Current Research in Pharmacology and Drug Discovery最新文献

{"title":"The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinib","authors":"Jing Zhang ,&nbsp;Zequn Wang ,&nbsp;Xihua Wei ,&nbsp;Mengyuan Han ,&nbsp;Ribai Yan ,&nbsp;Lijie Ma ,&nbsp;Yan Pan","doi":"10.1016/j.crphar.2024.100212","DOIUrl":"10.1016/j.crphar.2024.100212","url":null,"abstract":"<div><div>Non-small-cell lung cancer (NSCLC) represents a predominant histological subtype of lung cancer, characterized by high incidence and mortality rates. Despite significant advancements in therapeutic strategies and a deeper understanding of targeted therapies in recent years, tumor resistance remains an inevitable challenge, leading to poor prognostic outcomes. Several studies have indicated that sphingosine kinase 1 (SPHK1) plays a regulatory role in epidermal growth factor receptor (EGFR) signaling, and its elevated expression may be associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Furthermore, the catalytic product of SPHK1, sphingosine 1-phosphate (S1P), along with its receptor, sphingosine 1-phosphate receptor 3 (S1PR3), plays a regulatory role in the function of the EGFR. However, the specific effects of the SPHK1/S1P/S1PR3 axis on EGFR in NSCLC, as well as the combined effects of SPHK1/S1P/S1PR3 inhibitors with the EGFR-TKI gefitinib, remain to be elucidated. In the present study, we investigated the correlation between SPHK1 expression levels and the survival rates of NSCLC patients, the relationship between SPHK1 or S1PR3 and EGFR, and the impact of SPHK1 expression on the half-maximal inhibitory concentration (IC₅₀) of gefitinib in NSCLC. In A549 cells, the phosphorylation of EGFR was significantly reduced following SPHK1 knockdown. Utilizing SPHK1/S1P/S1PR3 inhibitors, namely PF543, TY52156, and FTY720, we established that the SPHK1/S1P/S1PR3 axis modulates EGFR activation in NSCLC. Furthermore, these signaling inhibitors enhanced the anti-proliferative efficacy of the EGFR-TKI gefitinib. RNA sequencing analysis revealed substantial alterations in 85 differentially expressed genes in NSCLC cells treated with the combination of FTY720 and gefitinib. These genes were predominantly associated with pathways such as axon guidance, microRNAs in cancer, and the JAK-STAT signaling pathway, among others. Overall, targeting the SPHK1/S1P/S1PR3 signaling pathway represents a promising therapeutic strategy to enhance gefitinib sensitivity in NSCLC.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100212"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin's impact on asprosin and FBN1 expression: Potential mechanisms beyond insulin sensitivity in type 2 diabetes in rats","authors":"Ali Dashtkar ,&nbsp;Mansour Karajibani ,&nbsp;Mohsen Saravani ,&nbsp;Roya zanganeh ,&nbsp;Hamed Fanaei","doi":"10.1016/j.crphar.2024.100207","DOIUrl":"10.1016/j.crphar.2024.100207","url":null,"abstract":"<div><h3>Background</h3><div>Asprosin, a novel adipokine released under fasting conditions, may play a significant role in the pathophysiology of type 2 diabetes mellitus (T2DM). The objective of this study is to investigate the effects of metformin on serum asprosin levels and FBN1 gene expression in white adipose tissue in male rats.</div></div><div><h3>Methods</h3><div>Thirty-two male Wistar rats were randomly and equally divided into four groups (n = 8): 1. Control Group (CON): Received standard food; 2. Non-Diabetic Metformin Group (CON + MET): Received standard food and were treated with metformin (400 mg/kg/day) for four weeks; 3. Diabetic Group (DM): Induced with T2DM; and 4. Diabetic Metformin Group (DM + MET): Induced with T2DM and treated with metformin (400 mg/kg/day) for four weeks. Finally, serum asprosin levels, lipid profiles, fasting glucose, and insulin concentrations were measured. The expression level of the FBN1 gene in white adipose tissue was quantified using quantitative real-time polymerase chain reaction (qRT-PCR).