British Journal of Pharmacology最新文献

{"title":"Opportunities of patient-derived organoids in drug development.","authors":"Antonia Büning, Elena Reckzeh","doi":"10.1111/bph.70010","DOIUrl":"https://doi.org/10.1111/bph.70010","url":null,"abstract":"<p><p>Various model systems are utilised during drug development starting from basic research, moving to preclinical research and development for clinical applications in order to identify new drugs to improve human health. However, there are characteristics of humans that are not captured by established models. Such models include homogeneous two-dimensional (2D) cell lines, which lack cellular heterogeneity and physiological relevance, and species differences of animal models. Organoids can mitigate these differences by providing more physiologically relevant three-dimensional (3D) cell models that resemble the molecular state in healthy and pathological tissue. This review presents exemplary approaches using patient-derived organoids (PDOs) that have been developed and the new opportunities that are evolving in drug development with a focus on patient adult stem cell (ASC)-derived organoids. These demonstrate the potential of PDOs used alongside established cell and animal models to improve drug development from basic research to clinical applications such as personalised medicine.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blockade of P2X7 receptors preserves blood retinal barrier integrity by modulating the plasmalemma vesicle-associated protein: Implications for diabetic retinopathy.","authors":"Chiara Bianca Maria Platania, Francesca Lazzara, Kenneth Mitton, Naomi Haque, Wendelin Dailey, Federica Conti, Erika Giuffrida, Filippo Drago, Anca Hermenean, Cornel Balta, Hildegard Herman, Alina Ciceu, Maria Consiglia Trotta, Michele D'Amico, Giuseppe Nicosia, Settimio Rossi, Claudio Bucolo","doi":"10.1111/bph.70007","DOIUrl":"https://doi.org/10.1111/bph.70007","url":null,"abstract":"<p><strong>Background and purpose: </strong>Plasmalemma vesicle-associated protein (PLVAP) regulates transcytosis in vascular endothelial cells. PLVAP expression is increased in pathological conditions, such as diabetic retinopathy. P2X7 receptor antagonists have been shown to preserve blood-retinal barrier (BRB) integrity. Here, we have tested the hypothesis that PLVAP expression is tightly linked to P2X7 receptor activity, leading to breakdown of the BRB in an in vitro model of diabetic retinopathy.</p><p><strong>Experimental approach: </strong>We integrated network approaches with an in vitro model of diabetic retinopathy using primary human retinal microvascular endothelial cells (HRMECs). Cells were treated with a P2X7 receptor antagonist, JNJ47965567, and expression of several genes predicted to belong to the P2X7 receptor signalling network were assessed. Levels and localisation of PLVAP, VE-cadherin and zonula occludens-1 (ZO-1) in HRMECs were evaluated. In vivo, the effects of JNJ47965567 on PLVAP expression in the retinas of diabetic mice were assessed.</p><p><strong>Key results: </strong>High levels of glucose increased PLVAP expression in HRMECs, which was blocked by JNJ47965567. Furthermore, JNJ47965567 preserved VE-cadherin and ZO-1. In the choroidal vasculature of diabetic mice, PLVAP immunostaining was increased, compared to levels in non-diabetic mice. This increase was significantly attenuated by treatment with JNJ47965567 CONCLUSIONS AND IMPLICATIONS: This study showed that P2X7 receptor signalling is an important component of a complex gene regulatory network, including PLVAP, mediating the pathophysiology of diabetic retinopathy. The P2X7 receptor antagonist JNJ47965567 showed a good pharmacodynamic profile, suggesting that this approach could be of value in the treatment of diabetic retinopathy.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered pulmonary artery tissues for measuring contractility, drug testing and disease modelling.","authors":"Adam L Fellows, Kate Quigley, Venus Leung, Alexander J Ainscough, Martin R Wilkins, Harry Barnett, David Miller, Manuel Mayr, Beata Wojciak-Stothard","doi":"10.1111/bph.17462","DOIUrl":"https://doi.org/10.1111/bph.17462","url":null,"abstract":"<p><strong>Background and purpose: </strong>Vasoreactivity of pulmonary arteries regulates blood flow through the lungs. Excessive constriction of these vessels contributes to pulmonary arterial hypertension (PAH), a progressive and incurable condition, resulting in right heart failure. The search for new and improved drug treatments is hampered by laboratory models that do not reproduce the vasoactive behaviour of healthy and diseased human arteries.