Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Reverse translational approach to clarify the strong potency of enavogliflozin, a novel sodium-glucose cotransporter 2 inhibitor.","authors":"Sun-Hwa Park, Hye-Young Ji, Ji-Soo Choi, Kyung Seok Oh, Jihoon Lee, Minyeong Pang, Im-Sook Song, Joon Seok Park","doi":"10.1016/j.jpet.2025.103650","DOIUrl":"10.1016/j.jpet.2025.103650","url":null,"abstract":"<p><p>Enavogliflozin is a novel sodium-glucose cotransporter (SGLT2) inhibitor approved by the Korea Ministry of Food and Drug Safety for the treatment of type 2 diabetes. Clinical trials have demonstrated that enavogliflozin provides superior blood glucose-lowering effects and urinary glucose excretion (UGE) at a low dose of 0.3 mg compared with 10 mg of dapagliflozin. This study aimed to elucidate the structural characteristics of enavogliflozin and its major metabolites, M1 and M2, using a reverse translational approach and to investigate the mechanisms underlying its potent efficacy at approximately 30-fold lower doses than other SGLT2 inhibitors using an in vitro SGLT2 inhibition system. Molecular docking simulations revealed distinct binding modes for enavogliflozin and its metabolites relative to dapagliflozin and empagliflozin. The rigid conformation of enavogliflozin, conferred by its dihydrobenzofuran moiety, enforces hydrophobic and π-π stacking interactions, enhancing binding affinity, ligand-protein stability, and SGLT2 inhibition, suggesting a slower dissociation rate. Additionally, M1 and M2 exhibited inhibitory effects with SGLT1/2 dual inhibition and SGLT2 inhibition, respectively, indicating that both are pharmacologically active metabolites. Consequently, M1 and M2 significantly reduced blood glucose levels and increased UGE in rats. In conclusion, the clinical efficacy of enavogliflozin, including its potent glycemic-lowering effects and long-lasting UGE, is attributable to its structural features that promote hydrogen bonding and hydrophobic interactions with the galactose-binding motif, prolonged binding affinity to SGLT2, and the additional benefits of active metabolites M1 and M2. SIGNIFICANCE STATEMENT: The clinical efficacy of enavogliflozin is attributable to its high and sustained binding affinity for sodium-glucose cotransporter 2 (SGLT2) and the additional benefits conferred by active metabolites M1 and M2. The dihydrobenzofuran moiety of enavogliflozin is key to its distinctive inhibitory profile, contributing to its rigid conformation and optimal spatial orientation for effective π-π stacking interactions with Phe98, thereby enhancing its inhibitory potency. This structural feature distinguishes enavogliflozin from other SGLT2 inhibitors such as dapagliflozin and empagliflozin.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103650"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707846","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":"Pharmacological study of the safety, efficacy, and potential of M201-A on paroxysmal and persistent atrial fibrillation.","authors":"Noboru Kaneko, Godfrey L Smith, Christopher M Loughrey, Ryuko Matsuda, Kengo Kusano, Yuko Inoue, Naoyuki Otani, Masashi Toda, Kayley Scott, Ana Da Silva Costa, Sara Dobi, Priyanka Saxena, Patrick B Mark, Makoto Shinozaki, Ryuichi Kambayashi, Alexandra Riddell, Elspeth B Elliott, Charlotte S McCarroll, Takeshi Kitai, Tomoko Hasunuma, Ken Shimamoto, Toshiya Sakai, Masahiko Nakamura, Migaku Kikuchi, Shigeru Toyoda, Tetsuya Ishikawa, Koichiro Kumagai, Isao Taguchi, Atsushi Sugiyama, Yasuki Kihara, Toshihiko Fujiwara, Yuji Kumagai, Kunio Iwata","doi":"10.1016/j.jpet.2025.103652","DOIUrl":"10.1016/j.jpet.2025.103652","url":null,"abstract":"<p><p>Conversion and prevention of atrial fibrillation (AF) are essential requirements for its treatment. Abnormal leakage of calcium from the sarcoplasmic reticulum via the ryanodine receptor 2 (RyR2) during diastole is considered a major cause of AF. Although catheter ablation has made it possible to stop persistent AF, it does not address recurrence. In this context, we describe the additional pharmacological and antiarrhythmic effects of the RyR2 inhibitor M201-A, including the results of a phase I study. M201-A inhibited G-protein-gated atrial K⁺ channel at an IC₅₀ value of 0.35 μM, which was associated with a 38% increase in the atrial effective refractory period (ERP) and high atrial selectivity with an atrial ERP/ventricular ERP of 5.7. M201-A inhibited rapid component of the delayed rectifier potassium current (IC₅₀ value of 0.43 μM) but induced only a limited prolongation in the action potential duration in rabbit ventricular cells and human induced pluripotent stem cell-derived cardiomyocytes. M201-A is an R-enantiomer of