with severe asthma on biological therapy is high. The majority of identified interactions have moderate to high level of clinical significance. Their identification, prevention and resolution could contribute to optimizing therapy, maximizing its therapeutic effect and avoiding undesirable adverse events.

Initiation and sequencing of guideline-directed medical therapy for heart failure across the ejection fraction spectrum.

Strong evidence supports the importance of rapid sequence or simultaneous initiation of quadruple guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) for substantially reducing risk of mortality and hospitalization. Barring absolute contraindications for each individual medication, employing the strategy of rapid sequence, simultaneous, and/or in-hospital initiation at the time of HF diagnosis best ensures patients with HFrEF have the opportunity to benefit from proven medications and achieve large absolute risk reductions for adverse clinical outcomes. However, despite guideline recommendations supporting this approach, implementation in clinical practice remains persistently low, with less than one-fifth of eligible patients being prescribed the quadruple GDMT regimen. Additionally, for heart failure with mildly reduced or preserved ejection fraction (HFpEF), sodium-glucose co-transporter 2 inhibitors (SGLT2i) and non-steroidal mineralocorticoid receptor antagonists (MRA)constitute foundational therapy for all eligible patients with significant clinicalbenefits within just weeks of medication initiation. Nonetheless, the burden of symptoms, functional limitations, and hospitalizations remains substantial for many of these patients, even with SGLT2iand non-steroidal MRA therapy. Additional evidence supports consideration of adjunctive therapies for HF with EF > 40% that can be tailored to the patient phenotype, including glucagon-like peptide-1 receptor agonists (GLP-1 RA) for patients with obesity, as well as angiotensin receptor-neprilysin inhibitors (ARNI) for patients with EF below normal. This article reviews the evidence-based sequencing of GDMT for HF across the spectrum of EF, emphasizing the rationale and benefits of early up-front initiation of quadruple medical therapy for HFrEF, rapid initiation of SGLT2i for HF regardless of EF, and prompt phenotype-specific tailored approach to adjunctive therapies for HF with EF > 40%.

Addition of an NK1 receptor antagonist to standard antiemetic prophylaxis in patients with B-cell lymphoma receiving EPOCH.

Data on the optimal management of patients with hematologic malignancies and chemotherapy-induced nausea and vomiting (CINV) are lacking, particularly for multiday chemotherapy regimens. We report our institutional experience in patients with B-cell lymphoma receiving multiday dose-adjusted R-EPOCH chemotherapy utilizing two CINV prophylaxis strategies. We performed a retrospective, single-center, cohort study evaluating hospitalized patients with aggressive non-Hodgkin B-cell lymphoma receiving DA-R-EPOCH (April 2016 to October 2022). All patients received prophylactic corticosteroid and 5HT3-receptor antagonist, and were categorized by the addition of an NK1 receptor antagonist (NK1RA) or not. The primary outcome was complete response (CR, no vomiting, and no rescue medication use) over 120 h. Secondary outcomes included as-needed antiemetic use (acute, delayed, and overall phases), CR without escalating prophylactic antiemetics in cycle 2, and complete control. We performed a descriptive analysis and multivariate logistic regression for NK1RA use, adjusting for age and sex. Of 128 patients, 56 (43.8%) received an NK1RA as part of their antiemetic regimen, and 72 (56.3%) did not. No patients received prophylactic olanzapine. CR was achieved in 32 (57.1%) of those who received an NK1RA and 30 (41.7%) who did not (OR 0.45; 95% CI, 0.21-0.96; p = 0.039). We observed trends between groups in as-needed antiemetics use (29 [51.8%] vs. 49 [68.1%]; p = 0.061), with most use in the delayed phase (22 [39.3%] vs. 37 [51.4%], p = 0.173). We found no difference in healthcare utilization between the first and second cycle. CINV control in patients with non-Hodgkin B-cell lymphoma receiving DA-R-EPOCH in the hospital was suboptimal. These data support the need to optimize prophylactic antiemetic regimens for patients receiving DA-R-EPOCH.

Ketamine Infusion for Complex Regional Pain Syndrome Treatment: A Narrative Review.