</p><p><strong>Experimental approach: </strong>We have developed an innovative technique for producing miniature, three-dimensional arterial structures that allow proxy evaluation of human pulmonary artery contractility. These \"engineered pulmonary artery tissues\" or \"EPATs\" are fabricated by suspending human pulmonary artery vascular smooth muscle cells (VSMCs) in fibrin hydrogels between pairs of silicone posts, located on custom-made racks, in 24-well culture plates.</p><p><strong>Key results: </strong>EPATs exhibit rapid, robust and reproducible contraction responses to vasoconstrictors (KCl, ET-1, U46619) as well as relaxation responses to clinically approved PAH vasodilatory drugs that target several signalling pathways, such as bosentan, epoprostenol, selexipag and imatinib. EPATs composed of pulmonary artery VSMCs from PAH patients exhibit enhanced contraction to vasoconstrictors and relaxation in response to vasodilators. We also demonstrate the incorporation of endothelial cells into EPATs for the measurement of endothelium-dependent dilatory responses.</p><p><strong>Conclusion and implications: </strong>We demonstrate the capacity and suitability of EPATs for studying the contractile behaviour of human arterial cells and preclinical drug testing. This novel biomimetic platform has the potential to dramatically improve our understanding and treatment of cardiovascular disease.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel drugs approved by the EMA, the FDA and the MHRA in 2024: A year in review.","authors":"Stavros Topouzis, Andreas Papapetropoulos, Steve P H Alexander, Miriam Cortese-Krott, Dave A Kendall, Kirill Martemyanov, Claudio Mauro, Nithyanandan Nagercoil, Reynold A Panettieri, Hemal H Patel, Rainer Schulz, Barbara Stefanska, Gary J Stephens, Mauro M Teixeira, Nathalie Vergnolle, Xin Wang, Péter Ferdinandy","doi":"10.1111/bph.17458","DOIUrl":"https://doi.org/10.1111/bph.17458","url":null,"abstract":"<p><p>In the past year, the European Medicines Agency (EMA), the Food and Drug Administration (FDA) and the Medicines and Healthcare Products Regulatory Agency (MHRA) authorised 53 novel drugs. While the 2024 harvest is not as rich as in 2023, when 70 new chemical entities were approved, the number of 'orphan' drug authorisations in 2024 (21) is similar to that of 2023 (24), illustrating the dynamic development of therapeutics in areas of unmet need. The 2024 approvals of novel protein therapeutics (15) and advanced therapy medicinal products (ATMPs, 6) indicate a sustained trend also noticeable in the 2023 new drugs reviewed in this journal last year (16 and 11, respectively). Clearly, the most striking characteristic of the 2024 drug yield is the creative pharmacological design, which allows these medicines to employ a novel approach to target a disease. Some notable examples are the first drug successfully using a 'dock-and-block' mechanism of inhibition (zenocutuzumab), the first approved drug for schizophrenia designed as an agonist of M₁/M₄ muscarinic receptors (xanomeline), the first biparatopic antibody (zanidatamab), binding two distinct epitopes of the same molecule, the first haemophilia therapy that instead of relying on external supplementation of clotting factors, restores Factor Xa activity by inhibiting TFPI (marstacimab), or the first ever authorised direct telomerase inhibitor (imetelstat) that reprogrammes the oncogenic drive of tumour cells. In addition, an impressive percentage of novel drugs were first in class (28 out of 53 or 53% of the total) and a substantial number can be considered disease agnostic, indicating the possibility of future approved extensions of their use for additional indications. The 2024 harvest demonstrates the therapeutic potential of innovative pharmacological design, which allows the effective targeting of intractable disorders and addresses crucial, unmet therapeutic needs.