the active metabolite M201-R of K201. After orally administering 540 mg K201 to patients with AF, the unbound drug concentration of M201-R was 30-fold higher (approximately 15-fold for M201-A) than that of K201, and AF was converted in 6 of the 12 patients (50%) during the first 2 hours following administration. M201-A was the main contributor with a stronger bioactive metabolite than M201-B (S-enantiomer) and M201-R. Furthermore, M201-A was 5-fold more biologically active than K201 in humans due to protein binding rates. These pharmacological properties hold promise as a new therapeutic strategy for AF, particularly the prevention of recurrence after catheter ablation. SIGNIFICANCE STATEMENT: Abnormal leakage of calcium from the sarcoplasmic reticulum via the ryanodine receptor 2 (RyR2) is considered a major cause of atrial fibrillation (AF). M201-A had inhibitory effects on RyR2 and G-protein-gated atrial K⁺ channel. It had high atrial selectivity with limited QT interval corrected by Fridericia's formula prolongation and proarrhythmic risk. It was the most active conversion metabolite when K201 was administered orally in patients with paroxysmal AF. These pharmacological effects of M201-A, combined with its inhibitory actions on RyR2, provide a promising therapeutic option for treating AF.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103652"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12489371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794774","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":"Evaluation of pharmacokinetics, pharmacodynamics, and toxicity of potential quinazoline bronchodilators derived from vasicinone.","authors":"Marcel Špulák, Dominik Nelic, Alena Randáková, Klára Konečná, Ondřej Janďourek, Lucie Smutná, Vladimír Kubíček, Nicholas Gathergood, Jana Pourová, Petr Pávek, Milan Pour, Dalibor Svoboda, Anna Ďurinová, Jan Jakubík, František Trejtnar","doi":"10.1016/j.jpet.2025.103636","DOIUrl":"10.1016/j.jpet.2025.103636","url":null,"abstract":"<p><p>Various synthetic modifications of the alkaloid (-)-vasicinone are known to exhibit a remarkable bronchodilatory effect. This study aimed to examine selected pharmacological and toxicological properties of 2 quinazolines derived from vasicinone with previously proven bronchodilatory action to consider their potential applicability for further preclinical development. Both compounds were found to have relatively low in vitro toxicity in a standard hepatic cell model. Pharmacokinetic studies in rats using oral and intravenous administration showed significant differences in oral availability (0.66 ± 0.11% vs 0.36 ± 0.18%), distribution volume, and elimination parameters of the 2 tested agents (for all parameters, P < .05). The different pharmacokinetic properties offer the possibility to select more convenient compounds for inhalation or systemic administration in further stages of development. The performed pharmacodynamic studies using an in vitro model showed that the tested quinazolines bind to the allosteric site on muscarinic acetylcholine receptors with micromolar affinity (pK_B higher than pK_I for M₁ and M₃ receptors, P < .05) and exert functional antagonism of carbachol-induced response. The main effect is not accompanied by a concomitant antibiotic effect. The proven inhibition of muscarinic receptors including the M₃ subtype is analogous to the effects of clinically used anticholinergic bronchodilators. Therefore, the findings suggest that the bronchodilating effect of the tested compounds is likely mediated by a similar mechanism. The muscarinic receptor blocking effect based on allosteric binding to the receptors may potentially allow the development of a new group of highly selective M₃ antagonists. SIGNIFICANCE STATEMENT: Two tested synthetic quinazoline derivatives with proven bronchodilator action exhibit allosteric binding to muscarinic receptors. Since the extracellular domain at which allosteric modulators commonly bind varies among subtypes of muscarinic receptors, this characteristic may allow further development of highly selective M₃ antagonists. The examined compounds exhibit low toxicity as well as no concomitant antimicrobial effect that would potentially affect the bronchial microbiome.