Pub Date : 2025-01-01Epub Date: 2025-04-17DOI: 10.1016/j.crphar.2025.100220
Medha Satti , Kavita Prasad , Yash Patel , Demi Poulathas , Lawrence Walker , Esha Paghdal , Samuel Gunderson , Lei Yu
U1 Adaptor is a novel gene-silencing technology, offering an innovative approach to target genes in the CNS for the treatment of diseases. Intrathecal delivery is a medically viable route of administration of CNS-bound nucleic acid drugs; therefore, it is important to investigate U1 Adaptor distribution after intrathecal drug delivery. We investigated the distribution patterns of U1 Adaptor upon intrathecal bolus administration in mice. It readily distributes to CNS tissues, including the lumbar and the cervical spinal cord, and the cerebellum. Over time, the U1 Adaptor also accumulates in the periphery, both in the liver and the kidneys, while plasma levels are undetectable. Our findings provide useful information for future in-depth pharmacokinetic modeling of U1 Adaptor distribution upon intrathecal administration.
{"title":"Tissue distribution pharmacokinetics of intrathecal U1 adaptor oligonucleotide in mice","authors":"Medha Satti , Kavita Prasad , Yash Patel , Demi Poulathas , Lawrence Walker , Esha Paghdal , Samuel Gunderson , Lei Yu","doi":"10.1016/j.crphar.2025.100220","DOIUrl":"10.1016/j.crphar.2025.100220","url":null,"abstract":"<div><div>U1 Adaptor is a novel gene-silencing technology, offering an innovative approach to target genes in the CNS for the treatment of diseases. Intrathecal delivery is a medically viable route of administration of CNS-bound nucleic acid drugs; therefore, it is important to investigate U1 Adaptor distribution after intrathecal drug delivery. We investigated the distribution patterns of U1 Adaptor upon intrathecal bolus administration in mice. It readily distributes to CNS tissues, including the lumbar and the cervical spinal cord, and the cerebellum. Over time, the U1 Adaptor also accumulates in the periphery, both in the liver and the kidneys, while plasma levels are undetectable. Our findings provide useful information for future in-depth pharmacokinetic modeling of U1 Adaptor distribution upon intrathecal administration.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100220"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-07-24DOI: 10.1016/j.crphar.2025.100230
Luis Sendra , Gladys G. Olivera-Pasquini , Enrique G. Zucchet , Fabiana D.V. Genvigir , María Isabel Beneyto , Julio Hernández-Jaras , María José Herrero , Salvador F. Aliño
Background
Pharmacogenetic variability has been reported to influence the efficacy and safety of immunosuppressive therapies in early stages of kidney transplantation. This study investigates long-term associations between pharmacogene variants and clinical outcomes in a cohort of kidney transplant recipients over a 12-year follow-up.
Materials and methods
We analyzed 37 SNPs from 14 genes related to drug metabolism and transport in 79 kidney transplant patients. Clinical parameters, including survival, renal function, tumor occurrence, and pharmacokinetics of tacrolimus, were evaluated. Logistic regression and Kaplan-Meier analyses assessed associations between gene variants and clinical outcomes.
Results
Variants in metabolizer (CYP3A5, CYP2B6) and transporter genes (ABCB1, ABCC2) were associated with 12-year survival. Increased tumor risk correlated with ABCC2 variants in donors and decreased risk with CYP2B6 rs3745274 in recipients. Renal function was influenced by variants in ABCB1, ABCC2, CYP3A5, CYP3A4, and CYP2B6. Tacrolimus dose-dependent concentration was affected by variants in CYP3A4, CYP3A5, CYP2C19, ABCB1, and SLCO1B1. Increased nephrotoxicity risk was associated with CYP2C19 rs4244285 and reduced by SLCO1B1 rs2306283 AA and AG variants. Gene variant interactions between metabolizer and transporter genes were also associated with altered risk of events incidence.
Discussion
Our findings support that pharmacogene variants influence transplant outcomes. Notable associations include survival related to ABCB1 and ABCC2 variants, tumor occurrence linked to CYP2B6 rs3745274, and renal function affected by multiple pharmacogenes. Variants in CYP2C19 and SLCO1B1 significantly impacted tacrolimus pharmacokinetics and nephrotoxicity risk. These results underline the importance of pharmacogenetic testing for personalized management in kidney transplantation, although further validation in larger cohorts is necessary.
