Pharmacological Reports最新文献

{"title":"Targeting glucocorticoid receptor signaling pathway for treatment of stress-related brain disorders.","authors":"Tansu Göver, Michal Slezak","doi":"10.1007/s43440-024-00654-w","DOIUrl":"10.1007/s43440-024-00654-w","url":null,"abstract":"<p><p>The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in governing stress-related disorders such as major depressive disorder (MDD), anxiety, and post-traumatic stress disorder. Chronic stress or early life trauma, known risk factors of disease, alter HPA axis activity and pattern of glucocorticoid (GC) secretion. These changes have consequences for physiological processes controlled by glucocorticoid receptor (GR) signaling, such as immune response and metabolism. In the brain, the aberrant GR signaling translates to altered behavior, making the GR pathway a viable target for therapies of stress-related disorders. One of the crucial elements of the pathway is FKBP5, a regulator of GR sensitivity and feedback control within the HPA axis, in which genetic variants were shown to moderate the risk of developing psychiatric conditions. The difficulty in targeting the GR-FKBP5 pathway stems from tailoring the intervention to specific brain regions and cell types, in the context of personalized genetic variations in GR and GR-associated genes, like FKBP5. The development of selective inhibitors, antagonists, and approaches based on targeted protein degradation offer insights into mechanistic aspects of disease and pave the way for improved therapy. These strategies can be employed either independently or in conjunction with conventional medications. Concomitant advancements in personalized drug screening (e.g. in vitro models exploiting induced pluripotent stem cells, iPSCs) bring the potential for optimization of therapy aiming to rescue central deficits originating from the HPA imbalance. In this mini-review, we discuss potential therapeutic strategies targeting GR signaling in stress-related disorders, with a focus on personalized approaches and advancements in drug development.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1333-1345"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions between metabotropic glutamate and CB1 receptors: implications for mood, cognition, and synaptic signaling based on data from mGluR and CB1R-targeting drugs.","authors":"Katarzyna Stachowicz","doi":"10.1007/s43440-024-00612-6","DOIUrl":"10.1007/s43440-024-00612-6","url":null,"abstract":"<p><p>Metabotropic glutamate receptors (mGluRs) are part of the G protein-coupled receptors (GPCRs) family. They are coupled to G_αq (group I) or G_i/o (groups II and III) proteins, which result in the generation of diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP₃) or the inhibition of adenylyl cyclase, respectively. mGluRs have been implicated in anxiety, depression, learning, and synaptic plasticity. Similarly, CB1 cannabinoid receptors (CB1Rs), also GPCRs, play roles in cognitive function and mood regulation through G_αi/o-mediated inhibition of adenylyl cyclase. Both mGluRs and CB1Rs exhibit surface labeling and undergo endocytosis. Given the similar cellular distribution and mechanisms of action, this review complies with fundamental data on the potential interactions and mutual regulation of mGluRs and CB1Rs in the context of depression, anxiety, and cognition, providing pioneering insights into their interplay.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1286-1296"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141470113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fiber photometry in neuroscience research: principles, applications, and future directions.","authors":"Michal Kielbinski, Joanna Bernacka","doi":"10.1007/s43440-024-00646-w","DOIUrl":"10.1007/s43440-024-00646-w","url":null,"abstract":"<p><p>In recent years, fluorescent sensors are enjoying a surge of popularity in the field of neuroscience. Through the development of novel genetically encoded sensors as well as improved methods of detection and analysis, fluorescent sensing has risen as a new major technique in neuroscience alongside molecular, electrophysiological, and imaging methods, opening up new avenues for research. Combined with multiphoton microscopy and fiber photometry, these sensors offer unique advantages in terms of cellular specificity, access to multiple targets - from calcium dynamics to neurotransmitter release to intracellular processes - as well as high capability for in vivo interrogation of neurobiological mechanisms underpinning behavior. Here, we provide a brief overview of the method, present examples of its integration with other tools in recent studies ranging from cellular to systems neuroscience, and discuss some of its principles and limitations, with the aim of introducing new potential users to this rapidly developing and potent technique.