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103636"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618685","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":"FFAR1/GPR40 agonists: Are new players in type 2 diabetes management on the horizon?","authors":"Andrea Cignarella, Samuel Tetteh-Quarshie","doi":"10.1016/j.jpet.2025.103630","DOIUrl":"10.1016/j.jpet.2025.103630","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103630"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618686","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":"Exploring novel protective role of semaglutide in 5-fluorouracil-induced hepatotoxicity: Insights into phosphorylated CREB, PINK1/Parkin-mediated mitophagy, and NF-κB/NLRP3 pathways.","authors":"Nermein F El Sayed, Sara A Baraka, Bassant M El-Mokadem, Heba H El Osaily, Abeer Bishr","doi":"10.1016/j.jpet.2025.103629","DOIUrl":"10.1016/j.jpet.2025.103629","url":null,"abstract":"<p><p>Semaglutide (Sema), a potent glucagon-like peptide-1 receptor agonist, is widely used in the management of type 2 diabetes mellitus due to its glucose-lowering effects. Beyond this, Sema also exhibits antioxidative, anti-inflammatory, antiapoptotic, and autophagy-enhancing properties. However, its potential role against 5-fluorouracil (5-FU)-induced hepatic injury has not yet been investigated. Hence, our study aims to investigate the hepatoprotective role of Sema against 5-FU-induced hepatotoxicity. Rats were randomly distributed in 5 groups: group I was the control group (saline only); group II and the rest of the groups except the normal group received 5-FU (150 mg/kg i.p.) to induce hepatotoxicity; group III received Sema (0.3 mg/kg orally) + 5-FU; group IV received Sema + 5-FU + chloroquine (CQ; 10 mg/kg i.p., 10 minutes prior to 5-FU);group V received 5-FU + CQ. Our results showed that 5-FU markedly increased hepatic enzyme levels, oxidative stress, inflammatory markers, and histological injury. However, pretreatment with Sema effectively counteracted these harmful effects by suppressing the reactive oxygen species/NF-κB/NLRP3 inflammasome pathway and enhancing PINK1/Parkin-mediated mitophagy. Notably, the addition of CQ, an autophagy inhibitor, abolished the protective role of Sema in autophagic flux. Furthermore, Sema reduced proinflammatory cytokines (tumor necrosis factor-α and interleukin-6), oxidative stress markers (malondialdehyde), and apoptotic markers (caspase-3), enhanced the antioxidant activity (glutathione), and promoted the activation of the phosphorylated CREB/Nrf2/HO-1 signaling pathway. In conclusion, Sema attenuates the 5-FU-induced liver injury through a multifaceted mechanism involving suppression of inflammation, oxidative stress, and apoptosis, as well as by increasing autophagic flux by inducing the phosphorylated CREB/PINK/Parkin trajectory pathway. These findings suggest that Sema holds promise as a novel therapeutic approach for preventing chemotherapy-induced liver toxicity. SIGNIFICANCE STATEMENT: Semaglutide, a GLP-1 receptor agonist, significantly mitigates 5-fluorouracil-induced hepatotoxicity in rats, suppressing the reactive oxygen species/NF-κB/NLRP3 inflammasome pathway and reducing oxidative stress and inflammation. Semaglutide also enhances mitophagy by activating the phosphorylated CREB/PINK1/Parkin pathway, aiding in the clearance of damaged mitochondria, confirmed using chloroquine, an autophagy inhibitor.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103629"},"PeriodicalIF":3.8,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560406","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":"Alleviation of metabolic dysfunction-associated steatotic liver disease by silymarin is associated with maintaining mitochondrial homeostasis via regulation of optic atrophy 1.","authors":"Ming-Qiang Liu, Yuan Wu, Ye Li, Yan-Bo Wei, Ling-Yue Dong, Wei An","doi":"10.1016/j.jpet.2025.103611","DOIUrl":"10.1016/j.jpet.2025.103611","url":null,"abstract":"<p><p>Silibinin (silybin) is the major active compound of silymarin used to treat several chronic liver diseases including metabolic dysfunction-associated steatotic liver disease (MASLD). However, the molecular mechanism of hepatic protection offered by silibinin remains still incompletely understood. In this study, we aimed to investigate whether silibinin could ameliorate hepatic steatosis by regulating mitochondrial function in Western diet (WD)-fed MASLD mice and free fatty acid-treated HepG2 cells. WD-fed mice and oleic acid/palmitic acid (OA/PA; 2:1)-treated HepG2 cells were established to evaluate the protection of silibinin against hepatocyte steatosis. Mitochondrial quality was detected using transmission electron microscope, confocal microscope, and cell analyzer for energy metabolism. Silibinin effectively attenuated WD-fed steatotic liver in mice and decreased lipid accumulation in hepatocytes, proved to be associated with stabilization of mitochondrial networked areas and inhibition of mitochondrial swelling. Functionally, silibinin at concentrations of 100 ng/μL was found to enhance mitochondrial respiratory capacity in the OA/PA-treated cells. RNA transcriptome analysis showed that, following