Complex Regional Pain Syndrome (CRPS) is a neuropathic pain disorder characterized by pain disproportionate to the inciting event that is constant for an extended duration. Numerous treatment options for this condition have been explored with unsatisfactory results in many cases. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist typically used as an anesthetic and analgesic, presents a promising potential treatment for CRPS in patients who fail to respond to traditional therapies. Numerous studies report significant improvement in the degree of pain, mobility of extremities, and other parameters after ketamine infusion in patients with CRPS. Although adverse effects were not reported often, some subjects experienced nausea, vomiting, headache or psychotropic or psychomimetic symptoms which could be mitigated with cessation of the drug. Although more research is needed to determine optimal dosing and duration, ketamine seems to be a safe and effective treatment for refractory cases of CRPS. The present investigation summarizes existing knowledge and research surrounding ketamine infusions for CRPS to provide a well-rounded depiction of advantages and disadvantages for physicians who may be considering it for patients with this challenging and complex condition.

Terminal complement complex deposition on chondrocytes promotes premature senescence in age- and trauma-related osteoarthritis

BackgroundThe complement system is locally activated after joint injuries and leads to the deposition of the terminal complement complex (TCC). Sublytic TCC deposition is associated with phenotypical alterations of human articular chondrocytes (hAC) and enhanced release of inflammatory cytokines. Chronic inflammation is a known driver of chondrosenescence in osteoarthritis (OA). Therefore, we investigated whether TCC deposition contributes to stress-induced premature senescence (SIPS) during aging in vivo and after ex vivo cartilage injury.MethodsFemoral condyles of male 13-week-old and 72-week-old CD59-ko (higher TCC deposition), C6-deficient (insufficient TCC formation), and C57BL/6 (WT) mice were collected to assess age-related OA. Furthermore, macroscopically intact human and porcine cartilage explants were traumatized and cultured with/without 30% human serum (HS) to activate the complement system. Explants were additionally treated with clusterin (CLU, TCC inhibitor), N-acetylcysteine (NAC, antioxidant), Sarilumab (IL-6 receptor inhibitor), STAT3-IN-1 (STAT3 inhibitor), or IL-1 receptor antagonist (IL-1RA) in order to investigate the consequences of TCC deposition. Gene and protein expression of senescence-associated markers such as CDKN1A and CDKN2A was determined.ResultsIn the murine aging model, CD59-ko mice developed after 72 weeks more severe OA compared to C6-deficient and WT mice. mRNA analysis revealed that the expression of Cdkn1a, Cdkn2a, Tp53, Il1b, and Il6 was significantly increased in the cartilage of CD59-ko mice. In human cartilage, trauma and subsequent stimulation with HS increased mRNA levels of CDKN1A, CDKN2A, and IL6, while inhibition of TCC formation by CLU reduced the expression. Antioxidative therapy with NAC had no anti-senescent effect. In porcine tissue, HS exposure and trauma had additive effects on the number of CDKN2A-positive cells, while Sarilumab, STAT-IN-1, and IL-1RA reduced CDKN2A expression by trend.ConclusionOur results demonstrate that complement activation and consequent TCC deposition is associated with chondrosenescence in age-related and trauma-induced OA. We provided evidence that the SIPS-like phenotype is more likely induced by TCC-mediated cytokine release rather than oxidative stress. Overall, targeting TCC formation could be a future approach to attenuate OA progression.

Expert Clinical Management of Inflammatory Immune-Related Arthritis in Patients with Cancer Receiving Immune Checkpoint Inhibitors.