{"title":"Pharmacogenetics association with long-term clinical evolution in a kidney transplant patients cohort","authors":"Luis Sendra , Gladys G. Olivera-Pasquini , Enrique G. Zucchet , Fabiana D.V. Genvigir , María Isabel Beneyto , Julio Hernández-Jaras , María José Herrero , Salvador F. Aliño","doi":"10.1016/j.crphar.2025.100230","DOIUrl":"10.1016/j.crphar.2025.100230","url":null,"abstract":"<div><h3>Background</h3><div>Pharmacogenetic variability has been reported to influence the efficacy and safety of immunosuppressive therapies in early stages of kidney transplantation. This study investigates long-term associations between pharmacogene variants and clinical outcomes in a cohort of kidney transplant recipients over a 12-year follow-up.</div></div><div><h3>Materials and methods</h3><div>We analyzed 37 SNPs from 14 genes related to drug metabolism and transport in 79 kidney transplant patients. Clinical parameters, including survival, renal function, tumor occurrence, and pharmacokinetics of tacrolimus, were evaluated. Logistic regression and Kaplan-Meier analyses assessed associations between gene variants and clinical outcomes.</div></div><div><h3>Results</h3><div>Variants in metabolizer (CYP3A5, CYP2B6) and transporter genes (ABCB1, ABCC2) were associated with 12-year survival. Increased tumor risk correlated with ABCC2 variants in donors and decreased risk with CYP2B6 rs3745274 in recipients. Renal function was influenced by variants in ABCB1, ABCC2, CYP3A5, CYP3A4, and CYP2B6. Tacrolimus dose-dependent concentration was affected by variants in CYP3A4, CYP3A5, CYP2C19, ABCB1, and SLCO1B1. Increased nephrotoxicity risk was associated with CYP2C19 rs4244285 and reduced by SLCO1B1 rs2306283 AA and AG variants. Gene variant interactions between metabolizer and transporter genes were also associated with altered risk of events incidence.</div></div><div><h3>Discussion</h3><div>Our findings support that pharmacogene variants influence transplant outcomes. Notable associations include survival related to ABCB1 and ABCC2 variants, tumor occurrence linked to CYP2B6 rs3745274, and renal function affected by multiple pharmacogenes. Variants in CYP2C19 and SLCO1B1 significantly impacted tacrolimus pharmacokinetics and nephrotoxicity risk. These results underline the importance of pharmacogenetic testing for personalized management in kidney transplantation, although further validation in larger cohorts is necessary.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100230"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144712926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The repeated dressing changes, especially for infected wounds and those with high exudate, and applying drugs daily, are huge demands in wound management. Sustained and regulated medication release of BCS II/IV antibiotics improves chronic wound therapy. The poor solubility and absorption of BCS-class medicines makes it challenging at target site. This work seeks to build 3D nano scaffolds for administering ciprofloxacin, a BCS II/IV class medication, using biocompatible sulphonated polyether ether ketone mat produced by electrospinning, which is flexible. We demonstrated a reliable method to prevent burst drug release and maintain it for three weeks, with good biocompatibility, minimal cytotoxicity, and excellent tensile strength characterizing sulphonated polyether ether ketone. Nanofibers improve medication interaction and delivery due to their high specific surface area ratio. In vitro and in vivo experiments were used to define and study ciprofloxacin release from 30 % w/v sulphonated polyether ether ketone nanofibers. The SPEEK polymer/mat was analysed using 1H- NMR, FESEM, FTIR, TGA, and EDAX for structural and morphological characteristics. The UV spectroscopy showed that the nanofibrous SPEEK released 90 % ciprofloxacin over 21 days by non-Fickian diffusion (supported by mathematical modelling). Both direct and indirect MTT experiments at 1st, 3rd, and 7th days reveal compatibility with RAW 264.7 cell lines. Live-dead staining and cell adhesion investigations, support adherent cells and growth; scratch assay display migration in electrospun scaffold exhibits wound healing behaviour. In vivo investigations on Balb/C mice demonstrated that SPEEK-CF impregnated healed wounds from 3rd day and preventing infection till 14th day and confirmed by histopathology. This nanofibrous mat is suitable for sustained drug delivery.