</div></div><div><h3>Results</h3><div>Serum asprosin levels were significantly higher in the DM group compared to both the CON and CON + MET groups (P &lt; 0.0001). However, serum asprosin levels were significantly lower in the DM + MET group than in the DM group (P = 0.0003). Additionally, the FBN1 gene expression level in white adipose tissue was significantly higher in the DM group compared to the CON group (P = 0.0053), while FBN1 gene expression was significantly lower in the DM + MET group than in the DM group (P &lt; 0.0001). Furthermore, lipid profile, insulin resistance, and fasting blood sugar improved in the CON + MET and DM + MET groups compared to the CON and DM groups, respectively.</div></div><div><h3>Discussion</h3><div>Our findings in diabetic male rats reveal that metformin treatment significantly downregulates FBN1 gene expression and reduces serum asprosin levels, suggesting a potential mechanism for its therapeutic benefits beyond improving insulin sensitivity.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100207"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of nebivolol-mediated effects on bFGF-induced vascular smooth muscle cell proliferation and migration","authors":"Elaina Seemann,&nbsp;Trevor Beeler,&nbsp;Mohammed Alfarra,&nbsp;Mark Cosio,&nbsp;Charles Chan,&nbsp;Peyton Grant,&nbsp;Yingzi Chang","doi":"10.1016/j.crphar.2025.100214","DOIUrl":"10.1016/j.crphar.2025.100214","url":null,"abstract":"<div><h3>Background</h3><div>Nebivolol is a β-adrenergic receptor antagonist that has intrinsic activity on β₃-adrenergic receptors (β₃-ARs). Previous studies suggest that nebivolol inhibits bFGF-induced vascular smooth muscle cell (VSMC) proliferation and migration and vascular injury-induced neointima formation through activation of β₃-ARs. However, our recently published data shown that activation of β₃-ARs produced the opposite results, suggesting that the mechanisms of nebivolol-mediated effects are not fully understood. The current project was to study the mechanisms of nebivolol’s effects on bFGF-induced VSMC proliferation and migration by comparing to the selective β₃-AR agonist, CL316,243.</div></div><div><h3>Methods</h3><div>VSMCs isolated from Sprague Dawley rat aortas were pretreated with nebivolol or CL316,243 followed by stimulation with bFGF. Cell proliferation and migration and phosphorylation of ERK and AKT were measured.</div></div><div><h3>Results</h3><div>We found that pretreatment of VSMCs with nebivolol produced biphasic effects on bFGF-induced VSMC proliferation, manifested as potentiation at lower concentrations and inhibition at the higher concentration. The effects of low concentrations of nebivolol on bFGF-induced VSMC proliferation was blocked by the selective β₃-AR antagonist, SR59230A. Nebivolol inhibited bFGF-induced cell migration at all concentrations tested. In addition, only higher concentrations of nebivolol significantly inhibited bFGF-induced AKT phosphorylation but not ERK phosphorylation whereas CL316,243 at all concentrations tested significantly enhanced bFGF-induced VSMC proliferation and migration and higher concentrations of CL316,243 not only enhanced bFGF-induced AKT phosphorylation but also ERK phosphorylation.</div></div><div><h3>Conclusion</h3><div>Our data suggest that the effect of nebivolol on bFGF-induced cell proliferation is concentration-dependent. The enhancement on bFGF-induced cell proliferation at lower concentrations appears to be mainly mediated by activation of β₃-ARs but the inhibitory effects on bFGF-mediated cell proliferation as well as migration may occur through different mechanisms. AKT signaling is only involved in high concentrations of nebivolol-mediated effects.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100214"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing ibrutinib bioavailability: Formulation and assessment of hydroxypropyl-β-cyclodextrin-based nanosponge delivery systems","authors":"Sunitha Sampathi ,&nbsp;Nitiraj Kulkarni ,&nbsp;D.V.R.N. Bhikshapathi ,&nbsp;Jagadish V. Tawade ,&nbsp;Nainaru Tarakaramu ,&nbsp;Rzgar Farooq Rashid ,&nbsp;Aziz Kubaev","doi":"10.1016/j.crphar.2025.100213","DOIUrl":"10.1016/j.crphar.2025.100213","url":null,"abstract":"<div><h3>Background</h3><div>The current research aims to improve the oral bioavailability of ibrutinib (IBR), a class II drug with low solubility, through the formulation of nanosponges (NSPs) that incorporate IBR, utilizing Hydroxypropyl β-cyclodextrin (HPβCD) and 1,1′-carbonyldiimidazole (CDI) as cross-linking agent.