Treatment guidelines for immune-related inflammatory arthritis (irAE-IA) in patients with cancer receiving immune checkpoint inhibitors (ICIs) are vague with respect to the use of specific agents. Patients are usually referred to rheumatologists for treatment. We conducted a survey of expert rheumatologists to determine current practices. We also assessed experts' views on the potential deleterious effects of various agents on tumor progression. We conducted a survey of international experts in the treatment of irAE-IA, identified as members of collaborative scientific workgroups in this area. Experts were presented with a case of a patient with moderate irAE-IA and were asked about their preferred management including glucocorticoids, timing and initial choice of disease-modifying antirheumatic drugs (DMARDs), and perception of the deleterious effects of different agents on tumor progression. We approached 25 experts, of whom 19 (76%) responded. Most experts (63%) agreed on 20 mg or less of prednisone as initial dose. Experts selected methotrexate (41%) or tumor necrosis factor inhibitor (TNFi) (23%) as the initial DMARD if there was no improvement with corticosteroids; most experts (42%) would initiate DMARDs after 4 weeks. For patients whose initial DMARD therapy failed, the second choice was either a tumor necrosis factor inhibitor (TNFi) (38%) or interleukin-6 receptor antagonist (IL6ri) (33%). Experts were most concerned about the potential deleterious effects on tumor progression of abatacept and prednisone at doses of 20 mg or higher. There was substantial heterogeneity in the initial management of irAE-IA. Further understanding of the pathophysiology of this immunotoxicity can assist in the classification of different presentations, selection of relevant outcomes, and planning of clinical trials to establish optimal therapeutic efficacy while minimizing potential deleterious effects of treatment on immune tumor responses.

Effects of the Nonsteroidal MRA Finerenone With and Without Concomitant SGLT2 Inhibitor Use in Heart Failure.

Patients with heart failure (HF) with mildly reduced or preserved ejection fraction face heightened long-term risks of morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal mineralocorticoid receptor antagonist finerenone have both been shown to reduce the risk of cardiovascular events in this population, but the effects of their combined use are not known. FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction ≥40%. Baseline SGLT2i use was a prespecified subgroup. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. We first assessed for evidence of treatment heterogeneity on the basis of baseline SGLT2i use. We further examined SGLT2i uptake during the trial and evaluated the treatment effects of finerenone accounting for baseline and during-trial use of SGLT2i in time-varying analyses. Among 6001 participants, 817 (13.6%) were treated with an SGLT2i at baseline. During 2.6 years median follow-up, treatment with finerenone similarly reduced the risk of the primary outcome in participants treated with an SGLT2i (rate ratio, 0.83 [95% CI, 0.60-1.16]) and without an SGLT2i at baseline (rate ratio, 0.85 [95% CI, 0.74-0.98]; Pinteraction=0.76). In follow-up, 980 participants initiated SGLT2i, which was less frequent in the finerenone arm compared with placebo (17.7% versus 20.1%; hazard ratio, 0.86 [95% CI, 0.76-0.97]). Time-updated analyses accounting for baseline and subsequent use of SGLT2i did not meaningfully alter the treatment effects of finerenone on the primary end point. The treatment benefits of the nonsteroidal mineralocorticoid receptor antagonist finerenone were observed irrespective of concomitant use of an SGLT2i. These data suggest that the combined use of SGLT2i and a nonsteroidal mineralocorticoid receptor antagonist may provide additive protection against cardiovascular events in patients with HF with mildly reduced or preserved ejection fraction. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626.

Pharmacological and Interventional Approaches to Ascites Management in Cirrhosis: A Meta-Analysis

Background: Ascites, a common complication of cirrhosis, significantly impacts patient morbidity and mortality. This meta-analysis evaluated the efficacy and safety of various pharmacological and interventional approaches for ascites management in patients with cirrhosis. Methods: A systematic search of PubMed, Embase, and Cochrane Library databases was conducted from January 2013 to December 2024, identifying randomized controlled trials (RCTs) comparing different pharmacological agents (diuretics, albumin, vasopressin receptor antagonists) and interventional procedures (large-volume paracentesis, transjugular intrahepatic portosystemic shunt [TIPS]) in cirrhotic patients with ascites. The primary outcome was complete ascites resolution. Secondary outcomes included time to ascites recurrence, adverse events, and mortality. A random-effects model was used to pool data, and heterogeneity was assessed using the I² statistic. Results: Twelve RCTs (n=2848 patients) met the inclusion criteria. Diuretics plus albumin was superior to diuretics alone in achieving complete ascites resolution (OR 2.18, 95% CI 1.65-2.88, p&lt;0.001; I²=38%). Vasopressin receptor antagonists were comparable to diuretics plus albumin in terms of ascites resolution (OR 1.09, 95% CI 0.88-1.35, p=0.42; I²=12%) but associated with a lower incidence of hyponatremia (OR 0.52, 95% CI 0.35-0.78, p=0.002; I²=23%). Large-volume paracentesis was more effective than repeated small-volume paracentesis for ascites control (OR 1.75, 95% CI 1.31-2.34, p&lt;0.001; I²=41%). TIPS was associated with a higher rate of complete ascites resolution compared to large-volume paracentesis (OR 2.45, 95% CI 1.78-3.38, p&lt;0001; I²=35%) but a higher risk of hepatic encephalopathy (OR 2.21, 95% CI 1.48-3.30, p&lt;0.001; I²=15%). Albumin reduced mortality in patients undergoing large-volume paracentesis (OR 0.68, 95% CI 0.49-0.94, p=0.02; I²=0%). Conclusion: This meta-analysis supports the use of diuretics plus albumin, vasopressin receptor antagonists, large-volume paracentesis, and TIPS for ascites management in cirrhosis, with the choice of therapy individualized based on patient characteristics, ascites severity, and the risk of complications.