{"title":"BCS II/IV antibiotics blended with SPEEK nanofibrous mat as an alternative for recurrent wound care: An in vitro and in vivo assessment","authors":"Himabindu Padinjarathil , Carmelo Drago , Sandro Dattilo , Libera Vitiello , Kaarthick Raaja Venkatachalam , Thirugnasambandam G. Manivasagam , Prasanna Ramani","doi":"10.1016/j.crphar.2025.100235","DOIUrl":"10.1016/j.crphar.2025.100235","url":null,"abstract":"<div><div>The repeated dressing changes, especially for infected wounds and those with high exudate, and applying drugs daily, are huge demands in wound management. Sustained and regulated medication release of BCS II/IV antibiotics improves chronic wound therapy. The poor solubility and absorption of BCS-class medicines makes it challenging at target site. This work seeks to build 3D nano scaffolds for administering ciprofloxacin, a BCS II/IV class medication, using biocompatible sulphonated polyether ether ketone mat produced by electrospinning, which is flexible. We demonstrated a reliable method to prevent burst drug release and maintain it for three weeks, with good biocompatibility, minimal cytotoxicity, and excellent tensile strength characterizing sulphonated polyether ether ketone. Nanofibers improve medication interaction and delivery due to their high specific surface area ratio. <em>In vitro</em> and <em>in vivo</em> experiments were used to define and study ciprofloxacin release from 30 % w/v sulphonated polyether ether ketone nanofibers. The SPEEK polymer/mat was analysed using <sup>1</sup>H- NMR, FESEM, FTIR, TGA, and EDAX for structural and morphological characteristics. The UV spectroscopy showed that the nanofibrous SPEEK released 90 % ciprofloxacin over 21 days by non-Fickian diffusion (supported by mathematical modelling). Both direct and indirect MTT experiments at 1st, 3rd, and 7th days reveal compatibility with RAW 264.7 cell lines. Live-dead staining and cell adhesion investigations, support adherent cells and growth; scratch assay display migration in electrospun scaffold exhibits wound healing behaviour. <em>In vivo</em> investigations on Balb/C mice demonstrated that SPEEK-CF impregnated healed wounds from 3rd day and preventing infection till 14th day and confirmed by histopathology. This nanofibrous mat is suitable for sustained drug delivery.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100235"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-02-20DOI: 10.1016/j.crphar.2025.100214
Elaina Seemann, Trevor Beeler, Mohammed Alfarra, Mark Cosio, Charles Chan, Peyton Grant, Yingzi Chang
Background
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.
Methods
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.
Results
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.
Conclusion
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.
{"title":"Mechanisms of nebivolol-mediated effects on bFGF-induced vascular smooth muscle cell proliferation and migration","authors":"Elaina Seemann, Trevor Beeler, Mohammed Alfarra, Mark Cosio, Charles Chan, Peyton Grant, 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 β<sub>3</sub>-adrenergic receptors (β<sub>3</sub>-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 β<sub>3</sub>-ARs. However, our recently published data shown that activation of β<sub>3</sub>-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 β<sub>3</sub>-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 β<sub>3</sub>-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 β<sub>3</sub>-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}
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.
Methods
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.
Results
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.
Conclusion
IBR-loaded HPβCD NSPs offer a promising strategy for improved drug release and bioavailability, which could significantly benefit melanoma treatment.