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM2 activation reduces white matter injury via PI3K/Akt/GSK-3β signalling after intracerebral haemorrhage.","authors":"Yuan Zhang, You Shi, Lin Wang, Zhao Li, Yingwen Wang, Jin Yan, Xiaochuan Sun, Qing Luo, Lin Li","doi":"10.1111/bph.17475","DOIUrl":"https://doi.org/10.1111/bph.17475","url":null,"abstract":"<p><strong>Background: </strong>White matter injury (WMI) considerably exacerbates the prognosis following intracerebral haemorrhage (ICH). While the triggering receptor on myeloid cells 2 (TREM2) is recognized for its neuroprotective roles in a range of neurological disorders through the modulation of neuroinflammation, phagocytosis, promoting cell survival, its specific function in WMI after ICH has yet to be fully elucidated.</p><p><strong>Methods: </strong>This study involved inducing ICH in mice through autologous blood injection. Neurological functions were tested via behavioural assessments and electrophysiological recordings. WMI was examined using immunofluorescence, Luxol fast blue staining, MRI and transmission electron microscopy. Microglia were isolated and analysed using real-time polymerase chain reaction (PCR). Microglia depletion was achieved with PLX3397, primary cultures of microglia and oligodendrocytes were investigated.</p><p><strong>Results: </strong>The activation of TREM2 resulted in improved neurological outcomes after ICH, correlated with reduced WMI, demonstrated by decreased white matter loss in the corpus striatum, reduced damage to the nodes of Ranvier, and better preservation of myelin and white matter tract integrity. These neuroprotective effects were attributed to changes in microglial states mediated via the PI3K/Akt/GSK-3β signalling pathway. However, the neuroprotective advantages conferred by TREM2 activation were negated in TREM2 KO mice, either through microglia depletion or inhibition of PI3K.</p><p><strong>Conclusions: </strong>This research is the first to illustrate that TREM2 activation mitigates WMI following ICH through a microglia-dependent mechanism involving the PI3K/Akt/GSK-3β pathway. TREM2 represents a potential therapeutic target for ICH.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imatinib aggravates pressure-overload-induced right ventricle failure via JNK/Runx2 pathway.","authors":"Xiaohui Zeng, Zhuoji Ma, Shanshan Wen, Liang Zhou, Wanxian Hong, Zhixiong Wu, Chunxian Cen, Qianwen Bai, Shangwei Ding, Xin Chen, Jian Wang, Lingdan Chen, Wenju Lu, Tao Wang","doi":"10.1111/bph.70006","DOIUrl":"https://doi.org/10.1111/bph.70006","url":null,"abstract":"<p><strong>Background and purpose: </strong>Right ventricular (RV) function is the key prognostic determinant of pulmonary hypertension (PH). In PH patients, imatinib treatment decreases pulmonary vascular resistance and improves exercise capacity, but does not change mortality or duration to clinical worsening. Imatinib has been reported to be cardiotoxic in the left heart. We hypothesise that imatinib damages the pressure overloaded RV via its direct effects within the heart, which may counteract its therapeutic effects in haemodynamic improvement of PH.</p><p><strong>Experimental approach: </strong>A pulmonary arterial banding (PAB) rat model with fixed pulmonary artery narrowing was performed to avoid changes in RV afterload.</p><p><strong>Key results: </strong>In PAB rats, imatinib treatment decreased the survival rate and exacerbated RV dysfunction, myocardial hypertrophy, apoptosis and fibrosis. In vitro, imatinib increased cardiomyocyte hypertrophy and did not change cardiac fibroblasts activation; however, imatinib-treated conditioned medium from cardiomyocytes promoted fibroblast activation. Mechanistically, imatinib increased the phosphorylation of c-jun N-terminal kinase (JNK) and the expression of RUNX family transcription factor 2 (Runx2), and subsequently promoted the transcription of thrombospondin 4 (THBS4) and connective tissue growth factor (CTGF) in RV cardiomyocytes. Finally, SP600125, a JNK inhibitor, significantly alleviated imatinib-induced RV failure in PAB rats and enhanced the effects of imatinib on RV function improvement in SU5416 + hypoxia-induced PH rats without affecting pulmonary artery narrowing.</p><p><strong>Conclusion and implications: </strong>We demonstrate for the first time that imatinib aggravates RV failure under pressure overload through JNK/Runx2 pathway, and JNK inhibition improves the therapeutic effects of imatinib on RV function in PH.