Pub Date : 2025-12-10DOI: 10.1016/j.ejps.2025.107408
Mandeep Kaur Marwah , Lissette Sanchez-Aranguren , Hala Shokr , Mohamad Anas Al Tahan , Keqing Wang , Shakil Ahmad
Hydrogen sulphide (H2S), is a well described essential physiological molecule that is finely balanced to maintain cellular functions. Considering its important biological roles, H2S has promising therapeutic potential resulting in the development of many H2S donors. Such donors have proved to have therapeutic benefit in cognitive pathways, inflammation, reproduction, and the regulation of blood pressure. However, controlled delivery and targeted administration of this reactive and hazardous gas are necessary yet challenging due to its rapid diffusivity, and toxicity at high doses. Drug delivery systems are vital for the effective administration of many active pharmaceutical excipients, and H2S donors stands to benefit significantly from the tuneable physical, chemical, and pharmacokinetic properties of various formulation systems. To date, few studies have focused on the formulation and delivery aspects of H2S and its donors. Instead, H2S usually is administered either by inhalation or via site-specific injections of donor solution. Whilst therapeutic benefit has been observed following such administration, these are not patient friendly solutions. This review focuses on highlighting the advances in H2S donor formulations and their ability in sustaining the release of H2S as well as improving drug targeting.
{"title":"Advancing therapeutics with targeted formulations of hydrogen sulphide donors","authors":"Mandeep Kaur Marwah , Lissette Sanchez-Aranguren , Hala Shokr , Mohamad Anas Al Tahan , Keqing Wang , Shakil Ahmad","doi":"10.1016/j.ejps.2025.107408","DOIUrl":"10.1016/j.ejps.2025.107408","url":null,"abstract":"<div><div>Hydrogen sulphide (H<sub>2</sub>S), is a well described essential physiological molecule that is finely balanced to maintain cellular functions. Considering its important biological roles, H<sub>2</sub>S has promising therapeutic potential resulting in the development of many H<sub>2</sub>S donors. Such donors have proved to have therapeutic benefit in cognitive pathways, inflammation, reproduction, and the regulation of blood pressure. However, controlled delivery and targeted administration of this reactive and hazardous gas are necessary yet challenging due to its rapid diffusivity, and toxicity at high doses. Drug delivery systems are vital for the effective administration of many active pharmaceutical excipients, and H<sub>2</sub>S donors stands to benefit significantly from the tuneable physical, chemical, and pharmacokinetic properties of various formulation systems. To date, few studies have focused on the formulation and delivery aspects of H<sub>2</sub>S and its donors. Instead, H<sub>2</sub>S usually is administered either by inhalation or via site-specific injections of donor solution. Whilst therapeutic benefit has been observed following such administration, these are not patient friendly solutions. This review focuses on highlighting the advances in H<sub>2</sub>S donor formulations and their ability in sustaining the release of H<sub>2</sub>S as well as improving drug targeting.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107408"},"PeriodicalIF":4.7,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735723","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}
Pub Date : 2025-12-10DOI: 10.1016/j.ejps.2025.107406
Yi Liu , Guiyun Song , Daniel Banov , Jennifer Denison , Courtaney Davis , Kendice Ip
This study aims to compare the single-dose pharmacokinetic profiles of semaglutide administered via sublingual, oral, and injectable routes in Sprague–Dawley rats. Semaglutide was delivered sublingually in a proprietary anhydrous suspension vehicle. Rats were randomized into five groups and received the following treatments: subcutaneous injection (0.011 mg/kg), sublingual suspension (1 mg/kg, prepared from either commercial tablets or peptide powder), and oral tablets (1 mg/kg and 20 mg/kg). Semaglutide was detectable in plasma within 2 minutes post-dosing in all groups except the oral 1 mg/kg group. Sublingual administration demonstrated lower variability in plasma concentrations compared to oral dosing. At 1 mg/kg, the sublingual route achieved a significantly higher area under the curve (AUC) than oral (82.53 vs.15.08 ng*h/ml, p=0.004), indicating improved bioavailability. The maximum plasma concentration (Cmax) was reached within 30 minutes for oral and sublingual routes, and at 8 hours for subcutaneous injection. The relative bioavailability was 0.06% for oral 1 mg/kg, 0.16% for oral 20 mg/kg, and 0.34% and 0.29% for sublingual 1 mg/kg using tablets or powder, respectively. No significant difference in AUC was observed between sublingual semaglutide prepared from oral tablets versus powder. These results highlight the potential of sublingual delivery of semaglutide and suggest this route may improve absorption while reducing variability. This proof-of-concept study supports further development of sublingual semaglutide formulations and pharmacokinetics research in humans.