{"title":"Optimizing ibrutinib bioavailability: Formulation and assessment of hydroxypropyl-β-cyclodextrin-based nanosponge delivery systems","authors":"Sunitha Sampathi , Nitiraj Kulkarni , D.V.R.N. Bhikshapathi , Jagadish V. Tawade , Nainaru Tarakaramu , Rzgar Farooq Rashid , 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}
Pub Date : 2025-01-01Epub Date: 2025-09-16DOI: 10.1016/j.crphar.2025.100234
Luigino Calzetta , Shima Gholamalishahi , Elena Pistocchini , Bartolomeo Zerillo , Maria Gabriella Matera , Paola Rogliani
Sex is a fundamental determinant in pharmacology, influencing disease prevalence, severity, and therapeutic responses. Differences in pharmacokinetics and pharmacodynamics between men and women contribute to variations in drug efficacy and safety profiles. While sex refers to biological and physiological characteristics, gender encompasses social and behavioral factors. Despite their distinct meanings, these terms are often used interchangeably in medical research, potentially leading to misinterpretations. Historically, female and intersex individuals have been underrepresented in clinical studies, resulting in biased treatment approaches. Acknowledging these disparities, researchers now emphasize the importance of sex-specific differences to enhance therapeutic outcomes.
This review explores the impact of sex on the pharmacological treatment of chronic obstructive respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD).
Asthma is more prevalent in women, whereas COPD severity is rising among female patients. Sex influences the response to bronchodilators, inhaled corticosteroids (ICS), and combination therapies. Studies suggest that men exhibit a greater response to β2-adrenoceptor agonists and sex differences in muscarinic acetylcholine receptor (mAChR) expression may influence bronchodilator response to muscarinic antagonists. Moreover, women display stronger immune responses and higher corticosteroid receptor expression, potentially modulating the efficacy of ICS. Women are also more likely to experience adverse drug reactions and face challenges in correct inhaler device use, impacting treatment adherence and clinical outcomes. Despite these differences between men and women, sex-specific approaches remain insufficiently integrated into clinical practice. Addressing sex disparities in pharmacotherapy is crucial to optimize treatment strategies. Further research is needed to elucidate sex-related differences and incorporate them into evidence-based guidelines for asthma and COPD management.
{"title":"Exploring the role of sex in asthma and COPD pharmacological treatment","authors":"Luigino Calzetta , Shima Gholamalishahi , Elena Pistocchini , Bartolomeo Zerillo , Maria Gabriella Matera , Paola Rogliani","doi":"10.1016/j.crphar.2025.100234","DOIUrl":"10.1016/j.crphar.2025.100234","url":null,"abstract":"<div><div>Sex is a fundamental determinant in pharmacology, influencing disease prevalence, severity, and therapeutic responses. Differences in pharmacokinetics and pharmacodynamics between men and women contribute to variations in drug efficacy and safety profiles. While sex refers to biological and physiological characteristics, gender encompasses social and behavioral factors. Despite their distinct meanings, these terms are often used interchangeably in medical research, potentially leading to misinterpretations. Historically, female and intersex individuals have been underrepresented in clinical studies, resulting in biased treatment approaches. Acknowledging these disparities, researchers now emphasize the importance of sex-specific differences to enhance therapeutic outcomes.</div><div>This review explores the impact of sex on the pharmacological treatment of chronic obstructive respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD).</div><div>Asthma is more prevalent in women, whereas COPD severity is rising among female patients. Sex influences the response to bronchodilators, inhaled corticosteroids (ICS), and combination therapies. Studies suggest that men exhibit a greater response to β<sub>2</sub>-adrenoceptor agonists and sex differences in muscarinic acetylcholine receptor (mAChR) expression may influence bronchodilator response to muscarinic antagonists. Moreover, women display stronger immune responses and higher corticosteroid receptor expression, potentially modulating the efficacy of ICS. Women are also more likely to experience adverse drug reactions and face challenges in correct inhaler device use, impacting treatment adherence and clinical outcomes. Despite these differences between men and women, sex-specific approaches remain insufficiently integrated into clinical practice. Addressing sex disparities in pharmacotherapy is crucial to optimize treatment strategies. Further research is needed to elucidate sex-related differences and incorporate them into evidence-based guidelines for asthma and COPD management.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100234"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-04-05DOI: 10.1016/j.crphar.2025.100218
Rowshne Jahan, Ziaul Huq
Background
Severe allergic asthma (SAA) requires high-dose inhaled corticosteroids and additional medications. It poses a substantial health and financial burden. Omalizumab, an antibody that targets IgE, has improved symptoms and quality of life in severe allergic asthma (SAA) patients. Its impact in Bangladeshi patients is unknown, and this study aimed to evaluate its effectiveness in improving lung function in severe allergic asthma (SAA) patients.