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1242-1255"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Practical application of melatonin for pancreas disorders: protective roles against inflammation, malignancy, and dysfunctions.","authors":"Mohammad Sheibani, Azam Hosseinzadeh, Iman Fatemi, Ali Jamshidi Naeini, Saeed Mehrzadi","doi":"10.1007/s43440-024-00683-5","DOIUrl":"https://doi.org/10.1007/s43440-024-00683-5","url":null,"abstract":"<p><p>Melatonin, a hormone primarily produced by the pineal gland, exhibits a range of physiological functions that extend beyond its well-known role in regulating circadian rhythms. This hormone influences energy metabolism, modulates insulin sensitivity, and plays a significant role in controlling sleep patterns and food intake. Notably, melatonin is also synthesized in various peripheral organs, including the gastrointestinal system and pancreas, suggesting its function as a local hormone. The presence of melatonin receptors in the pancreas underscores its relevance in pancreatic physiology. Pancreatic disorders, such as diabetes mellitus (DM), pancreatitis, and pancreatic cancer, often stem from inflammatory processes. The majority of these conditions are characterized by dysregulated immune responses and oxidative stress. Melatonin's anti-inflammatory properties are mediated through the inhibition of pro-inflammatory cytokines and the activation of antioxidant enzymes, which help to mitigate cellular damage. Furthermore, melatonin has demonstrated pro-apoptotic effects on cancer cells, promoting cell death in malignant tissues while preserving healthy cells. Thus, melatonin emerges as a multifaceted agent with significant therapeutic potential for pancreatic disorders. Its ability to reduce inflammation and oxidative stress positions it as a promising adjunct therapy for conditions such as diabetes mellitus, pancreatitis, and pancreatic cancer. By modulating immune responses and enhancing cellular resilience through antioxidant mechanisms, melatonin not only addresses the symptoms but also targets the underlying pathophysiological processes associated with these disorders. This review aims to categorize and summarize the impacts of melatonin on pancreatic functions and disorders, emphasizing its potential as a therapeutic agent for managing pancreatic dysfunctions. Future research should focus on elucidating the precise mechanisms by which melatonin exerts its protective effects on pancreatic tissues and exploring optimal dosing strategies for clinical applications. The integration of melatonin into treatment regimens may enhance existing therapies and offer new hope for individuals suffering from pancreatic dysfunctions.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antidepressant effects of selective adenosine receptor antagonists targeting the A1 and A2A receptors administered jointly with NMDA receptor ligands: behavioral, biochemical and molecular investigations in mice.","authors":"Aleksandra Szopa, Karolina Bogatko, Anna Serefko, Mariola Herbet, Marta Ostrowska-Leśko, Andrzej Wróbel, Maria Radziwoń-Zaleska, Jarosław Dudka, Piotr Wlaź, Ewa Poleszak","doi":"10.1007/s43440-024-00627-z","DOIUrl":"10.1007/s43440-024-00627-z","url":null,"abstract":"<p><strong>Background: </strong>The objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists.</p><p><strong>Methods: </strong>The forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1 mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5 mg/kg) in combination with L-701,324 (a potent NMDA receptor antagonist, 1 mg/kg), D-cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5 mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3 mg/kg) or MK-801 (a non-competitive NMDA receptor antagonist, 0.05 mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined.</p><p><strong>Results: </strong>The obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D-cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D-cycloserine-treated group. Adora1 expression increased with L-701,324, DPCPX + D-cycloserine, and DPCPX + CGP 37849, while D-cycloserine, CGP 37849, and MK-801 led to a decrease. Comt mRNA levels dropped with DPCPX + L-701,324, istradefylline + L-701,324/CGP 37849 but increased with D-cycloserine, MK-801, CGP 37849 and DPCPX + MK-801/ CGP 37849. Slc6a15 levels were reduced by D-cycloserine, DPCPX + L-701,324 but rose with DPCPX + CGP 37849/MK-801 and istradefylline + D-cycloserine/MK-801/CGP 37849.