Morphine-Induced Elevation of Reactive Oxygen Species Attenuates Chemotherapy Efficacy in Diverse Cancer Cell Types.

Morphine, a mu-opioid receptor (MOR) agonist commonly utilized in clinical settings alongside chemotherapy to manage chronic pain in cancer patients, has exhibited contradictory effects on cancer, displaying specificity toward certain cancer types and doses. The aim of this study was to conduct a systematic assessment and comparison of the impacts of morphine on three distinct cancer models in a preclinical setting. Viability and apoptosis assays were conducted on a panel of cancer cell lines following treatment with morphine, chemotherapy drugs alone, or their combination. Oxidative stress levels, along with the activities of superoxide dismutase and catalase, were measured. Rescue studies were also carried out using antioxidant reagents. Morphine induces resistance to conventional chemotherapeutic agents. It was observed that while morphine affected cell viability differently among ovarian cancer, anaplastic thyroid cancer, and oral squamous cell carcinoma, at concentrations that did not directly impact cancer cell viability, it significantly mitigated the inhibitory effects of chemotherapeutic agents across all tested cancer cells. This phenomenon persisted irrespective of the chemotherapeutic agent used, including cisplatin, doxorubicin, and 5-FU. It remained unaffected by adding naloxone, the MOR receptor antagonist, indicating that morphine's mechanism is independent of the μ- opioid receptor. Moreover, it was demonstrated that morphine heightened cellular reactive oxygen species (ROS) levels and suppressed the activities of superoxide dismutase and catalase. Rescue studies revealed that the addition of antioxidant reversed the protective impact of morphine on cancer cells against chemotherapy. These findings hold promise in potentially guiding the clinical application of morphine for cancer patients undergoing chemotherapy.

Pipeline for development of acylated peptide based CGRP receptor antagonist with extended half-life for migraine treatment

Migraine is a debilitating headache disorder. The disease has neurovascular origin and migraine attacks can be elicited by vasodilative neuropeptides such as alpha calcitonin gene-related peptide (αCGRP). Antagonizing CGRP actions in migraine patients has proven clinically efficient. Here, we present a pipeline for development of a peptide-based hCGRP receptor antagonist with increased half-life capable of antagonising the vasodilatory effect of hαCGRP. A series of hαCGRP8-37 analogues carrying a C18-or C20-diacid lipidation was screened for their antagonism against the hCGRP receptor. hαCGRP8-37 analogues with a C20-diacid were 2-6 fold more potent than analogues conjugated with a C18-diacid. Half-life of hαCGRP8-37 analogues carrying a C20-diacid was estimated in mice in a pilot study (n = 1–2). Half-lives ranged from 7.3 to 13.7 h. An hαCGRP8-37 analogue conjugated with a C20 diacid at position 25 was subjected to an amino acid substitution scan to identify mutations that could further enhance hCGRP receptor antagonism. Substituting alanine with serine at position 36 resulted in a ~ 4 fold gain of potency. Vasodilative actions of hαCGRP were successfully antagonized by hαCGRP8-37 analogues carrying a C20 diacid at position 25. Our findings demonstrate that lipidation can improve hαCGRP8-37 pharmacokinetics while maintaining hαCGRP antagonism, thus demonstrating potential for a peptide-based migraine treatment strategy.