Methods
This single-centre, real-world study aimed to assess omalizumab's effectiveness in 131 Bangladeshi patients with SAA. Information regarding demographics, BMI, and IgE levels, were collected from patients >12 years with poorly controlled SAA before and 3 months after omalizumab treatment. Pulmonary function tests (PFTs), including Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 s (FEV1 %), FEV1/FVC (%), and Fractional Exhaled Nitric Oxide (FeNO), were performed according to established guidelines. A structured questionnaire was used for data collection. Ethical measures were taken in accordance with the current Declaration of Helsinki.
Results
The mean age of study population was 42.7 ± 16.15 (SD) years with majority being female (67.9 %). The mean BMI and IgE level was 28 ± 5.37 kg/m2 and 594.3 ± 679.9 IU/mL respectively. The mean baseline FVC, FEV1 and FEV1/FVC ratio was 63.5 % ± 19.2, 61.3 % ± 21.8 and 80.4 % ± 12.6 respectively. The mean post-omalizumab FVC, FEV1 and FEV1/FVC ratio was 72.5 % ± 25.6, 68.3 % ± 28.2 and 79.1 % ± 13.8 respectively. The FeNO reading revealed that number of patients with <25 ppb reading increased post omalizumab treatment (70.2 % vs 84 %).FEV1 expressed was significantly higher in patients post-omalizumab treatment than at the baseline (p = 0.019) and percentage of patients with FEV1 below the predicted 50 % was higher at baseline compared to after omalizumab treatment (31.3 % vs 23.7 %). Similarly, the FVC was significantly higher post-omalizumab treatment compared to baseline (p = 0.001). The FEV1/FVC ratio was not significantly different post omalizumab treatment (p = 0.758).
Conclusion
Our study finding have suggested that omalizumab as add on therapy achieved an adequate asthma control in patients with severe allergic asthma.
{"title":"Real-world clinical utility (effectiveness) of omalizumab as add-on therapy in patient with difficult-to-treat severe allergic asthma","authors":"Rowshne Jahan, Ziaul Huq","doi":"10.1016/j.crphar.2025.100218","DOIUrl":"10.1016/j.crphar.2025.100218","url":null,"abstract":"<div><h3>Background</h3><div>Severe allergic asthma (SAA) requires high-dose inhaled corticosteroids and additional medications. It poses a substantial health and financial burden. Omalizumab, an antibody that targets IgE, has improved symptoms and quality of life in severe allergic asthma (SAA) patients. Its impact in Bangladeshi patients is unknown, and this study aimed to evaluate its effectiveness in improving lung function in severe allergic asthma (SAA) patients.</div></div><div><h3>Methods</h3><div>This single-centre, real-world study aimed to assess omalizumab's effectiveness in 131 Bangladeshi patients with SAA. Information regarding demographics, BMI, and IgE levels, were collected from patients >12 years with poorly controlled SAA before and 3 months after omalizumab treatment. Pulmonary function tests (PFTs), including Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 s (FEV1 %), FEV1/FVC (%), and Fractional Exhaled Nitric Oxide (FeNO), were performed according to established guidelines. A structured questionnaire was used for data collection. Ethical measures were taken in accordance with the current Declaration of Helsinki.</div></div><div><h3>Results</h3><div>The mean age of study population was 42.7 ± 16.15 (SD) years with majority being female (67.9 %). The mean BMI and IgE level was 28 ± 5.37 kg/m<sup>2</sup> and 594.3 ± 679.9 IU/mL respectively. The mean baseline FVC, FEV<sub>1</sub> and FEV<sub>1</sub>/FVC ratio was 63.5 % ± 19.2, 61.3 % ± 21.8 and 80.4 % ± 12.6 respectively. The mean post-omalizumab FVC, FEV<sub>1</sub> and FEV<sub>1</sub>/FVC ratio was 72.5 % ± 25.6, 68.3 % ± 28.2 and 79.1 % ± 13.8 respectively. The FeNO reading revealed that number of patients with <25 ppb reading increased post omalizumab treatment (70.2 % vs 84 %).FEV<sub>1</sub> expressed was significantly higher in patients post-omalizumab treatment than at the baseline (p = 0.019) and percentage of patients with FEV<sub>1</sub> below the predicted 50 % was higher at baseline compared to after omalizumab treatment (31.3 % vs 23.7 %). Similarly, the FVC was significantly higher post-omalizumab treatment compared to baseline (p = 0.001). The FEV<sub>1</sub>/FVC ratio was not significantly different post omalizumab treatment (p = 0.758).