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Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT 2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT 2A -Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT 2A -selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT 2A -Gq but not 5-HT 2A -β-arrestin2 recruitment efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT 2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT 2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT 2A agonists. We also demonstrate that β-arrestin-biased 5-HT 2A receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT 2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics. Serotonin 5-HT 2A receptor signaling mechanisms associated with predicting psychedelic potential remain elusive. Using 5-HT 2A -selective β-arrestin-biased ligands, here the authors show that a threshold level of 5-HT 2A -Gq efficacy and not β-arrestin recruitment is associated with psychedelic potential.

Chromosomal instability (CIN) is a driver of cancer metastasis 1 – 4 , yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing—a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell–cell interactions from single-cell transcriptomic data—we show that CIN-induced chronic activation of the cGAS–STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation. Chromosomal instability in cancer is linked to endoplasmic reticulum stress signalling, immune suppression and metastasis, which is mediated by the cGAS–STING pathway, suppression of which can reduce metastasis.

Abstract Context Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are established therapeutics for type 2 diabetes and obesity. Among other mechanisms, they slow gastric emptying and motility of the small intestine. This helps to limit postprandial glycemic excursions and reduce chylomicron formation and triglyceride absorption. Conversely, motility effects may have detrimental consequences, eg, retained gastric contents at endoscopy or general anesthesia, potentially complicated by pulmonary aspiration or bowel obstruction. Data Acquisition We searched the PubMed database for studies involving GLP-1RA therapy and adverse gastrointestinal/biliary events. Data Synthesis Retained gastric contents at the time of upper gastrointestinal endoscopy are found more frequently with GLP-1 RAs but rarely are associated with pulmonary aspiration. Well-justified recommendations for the periprocedural management of GLP-1RAs (eg, whether to withhold these medications and for how long) are compromised by limited evidence. Important aspects to be considered are (1) their long half-lives, (2) the capacity of GLP-1 receptor agonism to slow gastric emptying even at physiological GLP-1 concentrations, (c) tachyphylaxis observed with prolonged treatment, and (d) the limited effect on gastric emptying in individuals with slow gastric emptying before initiating treatment. Little information is available on the influence of diabetes mellitus itself (ie, in the absence of GLP-1 RA treatment) on retained gastric contents and pulmonary aspiration. Conclusion Prolonged fasting periods regarding solid meal components, point-of-care ultrasound examination for retained gastric content, and the use of prokinetic medications like erythromycin may prove helpful and represent an important area needing further study to increase patient safety for those treated with GLP-1 RAs.