Aryl Hydrocarbon Receptor Establishes a Delicate Balance between the Level of the Trace Amine Tryptamine and Monoamine Oxidase Activity in the Brain and Periphery in Health and Conditions such as Neurodegenerative, Neurodevelopmental, and Psychiatric Disorders.

The purpose of this review was to analyse the literature regarding the correlation between the level of tryptamine, aryl hydrocarbon receptor (AHR) signalling pathway activation, and monoamine oxidase (MAO)-A and MAO-B activity in health and conditions such as neurodegenerative, neurodevelopmental, and psychiatric disorders. Tryptamine is generated through the decarboxylation of tryptophan by aromatic amino acid decarboxylase (AADC) in the central nervous system (CNS), peripheral nervous system (PNS), endocrine system, and gut bacteria. Organ-specific metabolism of tryptamine, which is mediated by different MAO isoforms, causes this trace amine to have different pharmacokinetics between the brain and periphery. Reactive oxygen species (ROS) generated by MAO can influence miRNA-CYP enzyme regulatory network and affect mitochondrial function. Tryptamine regulates AHR function by acting as an endogenous ligand for AHR, initiating AHR activation and inhibiting the expression of the CYP1A1 and CYP1A2 genes. The dysregulation of AHR signalling, triggered by endogenous tryptamine binding, can disrupt the regulation of prolactin levels. Depending on the tryptamine concentration and context, tryptamine can be beneficial or harmful. By acting as an agonist of inhibitory serotonin receptors and trace-amine associated receptor 1 (TAAR1) and an antagonist of excitatory serotonin receptors, it can engage in diverse physiological interactions with serotonin. Increased tryptamine production is observed under hypoxic conditions and is associated with hypoxia-inducible factor 1α (HIF-1α) activation, leading to AHR activation. Dysregulation of the association between tryptamine levels, AHR signalling pathway activation, and MAO activity are observed in Alzheimer's disease (AD), Parkinson's Disease (PD), Autism Spectrum Disorder (ASD) and schizophrenia.

Importance of early use of tolvaptan in hyponatremic acutely decompensated heart failure patients, a retrospective study

BackgroundHyponatremia is one of the complicating findings in acute decompensated heart failure. Decrease in cardiac output and systemic blood pressure triggers activation of renin–angiotensin–aldosterone system, antidiuretic hormone, and norepinephrine due to the perceived hypovolemia. Fluid-overloaded heart failure patients are commonly treated with loop diuretics, acutely decompensated heart failure patients tend to be less responsive to conventional oral doses of a loop diuretic, while other different diuretics could work in different part of nephron circulation system. In this study, we aim to further examine the role of tolvaptan, a vasopressin receptor antagonist, in the treatment of hyponatremia secondary to acutely decompensated heart failure.ResultsA total of 71 patients with hyponatremia secondary to ADHF were included, and all patients were given tolvaptan. 37 patients were administered tolvaptan early (up until 5 th day of admission). 34 patients received tolvaptan after 5 th day of admission mean administration as 6.86 th day, and median administration was 5 th day. Analysis showed lower length of stay in patients receiving early administration of tolvaptan compared to late administration (8.86 ± 5.06 vs 18.5 ± 9.05 p0.001, respectively). Patients with early initiation of tolvaptan also achieved a larger net increase in sodium levels at discharge compared to admission (6.46 ± 6.69 vs 3.68 ± 4.70 p0.048, respectively).ConclusionsEarly administration of tolvaptan in treating hyponatremia in acutely decompensated heart failure patients is associated with a lower length of hospitalization and a higher increase in serum sodium of patients in hyponatremic ADHF patients.

Naphtho[1,2-b][1,4]diazepinedione-Based P2X4 Receptor Antagonists from Structure-Activity Relationship Studies toward PET Tracer Development.