</div></div><div><h3>Conclusion</h3><div>Our study finding have suggested that omalizumab as add on therapy achieved an adequate asthma control in patients with severe allergic asthma.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100218"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The multidrug-resistant fungal species Candida auris has drawn attention from across the world due to its capacity to elude traditional therapies and flourish in medical environments. Its resilience, which includes biofilm development and efflux-mediated drug resistance, highlighted the need for novel antifungal approaches. Despite advancements in antifungal therapeutics, the rising prevalence of resistance and limited antifungal arsenal demand ongoing research into novel and more effective treatments. To tackle this rising issue, the available literature suggests several approaches. Among those, the use of synthetic compounds (SCs) appears as first-line option. However, to prove the efficacy of these SCs against C. auris a complete coverage is still elusive in a single study. Thus, in this integrative review, we aimed to summarize the anti-C. auris SCs that are reported in literature. About 47 articles were included in this review using predefined selection criteria. Data were extracted for detailed reviews from PubMed, Google scholar and Science direct. All the included studies tested antifungal activities of the SCs and evaluated their mode of actions. These data highlighted diverse modes of action such as perturbation of biofilm formation, disruption of cell wall and organelles, inhibition of efflux and generation of reactive oxygen species to name few. Taken together, SCs represent viable candidates for effective antifungal treatment. The information gathered in the present study emphasizes the need for further investigations, including preclinical studies and clinical trials, to evaluate the therapeutic potential of these agents against C. auris.
{"title":"Unveiling the mechanisms of synthetic compounds against Candida auris: An integrative review","authors":"Yamini Saini , Zeeshan Fatima , Muriel Billamboz , Saif Hameed","doi":"10.1016/j.crphar.2025.100231","DOIUrl":"10.1016/j.crphar.2025.100231","url":null,"abstract":"<div><div>The multidrug-resistant fungal species <em>Candida auris</em> has drawn attention from across the world due to its capacity to elude traditional therapies and flourish in medical environments. Its resilience, which includes biofilm development and efflux-mediated drug resistance, highlighted the need for novel antifungal approaches. Despite advancements in antifungal therapeutics, the rising prevalence of resistance and limited antifungal arsenal demand ongoing research into novel and more effective treatments. To tackle this rising issue, the available literature suggests several approaches. Among those, the use of synthetic compounds (SCs) appears as first-line option. However, to prove the efficacy of these SCs against <em>C. auris</em> a complete coverage is still elusive in a single study. Thus, in this integrative review, we aimed to summarize the anti-<em>C. auris</em> SCs that are reported in literature. About 47 articles were included in this review using predefined selection criteria. Data were extracted for detailed reviews from PubMed, Google scholar and Science direct. All the included studies tested antifungal activities of the SCs and evaluated their mode of actions. These data highlighted diverse modes of action such as perturbation of biofilm formation, disruption of cell wall and organelles, inhibition of efflux and generation of reactive oxygen species to name few. Taken together, SCs represent viable candidates for effective antifungal treatment. The information gathered in the present study emphasizes the need for further investigations, including preclinical studies and clinical trials, to evaluate the therapeutic potential of these agents against <em>C. auris</em>.