silibinin administration, the expressions of numerous mitochondria-associated signaling molecules including AMP-activated protein kinase and mitophagy were upregulated. Among them, optic atrophy (OPA)1 expression increased prominently, which coincided with not only elevated mitochondrial fusion but also declined mitochondrial fragmentation in mouse steatotic livers and OA/PA-treated hepatocytes. In contrast, knockdown OPA1 abolished the protective effect offered by silibinin against lipid accumulation and deteriorated hepatocyte steatosis. Our findings suggest that silibinin attenuating hepatic steatosis is potentially attributed to stabilizing mitochondrial homeostasis via upregulation of OPA1. SIGNIFICANCE STATEMENT: The study results revealed that silibinin maintains mitochondrial homeostasis by upregulating optic atrophy 1 expression in hepatocytes to attenuate lipid accumulation and oxidative stress. Therefore, silibinin is a potential therapeutic candidate for the treatment of metabolic dysfunction-associated steatotic liver disease.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103611"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285004","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":"Determinants of drug effects in preclinical assays of pain-related behavioral depression: Considerations for analgesic drug development.","authors":"S Stevens Negus","doi":"10.1016/j.jpet.2025.103621","DOIUrl":"10.1016/j.jpet.2025.103621","url":null,"abstract":"<p><p>Pain-related behavioral depression is a cardinal sign of pain diagnosis and a target of pain treatment in both human and veterinary medicine. As such, pain-related behavioral depression can serve as class of translational endpoints in research on the expression, mechanisms, and treatment of pain, and prevailing evidence suggests that use of these endpoints can increase the accuracy of preclinical-to-clinical translation in analgesic drug discovery. In assays of pain-depressed behavior, a behavioral endpoint is selected that occurs at a high and reliable rate under baseline conditions and is depressed to lower levels after delivery of a noxious stimulus. Drugs are then evaluated for their effectiveness to rescue expression of the pain-depressed behavior. Net drug effects in these procedures reflect the integration of 2 general components: (1) analgesic effects that reduce sensory sensitivity to the noxious stimulus to increase expression of the target behavior and (2) nonanalgesic motor/cognitive effects that can both reduce behavior when the drug is administered alone and oppose expression of analgesic effects when the drug is administered in the context of a pain state. Drug effects can be further modulated by factors that include (1) the noxious stimulus type and intensity, (2) the target behavior depressed by that noxious stimulus, and (3) the genotype and individual history of the subject to which the noxious stimulus is delivered and by which the target behavior is emitted. Improved appreciation of factors that modulate drug effects on pain-depressed behavior could improve the utility of these procedures in analgesic drug discovery. SIGNIFICANCE STATEMENT: Preclinical procedures that evaluate drug effects on pain-related behavioral depression can improve preclinical-to-clinical translation of drug effects in analgesic drug discovery. This article reviews some of the determinants of drug effects in these procedures.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103621"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336629","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":"N-Methyldopamine and ibopamine can prevent chemically-induced oxidative ferroptosis in vitro and in vivo.","authors":"Yi-Chen Jia, Xiangyu Hao, Bao Ting Zhu","doi":"10.1016/j.jpet.2025.103620","DOIUrl":"10.1016/j.jpet.2025.103620","url":null,"abstract":"<p><p>Oxidative ferroptotic cell death can be selectively induced in cultured cells by chemicals like erastin (an inhibitor of system Xc^-) and RSL3 (an inhibitor of glutathione peroxidase 4). It was recently revealed that protein disulfide isomerase (PDI) is an upstream mediator of chemically-induced ferroptosis and thus also a drug target for ferroptosis protection. Here, we report that N-methyldopamine (MD), a metabolite of dopamine, can protect against erastin- and RSL3-induced ferroptosis in cultured cells, including rat hepatocytes and rat cardiomyocytes. Ibopamine, a prodrug that can release MD in vivo, also exhibits a similar cytoprotective effect in cultured cells in vitro. Mechanistically, MD can bind to PDI in live cells, and can also inhibit PDI's catalytic activities in vitro, likely through covalent interactions. Inhibition of PDI by MD