The P2X4 receptor is implicated in various pathological conditions, including neuropathic pain and cancer. This study reports the development of 1,4-naphthodiazepinedione-based P2X4 receptor antagonists aimed at both therapeutic applications and potential use as PET tracers for imaging P2X4 receptor expression in cancer. Structure-activity relationship studies aided by docking studies and molecular dynamics simulations led to a series of compounds with potent P2X4 receptor antagonism, promising in vitro inhibition of interleukin-1β release in THP-1 cells and suitability for radiolabeling with fluorine-18. The most potent compounds were further evaluated for their physicochemical properties, metabolic stability, and in vivo biodistribution using PET imaging in mice. While these antagonists exhibited strong receptor binding and serum stability, rapid in vivo metabolism limited their potential as PET tracers, highlighting the need for further structural optimization. This study advances the understanding of P2X4 receptor antagonism and underscores the challenges in developing effective PET tracers for this target.

The Research Progress of Drugs for Treatment of AlzheimerS Disease

In this society, Alzheimer's disease represents a significant public health concern. Nevertheless, the market offers only two FDA-approved drugs, which are capable of only partially inhibiting the symptoms. It is imperative that both patients and researchers are made aware of the mechanism by which AD is triggered and the fundamental logic underlying the action of each drug. This should include an understanding of how the drug reacts with the body and the ingredients that it contains. This section primarily discusses the therapeutic options for Alzheimer's disease, encompassing both the drugs and mechanisms that are currently available on the market and those that have not yet been approved but are theoretically feasible. This passage will introduce a number of potential treatments for Alzheimer's disease, including Chinese patent medicine, acetylcholinesterase inhibitors, NMDA receptor antagonists, Aduhelm, Leqembi, anti-amyloid therapies and A immunotherapies. Despite the existence of these treatments for many years, it is still not possible to cure Alzheimer's disease completely or to delay or prevent its progression. This passage aims to provide insights into the future direction of pharmaceutical research and the selection of appropriate medications

Off-Label Use of Anakinra in Inflammatory Conditions in Neonates and Infants Up to 3 Months of Age: A Case Series and a Review of the Literature.

Anakinra is an interleukin-1 receptor antagonist (IL-1Ra). Since IL-1 has been shown to play a key role in the etiology of different autoinflammatory diseases, blocking its pathway has become an important therapeutic target, even in neonates. We aimed to report our experience in using anakinra to treat specific neonatal inflammatory conditions. We described the clinical management with anakinra of five cases of neonates or infants up to 3 months of age admitted to the neonatal intensive care unit (NICU) of Bambino Gesù Children's Hospital IRCCS in Rome (Italy) from 2020 onwards. Medical history and clinical data concerning NICU hospitalization were collected from the electronic medical records. Furthermore, we performed a literature review of off-label anakinra in the first 3 months of life, up to 5 April 2024. We excluded from this review cases of cryopyrin-associated periodic syndrome, deficiency of the interleukin-1 receptor antagonist, and mevalonate kinase deficiency, for which anakinra is a known treatment. We reported three off-label cardiorespiratory reasons to use IL-1Ra from our series: (i) chronic lung disease with pulmonary hypertension, (ii) interstitial lung disease with pulmonary hypertension to facilitate the weaning from respiratory support, and (iii) post-surgical polyserositis if effusions accumulate despite drainage. In all our patients, the drug was administered at a dosage of 10mg/kg/day. The route of administration was chosen based on the patient's clinical characteristics, with the subcutaneous and intravenous routes being comparable in efficacy. The duration of therapy was modulated based on the patient's clinical response, with a minimum duration of 4 months. A total of 308 retrieved articles were screened, and then full texts of records deemed eligible for inclusion were assessed. Based on the literature search and our five cases, a total of 17 infants were treated with anakinra outside its approved indications. The major off-label use was for hemophagocytic lymphohistiocytosis/macrophage activation syndrome, followed by multisystem inflammatory syndrome in children and Kawasaki disease, as in two of our cases. According to the results of our case series and review of the literature, the off-label use of anakinra in neonates with inflammatory conditions refractory to first-line therapy could be considered. Prospective, multicenter research is necessary to determine whether anakinra is a safe treatment option for these infants to prevent early inflammatory illnesses and in which situations it could enhance clinical results.