</div></div><div><h3>Methods</h3><div>IBR-loaded HPβCD-NSPs were formulated by optimizing the molar proportion of HPβCD to CDI, as well as stirring rate and duration using a design-based methodology. The synthesized nanoparticles (NSPs) were examined for size, potential, and entrapment of drug. Characterization was performed by X-ray diffraction analysis, Fourier Transform Infrared Spectroscopy (FT-IR), and Differential Scanning Calorimetry (DSC), to assess compatibility. Permeability studies were conducted, followed by in vitro and in vivo assessments.</div></div><div><h3>Results</h3><div>The optimized IBR-loaded HPβCD NSPs demonstrated a mean particle size of 145.6 ± 6.8 nm, a PDI of 0.170 ± 0.036, and an EE of 71.04 ± 2.40%. Further validation through zeta sizing, microscopic and spectral analysis, release studies, and pharmacokinetic assessments confirmed the optimization. The HPβCD NSPs demonstrated 14.96 times higher AUC0-t (area under the curve) with a Cmax increase of 6.45 times compared to the free drug, indicating a substantial improvement in bioavailability.</div></div><div><h3>Conclusion</h3><div>IBR-loaded HPβCD NSPs offer a promising strategy for improved drug release and bioavailability, which could significantly benefit melanoma treatment.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100213"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143180668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of concern regarding the article titled “Variability in the serum and tissue concentrations of pre-incisional ceftriaxone for surgery in paediatric population and outcome of surgical-site infections; An open labelled, prospective, non-randomized, analytical study”","authors":"Luigino Calzetta","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100211"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143181615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quercetin prevents rats from type 1 diabetic liver damage by inhibiting TGF-ꞵ/apelin gene expression","authors":"Gholampour Firouzeh ,&nbsp;Abbasi Susan ,&nbsp;Karimi Zeinab","doi":"10.1016/j.crphar.2024.100201","DOIUrl":"10.1016/j.crphar.2024.100201","url":null,"abstract":"<div><h3>Background</h3><p>Hyperglycemia-induced oxidative stress is a significant contributor to diabetic complications, including hepatopathy. The current survey aimed to evaluate the ameliorative effect of quercetin (Q) on liver functional disorders and tissue damage developed by diabetes mellitus in rats.</p></div><div><h3>Methods</h3><p>Grouping of 35 male Wistar rats was performed as follows: sham; sham + quercetin (sham + Q: quercetin, 50 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage); diabetic control (Diabetes: streptozotocin (STZ), 65 mg/kg, i.p.); diabetic + quercetin 1 (D + Q1: quercetin, 25 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage after STZ injection); and diabetic + quercetin 2 (D + Q2: quercetin, 50 mg/kg/day in 1 ml 1% DMSO for 6 weeks, by gavage after STZ injection). Body weight, food intake, and water intake were measured. Ultimately, the samples of plasma and urine, as well as tissue samples of the liver and pancreas were gathered for later assays.</p></div><div><h3>Results</h3><p>STZ injection ended in elevated plasma blood glucose levels, decreased plasma insulin levels, liver dysfunction (increased activity levels of AST, ALT, and ALP, increased plasma levels of total bilirubin, cholesterol, LDL, triglyceride, decreased plasma levels of total protein, albumin and HDL), enhanced levels of malondialdehyde, diminished activities of antioxidant enzymes (superoxide dismutase, and catalase), reduced level of glutathione (GSH) increased gene expression levels of apelin and TGF-ꞵ, plus liver histological destruction. All these changes were diminished by quercetin. However, the measure of improvement in the D + Q2 group was higher than that of the D + Q1 group.