</p><p><strong>Conclusion: </strong>Our study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1012-1031"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review of serious adverse events linked with GLP-1 agonists in type 2 diabetes mellitus and obesity treatment.","authors":"Mansour Tobaiqy","doi":"10.1007/s43440-024-00629-x","DOIUrl":"10.1007/s43440-024-00629-x","url":null,"abstract":"<p><p>Glucagon-like peptide-1 (GLP-1) agonists play a crucial role in treating type 2 diabetes mellitus and obesity by providing glycemic control and aiding weight management. Despite their widespread use, concerns about serious adverse events have prompted extensive research. This review aims to describe the current understanding of serious adverse events associated with GLP-1 agonists. A comprehensive search of PubMed, Google Scholar and Embase databases was performed starting from 2010. Studies reporting evidence of an association between GLP-1 agonists and serious adverse events from 22 articles (5 case reports, 5 randomized controlled trials (RCTs), 9 real-world data cohort analyses, 2 meta-analyses and 1 systematic review and meta-analysis) were included and categorized by the type of adverse event. While some studies reported risks, including anaphylaxis, cardiovascular, gastrointestinal, psychiatric and thyroid-related events, others found no significant associations. The evidence remains mixed, necessitating further research to fully understand the safety profile of GLP-1 agonists and inform clinical practice.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"981-990"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fast-acting antidepressant-like effects of ketamine in aged male rats.","authors":"Elena Hernández-Hernández, Sandra Ledesma-Corvi, Jordi Jornet-Plaza, M Julia García-Fuster","doi":"10.1007/s43440-024-00636-y","DOIUrl":"10.1007/s43440-024-00636-y","url":null,"abstract":"<p><strong>Background: </strong>The aging process causes anatomical and physiological changes that predispose to the development of late-life depression while reduces the efficacy of classical antidepressants. Novel fast-acting antidepressants such as ketamine might be good candidates to be explored in the context of aging, especially given the lack of previous research on its efficacy for this age period. Thus, the aim of the present study was to characterize ketamine's effects in older rats.</p><p><strong>Methods: </strong>The fast-acting (30 min) and repeated (7 days) antidepressant-like effects of ketamine (5 mg/kg, ip) were evaluated in 14-month-old single-housed rats through the forced-swim and novelty-suppressed feeding tests. In parallel, the modulation of neurotrophic-related proteins (i.e., mBDNF, mTOR, GSK3) was assessed in brain regions affected by the aging process, prefrontal cortex and hippocampus, as well as possible changes in hippocampal cell proliferation.</p><p><strong>Results: </strong>Acute ketamine induced a fast-acting antidepressant-like response in male aged rats, as observed by a reduced immobility in the forced-swim test, in parallel with a region-specific increase in mBDNF protein content in prefrontal cortex. However, repeated ketamine failed to induce antidepressant-like efficacy, but decreased mBDNF protein content in prefrontal cortex. The rate of hippocampal cell proliferation and/or other markers evaluated was not modulated by either paradigm of ketamine.</p><p><strong>Conclusions: </strong>These results complement prior data supporting a fast-acting antidepressant-like effect of ketamine in rats, to further extend its efficacy to older ages. Future studies are needed to further clarify the lack of response after the repeated treatment as well as its potential adverse effects in aging.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"991-1000"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world experience with direct-acting antiviral therapy in HCV-infected patients with cirrhosis and esophageal varices.","authors":"Michał Brzdęk, Dorota Zarębska-Michaluk, Michał Kukla, Justyna Janocha-Litwin, Dorota Dybowska, Ewa Janczewska, Beata Lorenc, Hanna Berak, Włodzimierz Mazur, Magdalena Tudrujek-Zdunek, Jakub Klapaczyński, Anna Piekarska, Marek Sitko, Łukasz Laurans, Anna Parfieniuk-Kowerda, Robert Flisiak","doi":"10.1007/s43440-024-00639-9","DOIUrl":"10.1007/s43440-024-00639-9","url":null,"abstract":"<p><strong>Background: </strong>Hepatitis C virus (HCV) infection affects 50 million people worldwide with around 242,000 deaths annually, mainly due to complications such as cirrhosis and hepatocellular carcinoma (HCC). Portal hypertension (PH) caused by cirrhosis leads to severe consequences, including esophageal varices (EV). This study aimed to evaluate the effectiveness and safety of direct-acting antiviral (DAA) treatment in patients with and without EV.</p><p><strong>Methods: </strong>This retrospective analysis involved consecutive HCV-infected adults undergoing DAA therapy at 22 Polish hepatology centers from July 1, 2015, to December 31, 2022. Patients with cirrhosis were categorized based on the presence of EV diagnosed by gastroscopy. Treatment effectiveness was measured by sustained virologic response (SVR), with safety outcomes monitored for 12 weeks post-treatment.</p><p><strong>Results: </strong>A population of 3393 HCV-infected patients with cirrhosis was divided into groups with (A, n = 976) and without (B, n = 2417) EV. Group A showed a significantly higher prevalence of comorbidities and concomitant medications. Genotype (GT)1b infections predominated in both groups, and GT3 infections were more common in the EV group. Group A exhibited more severe liver disease, and higher rates of decompensation, HCC, and HBV co-infection. SVR was significantly higher in group B (91.5% vs. 96.3%, p < 0.0001). Male gender, GT3, EV presence, and Child-Pugh grade B were identified as independent negative SVR predictors. Group A had a worse safety profile, with notably higher adverse event incidence and mortality.