IntroductionVasospastic angina is characterised by sudden occlusive vasoconstriction of a segment of an epicardial coronary artery resulting in impaired myocardial blood flow causing ischaemia.Vascular smooth muscle cell hyperreactivity, endothelial dysfunction and oxidative stress are implicated in its pathogenesis.We present a case of a patient with vasospastic angina who developed a tachyphylaxis-mediated acute coronary syndrome following uptitration of oral nitrate therapy.Case presentationA 70 year old female with a long history of vasospastic angina was experiencing more frequent nocturnal anginal symptoms. Her symptoms were previously stable with diltiazem 60 mg twice daily and isosorbide mononitrate 40 mg once daily. She underwent coronary angiography with acetylcholine challenge at another centre, which demonstrated marked reduction in calibre of the epicardial coronary arteries consistent with vasospasm (figure 1). Subsequently her diltiazem was increased to 120 mg twice daily and isosorbide mononitrate dose was increased to 40 mg twice daily. She presented to our centre with severe nocturnal chest pain, which did not initially respond to sublingual GTN administration. Following multiple doses of sublingual GTN administration, the pain subsided. Clinical examination was unremarkable and ECG did not show any evidence of ischaemia. Her troponin-I was elevated at 14,000ng/l. 10-days prior to her presentation, she was issued an acute prescription of isosorbide nitrate 20 mg twice daily (evening dose taken before bedtime) by the GP.She underwent a cardiac MRI which confirmed a small transmural infarction in the mid anterolateral wall and a repeat coronary angiogram showed no evidence of obstructive disease or acute plaque rupture.The impression was of an acute coronary syndrome likely precipitated by a tachyphylaxis response to uptitration of nitrates. Her isosorbide mononitrate dose was halved to morning dose only and nicorandil was added. Since discharge, she remains symptom-free with no occurrence of angina.DiscussionThe aim of medical therapy in vasospastic angina is to augment myocardial blood flow through vasodilation. First line treatment with calcium channel antagonists and nitrates are effective in controlling symptoms; however nitrates must be used judiciously due to the phenomenon of drug tolerance which develops after chronic use. When this develops acutely in response to rapid uptitration, it is termed tachyphylaxis. Vascular remodelling and interruption of metabolic pathways constitute pharmacological and physiological drivers of this process.In our case, we believe that the myocardial injury sustained from the acute infarct was secondary to recent increase in long-acting nitrate doses. Introduction of a nitrate-free interval, typically 6–8 hours, provides a washout period that helps to alleviate the risk of nitrate-induced tachyphylaxis.ConclusionOral nitrate therapy is helpful in the management of vasospastic angina. However, rapid uptitration of dosage without a nitrate-free interval, can induce tachyphylaxis leading to worsening of symptoms, and potentially unstable arrhythmias and myocardial infarction. Early recognition of this phenomenon is key in managing such patients.Abstract 75 Figure 1Coronary angiogram demonstrating normal calibre of the left anterior descending artery at baseline (left) with subsequent reduction in vessel calibre secondary to epicardial spasm, after acetylcholine challenge (arrow, right)Conflict of InterestNone

Prokinetic agents amplify and coordinate the gastrointestinal muscular contractions to facilitate the transit of intra-luminal content. Following the institution of dietary recommendations, prokinetics are the first medications whose goal is to improve gastric emptying and relieve symptoms of gastroparesis. The recommended use of metoclopramide, the only currently approved medication for gastroparesis in the United States, is for a duration of less than 3 months, due to the risk of reversible or irreversible extrapyramidal tremors. Domperidone, a dopamine D2 receptor antagonist, is available for prescription through the FDA’s program for Expanded Access to Investigational Drugs. Macrolides are used off label and are associated with tachyphylaxis and variable duration of efficacy. Aprepitant relieves some symptoms of gastroparesis. There are newer agents in the pipeline targeting diverse gastric (fundic, antral and pyloric) motor functions, including novel serotonergic 5-HT 4 agonists, dopaminergic D 2/3 antagonists, neurokinin NK 1 antagonists, and ghrelin agonist. Novel targets with potential to improve gastric motor functions include the pylorus, macrophage/inflammatory function, oxidative stress, and neurogenesis. In the current review, we discuss the use of pharmacological approaches with potential to enhance motor functions in the management of gastroparesis.

G protein–coupled receptors display multifunctional signaling, offering the potential for agonist structures to promote conformational selectivity for biased outputs. For β₂-adrenergic receptors (β₂AR), unbiased agonists stabilize conformation(s) that evoke coupling to Gαs (cyclic adenosine monophosphate [cAMP] production/human airway smooth muscle [HASM] cell relaxation) and β-arrestin engagement, the latter acting to quench Gαs signaling, contributing to receptor desensitization/tachyphylaxis. We screened a 40-million-compound scaffold ranking library, revealing unanticipated agonists with dihydroimidazolyl-butylcyclic urea scaffolds. The S-stereoisomer of compound C1 shows no detectable β-arrestin engagement/signaling by four methods. However, C1-S retained Gαs signaling—a divergence of the outputs favorable for treating asthma. Functional studies with two models confirmed the biasing: β₂AR-mediated cAMP signaling underwent desensitization to the unbiased agonist albuterol but not to C1-S, and desensitization of HASM cell relaxation was observed with albuterol but not with C1-S. These HASM results indicate biologically pertinent biasing of C1-S, in the context of the relevant physiologic response, in the human cell type of interest. Thus, C1-S was apparently strongly biased away from β-arrestin, in contrast to albuterol and C5-S. C1-S structural modeling and simulations revealed binding differences compared with unbiased epinephrine at transmembrane (TM) segments 3,5,6,7 and ECL2. C1-S (R2 = cyclohexane) was repositioned in the pocket such that it lost a TM6 interaction and gained a TM7 interaction compared with the analogous unbiased C5-S (R2 = benzene group), which appears to contribute to C1-S biasing away from β-arrestin. Thus, an agnostic large chemical-space library identified agonists with receptor interactions that resulted in relevant signal splitting of β₂AR actions favorable for treating obstructive lung disease.