</p></div><div><h3>Conclusions</h3><p>Quercetin improved liver function after diabetes mellitus type 1, possibly due to reduced lipid peroxidation, increased antioxidant systems, and inhibiting the apelin/TGF-ꞵ signaling pathway.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100201"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000282/pdfft?md5=7e3380387bfbea656bb9d299b057e0f1&pid=1-s2.0-S2590257124000282-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatoprotective effect of Nobiletin against 5-fluorouracil induce hepatotoxicity","authors":"Safa A. Yahya,&nbsp;Nada N. Al-Shawi","doi":"10.1016/j.crphar.2024.100199","DOIUrl":"10.1016/j.crphar.2024.100199","url":null,"abstract":"<div><div>5-florouracil is a widely used anticancer/anti-metabolite drug used to treat solid tumor like colon cancer, head and neck, rectum, stomach, pancreas and breast cancer; but, it can cause hepatotoxicity by induction of apoptosis through activation of caspases enzymes and oxidative stress. Nobiletin is a citrus fruit-derived flavonoid that possess significant biological activity, including anticancer, and anti-inflammatory. This study was design to investigate the effects of nobiletin against 5-florouracil-indcued hepatotoxicity in male rats through the measurement of selected -inflammatory, -apoptosis, and -oxidative stress markers. By use male Albino rats weighing 150-250gm around 28 animals; giving them tap water ad libitum and fed commercial pellets; and randomized into four groups (7animals/group) as following arrangement: Group I oral administered only corn oil for rats 1 ml for each kilogram for day by using of oral gavage for rat for 14 days. Group II: oral administered Nobiletin at dose 10 mg for each kilogram for each day (dissolved in corn oil) via oral gavage for 14 days. Group III: oral administered corn oil via oral gavage for 14 days after that single IP injection of 5-FU (150 mg/kg) on the day fourteenth (14). Group VI: Rats oral administered nobiletin dissolved in corn oil daily by oral gavage at a dose 10 mg/kg for each day for 14 days and a single IP injection of (150 mg/kg) 5-florouracil was given on day 14. All groups, seven animals of each group were sacrificed at day fifteenth (15); and, serum was collected to measure inflammatory and anti-inflammatory markers (interlukin-6 and interlukin-10) and liver function tests(ALT, LDH and AST); furthermore, liver tissue samples were collected to measure level of caspase-3, malondialdehyde and reduced form of glutathione, assessment of Hemeoxygenase-1 and NADPH quinone dehydrogenase-1 enzymes. In addition, histopathological study of the liver tissue of rats was perform to detect difference between architecture of liver cells in all rats’ groups. The protective effect of Nobiletin noted by decrease in apoptosis of hepatocytes by decreasing of caspase-3 and reduction on free radical through reduce in malondialdehyde level, also increase in Hemeoxygenase-1gene expression. Increase in NADPH quinone dehydrogenase-1 dehydrogenase enzyme. On histopath reduce in congestion and some inflammatory infiltration by using of nobiletin prior to give 5-florouracil.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100199"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142421287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoplasmic reticulum stress in pancreatic β-cell dysfunction: The potential therapeutic role of dietary flavonoids","authors":"Kingsley C. Mbara ,&nbsp;Marthe C.D. Fotsing ,&nbsp;Derek T. Ndinteh ,&nbsp;Claudine N. Mbeb ,&nbsp;Chinekwu S. Nwagwu ,&nbsp;Rene Khan ,&nbsp;Kopang C. Mokhetho ,&nbsp;Himansu Baijnath ,&nbsp;Manimbulu Nlooto ,&nbsp;Shoeshoe Mokhele ,&nbsp;Carmen M. Leonard ,&nbsp;Vuyelwa J. Tembu ,&nbsp;Clemence