markedly abrogates chemically-induced, PDI-mediated nitric oxide synthase (NOS) dimerization (ie, catalytic activation) and nitric oxide (NO) accumulation, which is followed by reduced buildup of cellular reactive oxygen species (ROS) and lipid-ROS. These changes resulting from the inhibition of PDI-mediated NOS activation and reduction in cellular NO and ROS/lipid-ROS levels jointly contribute, in a predominant manner, to the prevention of chemically-induced ferroptosis by MD. In addition, animal studies showed that MD and ibopamine each can prevent acetaminophen-induced liver injury in mice. In conclusion, the results of this study demonstrate that MD can prevent chemically-induced ferroptosis both in vitro and in vivo through inhibition of PDI-mediated NOS dimerization and NO accumulation. SIGNIFICANCE STATEMENT: It was recently shown that PDI is a pivotal upstream mediator of chemically-induced oxidative ferroptosis and thus a drug target for ferroptosis protection. This study reports that N-methyldopamine, a metabolite of dopamine, is an inhibitor of PDI, and can prevent chemically-induced ferroptosis both in vitro and in vivo. Ibopamine, a prodrug designed to release N-methyldopamine following oral administration, is also highly effective as a cytoprotective agent. This work reveals the PDI-mediated mechanism of cytoprotection by N-methyldopamine and its prodrug ibopamine.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103620"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506043","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":"Subjective drug-effect ratings predict cannabis self-administration in people who use cannabis daily.","authors":"Thomas P Shellenberg, Justin C Strickland, Sean D Regnier, Preston T Tolbert, Stephanie Lake, Michael J Wesley, William W Stoops, Ziva D Cooper, Margaret Haney, Joshua A Lile","doi":"10.1016/j.jpet.2025.103622","DOIUrl":"10.1016/j.jpet.2025.103622","url":null,"abstract":"<p><p>As interest in the potential therapeutic benefits of cannabis-derived products grows, accurate predictors of abuse potential will be vital for informing regulatory decisions. Currently, the Food and Drug Administration recommends using subjective effect ratings of Drug Liking as the primary measure in human abuse potential studies. However, dissociations between subjective ratings and drug-taking behavior have been previously reported. This retrospective analysis determined if any subjective effects questionnaire items uniquely predicted cannabis self-administration in people who use cannabis daily (N = 89; 71 male and 18 female). Data from 4 previous studies across 2 research sites that included cannabis self-administration and subjective effects assessments were combined. Concentrations of Δ⁹-tetrahyrdocannabinol (THC) were similar across studies (5.5%, 5.6%, or 5.9%), although milligram THC dose varied based on administration procedures. Ratings of Good Effect, High, Sedated/Tired, Drug Liking, Stimulated, and Willingness to Take Again were used as predictors. In each study, a money option ($0.50 or $1.00) was scheduled as an alternative to cannabis puffs in self-administration procedures. Proportion of choices for cannabis puffs over total choice trials (3 or 8 trials) was used as the primary outcome. Generalized linear models revealed that higher ratings of Willingness to Take Again (OR = 1.04) were associated with increased odds of self-administering active THC cannabis, while higher ratings of Stimulated were associated with decreased odds of self-administering placebo cannabis (OR = 0.94). These results suggest that subjective ratings of Willingness to Take Again should be considered as a primary outcome when assessing abuse potential for novel cannabinoid products. SIGNIFICANCE STATEMENT: This retrospective analysis found that subjective ratings of Willingness to Take Again was a more predictive measure of cannabis self-administration than Drug Liking in people who use cannabis daily. Refining human abuse potential assessments to prioritize measures that better align with drug-taking behavior could improve regulatory evaluations of novel cannabinoid products.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103622"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506045","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":"Can a novel lysophosphatidic acid receptor 1 antagonist ACT in time to halt pulmonary fibrosis and improve breathing?","authors":"Bradley T Andresen","doi":"10.1016/j.jpet.2025.103610","DOIUrl":"10.1016/j.jpet.2025.103610","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103610"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248412","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}