Background11β-hydroxysteroid dehydrogenase type 1 (HSD-1), an intracellular enzyme that converts glucocorticoids (GC) from inactive (e.g., prednisone, cortisone) to active (e.g., prednisolone, cortisol) form is a main source of intracellular GC that can bind to intracellular GC, mineralocorticoid, and non-genomic receptors. Prior clinical and non-clinical results support the hypothesis that HSD-1 inhibitors have potential to mitigate GC toxicity without eliminating GC efficacy. Results from tissue-specific HSD-1 knockout mouse studies indicate that adipose is a key target tissue for GC cardiometabolic toxicity prevention or reversal. However, several HSD-1 inhibitors have shown tachyphylaxis on adipose inhibition in human within 14 days of dosing.ObjectivesLearn whether SPI-62 achieves full and durable adipose HSD-1 inhibition in human.MethodsParticipants with type 2 diabetes and BMI 30-45 kg/m2 received SPI-62 daily for up to 14 days in an open label Phase 1 clinical trial. Microdialysis catheters (Type 63, µ dialysis, Stockholm Sweden) inserted in subcutaneous abdominal adipose were infused continuously with [2,2,4,6,6,9,12,12-2H8]cortisone (D8E) 1 µg/mL at 1 µL/min. Following selected SPI-62 doses, dialysate samples were collected at 0-2, 2-4, 4-6, 6-8, 8-10, 20-22, and 22-24 hours. D8E and [2,2,4,6,6,9,12,12-2H8]cortisol (D8F) concentrations in dialysate were measured using a validated LC-MS/MS assay. D8E results below the limit of quantitation (LOQ = 0.100 ng/mL) were imputed as the LOQ. The molar ratio D8F/D8E was used as a biomarker of adipose HSD-1 activity.ResultsData from the 2 participants who received SPI-62 6 mg QD for 14 days, and from whom data were collected on Days 1, 2, and 14, are presented. D8F/D8E declined from baseline 90.8% and 93.5% during Day 1. D8F/D8E was on average decreased from baseline 94.2% and 95.6% during Day 2, and 92.0% and 93.9% during Day 14.Figure 1.ConclusionHuman adipose HSD-1 activity and inhibition can be quantitated via D8E infusion of subcutaneous tissue via measurement of the molar ratio of the corresponding HSD-1 product D8F/D8E in dialysate. SPI-62 does not show tachyphylaxis on adipose HSD-1 inhibition within 14 days. A combination product of prednisolone with the HSD-1 inhibitor SPI-62 is now in a Phase 2 clinical trial as a steroid symptom sparing agent, initially for patients with polymyalgia rheumatica. The selected regimen for that trial, SPI-62 6 mg QD, is appropriate to assess clinical effects that might be associated with adipose HSD-1 inhibition. Data from all 12 participants will be used to model dose-exposure-response relationships to refine dose selection for future clinical trials.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsDavid Katz Shareholder of: Sparrow Pharmaceuticals, Employee of: Sparrow Pharmaceuticals, Guohua An Consultant of: Sparrow Pharmaceuticals, Caleb Schmicker: None declared, Brian Engel: None declared, Tobias Magers: None declared, Rita Basu Consultant of: Sparrow Pharmaceuticals, Julio Gutierrez: None declared.