Tarirai","doi":"10.1016/j.crphar.2024.100184","DOIUrl":"10.1016/j.crphar.2024.100184","url":null,"abstract":"<div><p>Diabetes mellitus (DM) is a global health burden that is characterized by the loss or dysfunction of pancreatic β-cells. In pancreatic β-cells, endoplasmic reticulum (ER) stress is a fact of life that contributes to β-cell loss or dysfunction. Despite recent advances in research, the existing treatment approaches such as lifestyle modification and use of conventional therapeutics could not prevent the loss or dysfunction of pancreatic β-cells to abrogate the disease progression. Therefore, targeting ER stress and the consequent unfolded protein response (UPR) in pancreatic β-cells may be a potential therapeutic strategy for diabetes treatment. Dietary phytochemicals have therapeutic applications in human health owing to their broad spectrum of biochemical and pharmacological activities. Flavonoids, which are commonly obtained from fruits and vegetables worldwide, have shown promising prospects in alleviating ER stress. Dietary flavonoids including quercetin, kaempferol, myricetin, isorhamnetin, fisetin, icariin, apigenin, apigetrin, vitexin, baicalein, baicalin, nobiletin hesperidin, naringenin, epigallocatechin 3-O-gallate hesperidin (EGCG), tectorigenin, liquiritigenin, and acacetin have shown inhibitory effects on ER stress in pancreatic β-cells. Dietary flavonoids modulate ER stress signaling components, chaperone proteins, transcription factors, oxidative stress, autophagy, apoptosis, and inflammatory responses to exert their pharmacological effects on pancreatic β-cells ER stress. This review focuses on the role of dietary flavonoids as potential therapeutic adjuvants in preserving pancreatic β-cells from ER stress. Highlights of the underlying mechanisms of action are also presented as well as possible strategies for clinical translation in the management of DM.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100184"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000117/pdfft?md5=e9be6bef98dc4f953504348decab6dff&pid=1-s2.0-S2590257124000117-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141135981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scaling approaches for the prediction of human clearance of LNA-i-mir-221: A retrospective validation","authors":"Massimiliano Fonsi ,&nbsp;Jacques Fulbert ,&nbsp;Pierre-Andre Billat ,&nbsp;Mariamena Arbitrio ,&nbsp;Pierosandro Tagliaferri ,&nbsp;Pierfrancesco Tassone ,&nbsp;Maria Teresa Di Martino","doi":"10.1016/j.crphar.2024.100197","DOIUrl":"10.1016/j.crphar.2024.100197","url":null,"abstract":"<div><p>LNA-i-miR-221 is a novel microRNA(miRNA)-221 inhibitor designed for the treatment of human malignancies. It has recently undergone phase 1 clinical trial (P1CT) and early pharmacokinetics (PKs) data in cancer patients are now available. We previously used multiple allometric interspecies scaling methods to draw inferences about LNA-i-miR-221 PKs in humans and estimated the patient dose based on the safe and pharmacodynamic (PD) active dose observed in mice, therefore providing a framework for the definition of safe starting and escalation doses for the P1CT. The preliminary data collected during the P1CT showed that the LNA-i-miR-221 anticipated doses, according to our human PK estimation approach, were indeed well tolerated and effective. PD data demonstrated concentration-dependent downregulation of miR-221 and upregulation of its CDKN1B/p27 and PTEN canonical targets as well as stable disease in 8 (50.0%) patients and partial response in 1 (6.3%) colorectal cancer case. Here, we detail the experimentally evaluated PK parameters of LNA-i-miR-221 in human, using both a non-compartmental and a population PKs approach. The population approach was adequately described by a three-compartments model with first-order elimination. The recorded age, sex and body weight of patients were evaluated as potential covariates. The estimated typical population parameter values were clearance (CL = 200 mL/h/kg), central volume of distribution (V1 = 45 mL/kg), peripheral