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100231"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inflammation plays a significant role in cancer progression. Chemopreventive strategies against cellular response to pro-inflammatory cues may therefore contribute to inhibit the acquisition of an invasive phenotype. 1,3,6-Tri-O-Galloyl-β-D-Glucose (β-TGG) is a type of gallotannin naturally found in plants like Paeonia lactiflora and Terminalia chebula. Unfortunately, the overall yields of β-TGG extraction require complex purification protocols from plant sources and are relatively low. Here, a new synthetic α-anomer of TGG (α-TGG) was characterized for anti-inflammatory and anticancer biological properties. In vitro pro-inflammatory and epithelial-to-mesenchymal transition (EMT) cues, triggered by phorbol 12-myristate 13-acetate (PMA), concanavalin A (ConA), tumor necrosis factor (TNF) α, and transforming growth factor (TGF) β, were used to screen α-TGG in two highly aggressive human cancer cell models, namely the U87 glioblastoma and the MDA-MB-231 triple-negative breast cancer (TNBC)-derived cells. α-TGG dose-dependently inhibited ConA-mediated activation of the latent matrix metalloproteinase pro-MMP-2 into its active MMP-2 form as well as the ConA- and PMA-mediated cyclooxygenase (COX)-2 expression, two biomarkers of inflammation, in U87 cells. In MDA-MB-231, α-TGG inhibited PMA- and TNFα-mediated induction of pro-MMP-9, a marker of inflammation and invasive phenotype. Finally, in both cell lines, α-TGG further inhibited TGFβ-induced chemotaxis, as well as TGFβ-induced Smad2 phosphorylation and Snail expression, crucial upstream signaling pathway and downstream biomarkers associated with EMT. Collectively, we confirm that α-TGG retained potent anti-inflammatory and anti-invasive pharmacological properties which support its chemopreventive potential.
炎症在癌症进展中起着重要作用。因此，针对细胞对促炎线索的反应的化学预防策略可能有助于抑制侵入性表型的获得。1,3,6-三- o -没食子酰-β- d -葡萄糖（β-TGG）是一种天然存在于芍药和chebula等植物中的没食子酰素。不幸的是，β-TGG提取的总体产量需要复杂的植物源纯化方案，并且相对较低。本文合成了一种新的TGG α-异头物（α-TGG），具有抗炎和抗癌的生物学特性。采用体外促炎和上皮-间质转化（EMT）信号，分别由phorbol 12-肉豆肉酸13-乙酸酯（PMA）、魔豆蛋白A （ConA）、肿瘤坏死因子(TNF) α和转化生长因子(TGF) β触发，在两种高侵袭性人肿瘤细胞模型(U87胶质母细胞瘤和MDA-MB-231三阴性乳腺癌（TNBC）来源细胞中筛选α- tgg。α-TGG剂量依赖性地抑制了ConA介导的潜在基质金属蛋白酶pro-MMP-2向活性MMP-2形式的激活，以及ConA-和pma介导的两种炎症生物标志物环氧化酶(COX)-2的表达。在MDA-MB-231中，α-TGG抑制PMA-和tnf - α介导的促mmp -9的诱导，促mmp -9是炎症和侵袭表型的标志。最后，在这两种细胞系中，α-TGG进一步抑制tgf β诱导的趋化性，以及tgf β诱导的Smad2磷酸化和Snail表达，这是与EMT相关的重要上游信号通路和下游生物标志物。总的来说，我们证实α-TGG保留了有效的抗炎和抗侵袭药理特性，这支持了其化学预防潜力。
{"title":"Probing into the chemopreventive properties of synthetic 1,3,6-tri-O-galloyl-α-D-glucose (α-TGG) against glioblastoma and triple-negative breast cancer-derived cell models","authors":"Carolane Veilleux , Jihane Khalifa , Alain Zgheib , Angélique Sabaoth Konan , Roger Gaudreault , Borhane Annabi","doi":"10.1016/j.crphar.2025.100219","DOIUrl":"10.1016/j.crphar.2025.100219","url":null,"abstract":"<div><div>Inflammation plays a significant role in cancer progression. Chemopreventive strategies against cellular response to pro-inflammatory cues may therefore contribute to inhibit the acquisition of an invasive phenotype. 1,3,6-Tri-O-Galloyl-β-D-Glucose (β-TGG) is a type of gallotannin naturally found in plants like <em>Paeonia lactiflora</em> and <em>Terminalia chebula.</em> Unfortunately, the overall yields of β-TGG extraction require complex purification protocols from plant sources and are relatively low. Here, a new synthetic α-anomer of TGG (α-TGG) was characterized for anti-inflammatory and anticancer biological properties. <em>In vitro</em> pro-inflammatory and epithelial-to-mesenchymal transition (EMT) cues, triggered by phorbol 12-myristate 13-acetate (PMA), concanavalin A (ConA), tumor necrosis factor (TNF) α, and transforming growth factor (TGF) β, were used to screen α-TGG in two highly aggressive human cancer cell models, namely the U87 glioblastoma and the MDA-MB-231 triple-negative breast cancer (TNBC)-derived cells. α-TGG dose-dependently inhibited ConA-mediated activation of the latent matrix metalloproteinase pro-MMP-2 into its active