Glucagon-like peptide (GLP)-1 lowers postprandial glycemia primarily through inhibition of gastric emptying. We addressed whether the GLP-1-induced deceleration of gastric emptying is subject to rapid tachyphylaxis and if so, how this would alter postprandial glucose control. Nine healthy volunteers (25 ± 4 years old, BMI: 24.6 ± 4.7 kg/m(2)) were examined with intravenous infusion of GLP-1 (0.8 pmol · kg(-1) · min(-1)) or placebo over 8.5 h. Two liquid mixed meals were administered at a 4-h interval. Gastric emptying was determined, and blood samples were drawn frequently. GLP-1 decelerated gastric emptying significantly more after the first meal compared with the second meal (P = 0.01). This was associated with reductions in pancreatic polypeptide levels (marker of vagal activation) after the first but not the second meal (P < 0.05). With GLP-1, glucose concentrations declined after the first meal but increased after the second meal (P < 0.05). The GLP-1-induced reductions in postprandial insulin and C-peptide levels were stronger during the first meal course (P < 0.05). Likewise, glucagon levels were lowered by GLP-1 after the first meal but increased after the second test meal (P < 0.05). The GLP-1-induced delay in gastric emptying is subject to rapid tachyphylaxis at the level of vagal nervous activation. As a consequence, postprandial glucose control by GLP-1 is attenuated after its chronic administration.

PurposeTreatment of choroidal neovascularization due to age-related macular degeneration is a challenging topic since an increasing number of patients show reduced morphological response to conventional treatment with intravitreal injections. The present study tested the hypothesis that the newly introduced anti-VEGF antibody brolucizumab does not only show promising results in pre-treated patients but is also a viable option in cases of tachyphylaxis to aflibercept or bevacizumab.MethodsThirty-six eyes of 34 patients with a history of at least 10 anti-VEGF injections as well as persistent retinal fluid following the past 5 monthly injections with aflibercept and bevacizumab prior to first treatment with brolucizumab were included in the study. Morphological and functional treatment response was compared before and after switching to brolucizumab.ResultsMean best-corrected visual acuity did not significantly change after treatment with brolucizumab. In contrast, central retinal thickness significantly decreased 4 weeks after treatment with brolucizumab from 340.36 to 282.22 µm (p < 0.001) as well as pigment epithelial detachment from 346.73 to 280.47 µm (p < 0.001). In 24 eyes (66.67%), complete resolution of intra-and subretinal fluid was observed after a single dose of brolucizumab. No serious adverse events, such as intraocular inflammation and retinal vasculitis, were reported after a single injection of brolucizumab.ConclusionBrolucizumab is not only effective in treatment-naïve patients as shown in the pivotal HAWK and Harrier trials, but also in pre-treated patients as seen in the present study. Our data also suggest that brolucizumab is potent in patients with signs of tachyphylaxis to other anti-VEGF agents and thus a viable treatment option.

The transient receptor potential vanilloid-1 (TRPV1) ion channel is essential for sensation of thermal and chemical pain. TRPV1 activation is accompanied by Ca2+-dependent desensitization; acute desensitization reflects rapid reduction in channel activity during stimulation, whereas tachyphylaxis denotes the diminution in TRPV1 responses to repetitive stimulation. Acute desensitization has been attributed to conformational changes of the TRPV1 channel; however, the mechanisms underlying the establishment of tachyphylaxis remain to be defined. Here, we report that the degree of whole-cell TRPV1 tachyphylaxis is regulated by the strength of inducing stimulation. Using light-sheet microscopy and pH-sensitive sensor pHluorin to follow TRPV1 endocytosis and exocytosis trafficking, we provide real-time information that tachyphylaxis of different degrees concurs with TRPV1 recycling to the plasma membrane in a proportional manner. This process controls TRPV1 surface expression level thereby the whole-cell nociceptive response. We further show that activity-gated TRPV1 trafficking associates with intracellular Ca2+ signals of distinct kinetics, and recruits recycling routes mediated by synaptotagmin 1 and 7, respectively. These results suggest that activity-dependent TRPV1 recycling contributes to the establishment of tachyphylaxis.