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions between ADGRF1 (GPR110) and extracellular matrix proteins govern its effects on tumorigenesis in HER2-positive breast cancer.","authors":"Noor Mazin Abdulkareem, Raksha Bhat, Micah Castillo, Sung Yun Jung, Suhas Vasaikar, Sarmistha Nanda, Alexis Ruiz, Martin Shea, Wangjia Cao, Jamunarani Veeraraghavan, Hee-Yong Kim, Tasneem Bawa-Khalfe, Tahir Hussain, Xinli Liu, Preethi Gunaratne, Rachel Schiff, Meghana V Trivedi","doi":"10.1111/bph.17463","DOIUrl":"https://doi.org/10.1111/bph.17463","url":null,"abstract":"<p><strong>Background and purpose: </strong>We and others have previously shown that ADGRF1, an adhesion G protein-coupled receptor, is overexpressed and associated with poor survival in many cancers, including human epidermal growth factor receptor-2 (HER2) breast cancer (BC). Also, we have reported the tumour-promoting function of ADGRF1 using preclinical models of HER2+ BC. In this study, we investigated the effect of ADGRF1 overexpression in an orthotopic in vivo model as well as downstream signalling of ADGRF1 in HER2+ BC.</p><p><strong>Experimental approach: </strong>We utilized a doxycycline (Dox)-induced ADGRF1 overexpression system in HER2+ BC cell lines and performed various in vitro and in vivo studies. Following ADGRF1 overexpression in the presence/absence of Matrigel, laminin-111 or collagen-IV, we performed the mammosphere assay to assess the tumorigenicity of breast epithelial cells, as well as cAMP/IP1 assays and RNA-sequencing, to understand the receptor function and pharmacology. We conducted cross-linking-aided immunoprecipitation and mass spectrometry to confirm the physical interaction between ADGRF1 and the extracellular matrix proteins present in Matrigel.</p><p><strong>Key results: </strong>We found that ADGRF1 switched from a tumour-promoting to tumour-suppressive function upon interaction with laminin-111. Interaction of ADGRF1 with laminin-111 resulted in inhibition of Gαs coupling and STAT3 phosphorylation, induction of senescence, increase in HER2 expression, and improvement of sensitivity to anti-HER2 drugs in HER2+ BC.</p><p><strong>Conclusions: </strong>ADGRF1 switches from a tumour-promoting to tumour-suppressive function upon interaction with laminin-111, leading to improvements in sensitivity to anti-HER2 drugs. Leveraging ADGRF1 interactions with laminin-111 may allow the design of novel therapies against ADGRF1 in HER2+ BC.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in the vasoactive effect of transient receptor potential channels: TRPM3 as a new therapeutic target for (neuro)vascular disorders.","authors":"Eduardo Rivera-Mancilla, Usha M Musterd-Bhaggoe, Dennis Schutter, Antoon van den Bogaerdt, Arnaud J P E Vincent, Carlos M Villalón, Alexander H J Danser, Antoinette MaassenVanDenBrink","doi":"10.1111/bph.17472","DOIUrl":"https://doi.org/10.1111/bph.17472","url":null,"abstract":"<p><strong>Background and purpose: </strong>Sex-dependent vascular effects of transient receptor potential (TRP) channels and sex dimorphism in migraine are not yet fully characterized. We investigated the differential vasoactive effects of TRP ankyrin 1 (TRPA1), TRP melastatin 3 (TRPM3) and TRP vanilloid 1 (TRPV1) channels, their pharmacological mechanism(s), and localization and expression in human isolated blood vessels.</p><p><strong>Experimental approach: </strong>Agonist responses to cinnamaldehyde (TRPA1), pregnenolone sulfate (PregS, TRPM3) or capsaicin (TRPV1) were analysed using wire myography in segments of human coronary (HCAs) and middle meningeal (HMMAs) arteries from men and women. The mechanisms involved in these responses were investigated using the antagonists/blockers/inhibitors: HC-030031 (TRPA1), isosakuranetin (TRPM3), capsazepine (TRPV1), olcegepant (calcitonin gene-related peptide [CGRP] receptor), L-NAME (nitric oxide synthase [NOS]), indomethacin (cyclooxygenase [COX]), TRAM-34 + apamin (K⁺ channels) or MK-801 (N-methyl-d-aspartate [NMDA] receptor). Fluorescence microscopy, quantitative polymerase chain reaction (qPCR), and western blotting were performed to investigate their location and expression, respectively.</p><p><strong>Key results: </strong>In HCAs and HMMAs, (i) capsaicin-induced relaxation remained unchanged after the above-mentioned antagonists/blockers/inhibitors and (ii) cinnamaldehyde-induced relaxation was blocked by olcegepant. PregS-induced maximal relaxation was significantly enhanced in isolated arteries from females compared with males and was inhibited after isosakuranetin, MK-801 or L-NAME. TRPM3 mRNA and protein expression, along with NMDA protein levels, were higher in arteries from females than males.