MMP-2 form as well as the ConA- and PMA-mediated cyclooxygenase (COX)-2 expression, two biomarkers of inflammation, in U87 cells. In MDA-MB-231, α-TGG inhibited PMA- and TNFα-mediated induction of pro-MMP-9, a marker of inflammation and invasive phenotype. Finally, in both cell lines, α-TGG further inhibited TGFβ-induced chemotaxis, as well as TGFβ-induced Smad2 phosphorylation and Snail expression, crucial upstream signaling pathway and downstream biomarkers associated with EMT. Collectively, we confirm that α-TGG retained potent anti-inflammatory and anti-invasive pharmacological properties which support its chemopreventive potential.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100219"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784989","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}
Pub Date : 2025-01-01Epub Date: 2025-07-03DOI: 10.1016/j.crphar.2025.100227
Maria João Ferreira , Sarah Colombani , Albin Bernardin , Alain Lacampagne , Jean-Luc Pasquié , Pedro F. Costa , Benoit Charlot , Albano C. Meli
The neuro-cardiac junction is involved in many pathological conditions in humans, but no model currently allows translational studies to investigate its role. Animal models fail to accurately represent this interaction. This review explores the role of microfluidic technologies in advancing organ-on-chip systems that simulate neuro-cardiac interactions in a controlled environment. By offering precise control over cellular environments, microfluidic platforms significantly enhance the modeling of dynamic cardiac-neural cell interactions. These systems allow the development of more accurate and functional neuro-cardiac junctions, vital for investigating cardiovascular diseases and the neuronal impact in these pathologies. While traditional animal models and co-culture techniques have their merits, they are limited in replicating human-specific physiology. Recent innovations in microfluidics, in combination with human-induced pluripotent stem cell technology, provide more physiologically relevant models and address ethical concerns regarding animal use. This review emphasizes the potential of these advanced microfluidic models in improving disease modeling, drug screening, and therapeutic strategies, ultimately advancing personalized medicine.
{"title":"Advancing organ-on-chip systems: the role of microfluidics in neuro-cardiac research","authors":"Maria João Ferreira , Sarah Colombani , Albin Bernardin , Alain Lacampagne , Jean-Luc Pasquié , Pedro F. Costa , Benoit Charlot , Albano C. Meli","doi":"10.1016/j.crphar.2025.100227","DOIUrl":"10.1016/j.crphar.2025.100227","url":null,"abstract":"<div><div>The neuro-cardiac junction is involved in many pathological conditions in humans, but no model currently allows translational studies to investigate its role. Animal models fail to accurately represent this interaction. This review explores the role of microfluidic technologies in advancing organ-on-chip systems that simulate neuro-cardiac interactions in a controlled environment. By offering precise control over cellular environments, microfluidic platforms significantly enhance the modeling of dynamic cardiac-neural cell interactions. These systems allow the development of more accurate and functional neuro-cardiac junctions, vital for investigating cardiovascular diseases and the neuronal impact in these pathologies. While traditional animal models and co-culture techniques have their merits, they are limited in replicating human-specific physiology. Recent innovations in microfluidics, in combination with human-induced pluripotent stem cell technology, provide more physiologically relevant models and address ethical concerns regarding animal use. This review emphasizes the potential of these advanced microfluidic models in improving disease modeling, drug screening, and therapeutic strategies, ultimately advancing personalized medicine.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100227"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144572190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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