volume of distribution (V2 = 200 mL/kg, volume of the second peripheral compartment V3 = 930 mL/h/kg) and inter-compartmental clearance (Q2 = 480 mL/h/kg and Q3 = 68 mL/h/kg). Age was found to be a predictor of Q3, with a statistically significant correlation. This work aimed also at retrospectively comparing the measured plasmatic clearance values with those predicted by different allometric scaling approaches. Our comparative analysis showed that the most accurate prediction was achieved by applying the single species allometric scaling approach and that the use of more than one species in allometric scaling to predict therapeutic oligonucleotides PKs would not necessarily generate the best prediction. Finally, our predictive approach was found accurate not only in predicting the main PK parameters in human but suggesting the range of effective and safe dose to be applied in the next clinic phase 2.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"7 ","pages":"Article 100197"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000245/pdfft?md5=14be37eb3e3e1daad2b299ed49e09672&pid=1-s2.0-S2590257124000245-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141952149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of survival rate and persistence predictors of baricitinib in real-world data from a large cohort of rheumatoid arthritis patients","authors":"Simone Parisi ,&nbsp;Becciolini Andrea ,&nbsp;Ditto Maria Chiara ,&nbsp;Lo Gullo Alberto ,&nbsp;Larosa Maddalena ,&nbsp;Scolieri Palma ,&nbsp;Addimanda Olga ,&nbsp;Reta Massimo ,&nbsp;Paroli Marino (Prof) ,&nbsp;Caccavale Rosalba ,&nbsp;Visalli Elisa ,&nbsp;Foti Rosario ,&nbsp;Amato Giorgio ,&nbsp;De Lucia Francesco ,&nbsp;Dal Bosco Ylenia ,&nbsp;Foti Roberta ,&nbsp;Farina Antonella ,&nbsp;Girelli Francesco ,&nbsp;Bernardi Simone ,&nbsp;Camellino Dario ,&nbsp;Fusaro Enrico","doi":"10.1016/j.crphar.2024.100178","DOIUrl":"https://doi.org/10.1016/j.crphar.2024.100178","url":null,"abstract":"<div><h3>Objectives</h3><p>The persistence in therapy of rheumatoid arthritis drugs and particularly bDMARD is a limiting factor for their long-term use. The randomized controlled trials (RCTs) may not reflect real-world contexts due to strict inclusion and exclusion criteria. Baricitinib, which targets both JAK1 and JAK2, has been used in Italy for several years. The aim of this multi-center study is to assess the real world persistence on therapy of baricitinib in RA patients and to identify predictive factors of baricitinib's survival rate.</p></div><div><h3>Methods</h3><p>This is a retrospective, multicentric, Italian, longitudinal study. All patients were enrolled according to the following criteria: a) age ≥ 18 years old; b) diagnosed with RA according 2010 ACR/EULAR classification criteria; c) treated with baricitinib. In order to describe baricitinib clinical efficacy, the survival rate was evaluated by The Kaplan–Meier curve. Then, predictive factors of drug retention rate were assessed by performing the Cox analysis, identifying which risk factors influenced treatment persistence.</p></div><div><h3>Results</h3><p>Overall, we included 478 patients treated with baricitinib. Among them, 380 (79.5%) were females. Baricitinib's survival rate was 94.6% at 6 months, 87.9% at 12 months, 81.7% at 24 months and 53.4% at 48 months. The Cox analysis regression showed that a higher bDMARDs/tsDMARD line of therapy seems to be a negative prognostic factor for the drug retention rate (HR 1.26 CI 95% 1.07–1.49, p = 0.006.</p></div><div><h3>Conclusion</h3><p>Real-life study confirms baricitinib effectiveness up to 4 years, but previous treatment with bDMARDs was a negative prognostic factor for its survival rate.</p></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"6 ","pages":"Article 100178"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590257124000051/pdfft?md5=de00ff9c3ff118ac9487540fc26e78bb&pid=1-s2.0-S2590257124000051-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139935265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}