</p><p><strong>Conclusion and implications: </strong>Modulation of vascular tone in HCAs and HMMAs by activation of TRPM3 is sex-dependent, likely involving NMDA receptors. This represents a new therapeutic direction, targeting sex dimorphism in migraine and its related cardiovascular events.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral hyoscine butylbromide exerts spasmolytic effects in both gastrointestinal and urogenital tissues in rats.","authors":"Sara Traserra, Terence Appelqvist, Robert Lange, Maura Corsetti, Marcel Jimenez","doi":"10.1111/bph.17474","DOIUrl":"https://doi.org/10.1111/bph.17474","url":null,"abstract":"<p><strong>Background and purpose: </strong>Hyoscine butylbromide (HBB) has a low oral (PO) bioavailability. Further, limited data on its activity on non-gastrointestinal (GI) smooth muscle spasms after oral dosing are available, causing its effects beyond the GI tract to be questioned. This pharmacokinetic/pharmacodynamic (PK/PD) study, conducted using female rats, aimed to cover this gap.</p><p><strong>Experimental approach: </strong>PK study: HBB and atropine (as a comparator agent) were administered PO and IV to rats, and concentrations in plasma and tissues (colon, uterus and urinary bladder; CUB) were measured. PD study 1: concentration-response curves of HBB and atropine (10^-9-10^-4 M) were obtained for carbachol-induced (10^-5 M) pre-contracted tissues; PD study 2: CUB were pre-incubated with HBB and atropine at maximum concentrations (C_max) from PK studies and carbachol concentration-response curves (10^-9-10^-4 M) were obtained; PD study 3: HBB and atropine were administered PO and IV to rats as for PK study, CUB tissues were collected at 0.5 h (IV) and 4 h (PO), and carbachol concentration-response curves (10^-9-10^-4 M) obtained.</p><p><strong>Key results: </strong>PO HBB showed higher C_max in CUB tissues than in plasma. HBB and atropine reduced, concentration-dependently, carbachol-induced contractions in CUB tissues. PO HBB showed highest spasmolytic activity in colon (40%), followed by uterus (30%) and urinary bladder (10%).</p><p><strong>Conclusion and implications: </strong>This is the first comparison of PO and IV HBB and atropine in GI and non-GI tissues. Despite low bioavailability, PO HBB accumulated and exerted spasmolytic effects in tissues beyond the GI tract.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How 'miracle' weight-loss semaglutide promises to change medicine but can we afford the expense?","authors":"Ralf Weiskirchen, Amedeo Lonardo","doi":"10.1111/bph.70003","DOIUrl":"https://doi.org/10.1111/bph.70003","url":null,"abstract":"<p><p>Obesity is a complex and growing global concern, affecting one in eight individuals and compromising health, quality of life and life expectancy. It carries significant metabolic, cardiovascular, oncological, hepatorenal, skeletal and psychiatric risks, imposing substantial costs on health-care systems. Traditional treatments have often been ineffective or have led to relapse after lifestyle changes. Whereas bariatric surgery is effective, it also involves risks such as mortality and hospitalisation. Semaglutide, licensed in 2018, is a synthetic analogue of glucagon-like peptide 1 which regulates glucose metabolism and gastrointestinal (GI) motility. Studies show that semaglutide, administered either weekly and subcutaneously, or daily orally, induces an average weight loss of -11.62 kg compared to placebo and reduces waist circumference by up to -9.4 cm. It also improves blood pressure, fasting glucose levels, C-reactive protein levels and lipid profiles. The most common adverse events are mild-to-moderate GI complaints occurring more frequently with daily administration than weekly doses; hypoglycaemia is more common without lifestyle intervention. Weight regain often follows semaglutide withdrawal. Furthermore, semaglutide offers cardiovascular benefits for patients with established atherosclerotic cardiovascular disease (CVD), lowers the risk of kidney outcomes and cardiovascular-related death, resolves nonalcoholic steatohepatitis in many cases, and positively impacts mental health and quality of life. In conclusion, semaglutide therapy could significantly benefit many adults regarding CVD and mortality if made widely accessible. Ethical and financial considerations must be addressed for personalised obesity treatment approaches.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}