</p><p><strong>Conclusions: </strong>DAA therapies are highly effective and well tolerated in patients with cirrhosis, but EV presence predicts poorer virologic responses.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1114-1129"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of 28 days treatment of baricitinib on mechanical allodynia, osteopenia, and loss of nerve fibers in an experimental model of type-1 diabetes mellitus.","authors":"Rosa I Acosta-González, Angélica Y Hernández-Jiménez, Laura Y Ramírez-Quintanilla, Héctor F Torres-Rodríguez, Virginia M Vargas Muñoz, Juan M Jiménez-Andrade","doi":"10.1007/s43440-024-00634-0","DOIUrl":"10.1007/s43440-024-00634-0","url":null,"abstract":"<p><strong>Background: </strong>Type-1 diabetes mellitus (T1DM) is associated with numerous health problems, including peripheral neuropathy, osteoporosis, and bone denervation, all of which diminish quality of life. However, there are relatively few therapies to treat these T1DM-related complications. Recent studies have shown that Janus kinase (JAK) inhibitors reverse aging- and rheumatoid arthritis-induced bone loss and reduce pain associated with peripheral nerve injuries, and rheumatoid arthritis. Thus, we assessed whether a JAK1/JAK2 inhibitor, baricitinib, ameliorates mechanical pain sensitivity (a measure of peripheral neuropathy), osteoporosis, and bone denervation in the femur of mice with T1DM.</p><p><strong>Methods: </strong>Female ICR mice (13 weeks old) received five daily administrations of streptozotocin (ip, 50 mg/kg) to induce T1DM. At thirty-one weeks of age, mice were treated with baricitinib (po; 40 mg/kg/bid; for 28 days) or vehicle. Mechanical sensitivity was evaluated at 30, 33, and 35 weeks of age on the plantar surface of the right hind paw. At the end of the treatment, mice were sacrificed, and lower extremities were harvested for microcomputed tomography and immunohistochemistry analyses.</p><p><strong>Results: </strong>Mice with T1DM exhibited greater blood glucose levels, hind paw mechanical hypersensitivity, trabecular bone loss, and decreased density of calcitonin gene-related peptide-positive and tyrosine hydroxylase-positive axons within the marrow of the femoral neck compared to control mice. Baricitinib treatment significantly reduced mechanical hypersensitivity and ameliorated sensory and sympathetic denervation at the femoral neck, but it did not reverse trabecular bone loss.</p><p><strong>Conclusions: </strong>Our findings suggest that baricitinib may represent a new therapeutic alternative to treat T1DM-induced peripheral neuropathy and bone denervation.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1079-1088"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142000526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determination of bisphosphonate properties in terms of bioavailability, bone affinity, and cytotoxicity.","authors":"Monika Zielińska, Amanda Pacholak, Natalia Burlaga, Ewa Chmielewska, Adam Voelkel, Ewa Kaczorek","doi":"10.1007/s43440-024-00624-2","DOIUrl":"10.1007/s43440-024-00624-2","url":null,"abstract":"<p><strong>Background: </strong>The study aimed to evaluate the therapeutic potential of fourteen newly synthesized bisphosphonates by assessing their bioavailability, bone affinity, and cytotoxicity. These bisphosphonates included a series of aminomethylenebisphosphonates and standard compounds such as risedronate and tiludronate.</p><p><strong>Methods: </strong>Drug permeability was determined using Parallel Artificial Membrane Permeability Assays (PAMPA), while bone affinity was assessed by sorption on hydroxyapatite. Bacterial cell response to the bisphosphonates was also examined using Lactobacillus paracasei cells as a model.</p><p><strong>Results: </strong>Several tested compounds, including BP3 to BP8 and BP11, which feature substituents in the pyridine ring such as methyl groups, iodine, bromine, chlorine, or hydroxyl groups, demonstrated potentially more beneficial therapeutic properties than commercially used bisphosphonates. These compounds showed stronger bone affinity and higher gastrointestinal absorption with comparable or lower cytotoxic effects. Specifically, BP11 exhibited the highest bone affinity, while BP8 and BP11 showed the greatest permeability.</p><p><strong>Conclusions: </strong>The findings suggest that BP3 BP8, and BP11 are promising candidates for further research. These results highlight the importance of comprehensively evaluating bisphosphonates' therapeutic properties to identify effective treatments for osteoporosis and other bone diseases.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1160-1173"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11387443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141617020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}