{"title":"Single-dose pharmacokinetics of sublingual semaglutide in rats","authors":"Yi Liu , Guiyun Song , Daniel Banov , Jennifer Denison , Courtaney Davis , Kendice Ip","doi":"10.1016/j.ejps.2025.107406","DOIUrl":"10.1016/j.ejps.2025.107406","url":null,"abstract":"<div><div>This study aims to compare the single-dose pharmacokinetic profiles of semaglutide administered via sublingual, oral, and injectable routes in Sprague–Dawley rats. Semaglutide was delivered sublingually in a proprietary anhydrous suspension vehicle. Rats were randomized into five groups and received the following treatments: subcutaneous injection (0.011 mg/kg), sublingual suspension (1 mg/kg, prepared from either commercial tablets or peptide powder), and oral tablets (1 mg/kg and 20 mg/kg). Semaglutide was detectable in plasma within 2 minutes post-dosing in all groups except the oral 1 mg/kg group. Sublingual administration demonstrated lower variability in plasma concentrations compared to oral dosing. At 1 mg/kg, the sublingual route achieved a significantly higher area under the curve (AUC) than oral (82.53 <em>vs.</em>15.08 ng*h/ml, <em>p</em>=0.004), indicating improved bioavailability. The maximum plasma concentration (C<sub>max</sub>) was reached within 30 minutes for oral and sublingual routes, and at 8 hours for subcutaneous injection. The relative bioavailability was 0.06% for oral 1 mg/kg, 0.16% for oral 20 mg/kg, and 0.34% and 0.29% for sublingual 1 mg/kg using tablets or powder, respectively. No significant difference in AUC was observed between sublingual semaglutide prepared from oral tablets <em>versus</em> powder. These results highlight the potential of sublingual delivery of semaglutide and suggest this route may improve absorption while reducing variability. This proof-of-concept study supports further development of sublingual semaglutide formulations and pharmacokinetics research in humans.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107406"},"PeriodicalIF":4.7,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735623","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}
Pub Date : 2025-12-09DOI: 10.1016/j.ejps.2025.107407
Ya-Min Liu , Wei Huang , Yong-Zhe Tang , Hai Zhang , Sheng-Ying Qin , Jin Zhang , Jun-Wei Fan , Rui-Zhuo Ouyang , Hai-Ou Yang , Xiao-Qing Zhang
Background
Docetaxel is a first-line chemotherapy drug for breast cancer and is traditionally dosed based on body surface area (BSA). However, this method often leads to significant inter-patient variability and a high incidence of adverse drug reactions (ADRs). Therapeutic drug monitoring (TDM) offers a personalized dosing approach that may improve drug safety and efficacy. This study aimed to evaluate the clinical and pharmacoeconomic benefits of TDM-guided dosing compared to traditional BSA-based dosing in breast cancer patients receiving docetaxel-based chemotherapy.
Methods
A randomized controlled study was conducted at the Department of Breast Surgery, IPMCH, from October 2022 to July 2024. A total of 208 breast cancer patients were enrolled and randomly assigned to two groups: the BSA group (n = 104) and the TDM-guided pharmacokinetics (PK) group (n = 104). Adverse drug reactions—including hematological, gastrointestinal, skin, neurotoxic, and cardiotoxic events—were monitored and compared between groups. Liver function markers (ALT, AST, ALP) and pharmacoeconomic data (treatment-related costs) were also assessed. Statistical analyses included univariate and interaction models to evaluate the impact of dosing strategy on ADRs and costs.
Results
Patients in the TDM-guided PK group exhibited significantly lower levels of ALT, AST, and ALP, indicating reduced hepatic toxicity. Gastrointestinal ADRs—including nausea, diarrhea, and constipation—were less frequent and less severe in the PK group compared to the BSA group. Overall, the incidence and severity of ADRs were markedly reduced in the PK group. Pharmacoeconomic analysis demonstrated consistently lower treatment-related costs in the PK group. Both univariate and interaction analyses confirmed the clinical and economic benefits of TDM-guided dosing.
Conclusion
TDM-guided docetaxel dosing significantly reduced ADRs and improved cost efficiency in breast cancer chemotherapy. These findings support the implementation of TDM as a superior strategy to traditional BSA-based dosing, with potential to enhance both patient safety and healthcare resource utilization.
{"title":"Individualized dosing strategies in breast cancer chemotherapy: Evidence for therapeutic drug monitoring-guided docetaxel treatment","authors":"Ya-Min Liu , Wei Huang , Yong-Zhe Tang , Hai Zhang , Sheng-Ying Qin , Jin Zhang , Jun-Wei Fan , Rui-Zhuo Ouyang , Hai-Ou Yang , Xiao-Qing Zhang","doi":"10.1016/j.ejps.2025.107407","DOIUrl":"10.1016/j.ejps.2025.107407","url":null,"abstract":"<div><h3>Background</h3><div>Docetaxel is a first-line chemotherapy drug for breast cancer and is traditionally dosed based on body surface area (BSA). However, this method often leads to significant inter-patient variability and a high incidence of adverse drug reactions (ADRs). Therapeutic drug monitoring (TDM) offers a personalized dosing approach that may improve drug safety and efficacy. This study aimed to evaluate the clinical and pharmacoeconomic benefits of TDM-guided dosing compared to traditional BSA-based dosing in breast cancer patients receiving docetaxel-based chemotherapy.</div></div><div><h3>Methods</h3><div>A randomized controlled study was conducted at the Department of Breast Surgery, IPMCH, from October 2022 to July 2024. A total of 208 breast cancer patients were enrolled and randomly assigned to two groups: the BSA group (<em>n</em> = 104) and the TDM-guided pharmacokinetics (PK) group (<em>n</em> = 104). Adverse drug reactions—including hematological, gastrointestinal, skin, neurotoxic, and cardiotoxic events—were monitored and compared between groups. Liver function markers (ALT, AST, ALP) and pharmacoeconomic data (treatment-related costs) were also assessed. Statistical analyses included univariate and interaction models to evaluate the impact of dosing strategy on ADRs and costs.</div></div><div><h3>Results</h3><div>Patients in the TDM-guided PK group exhibited significantly lower levels of ALT, AST, and ALP, indicating reduced hepatic toxicity. Gastrointestinal ADRs—including nausea, diarrhea, and constipation—were less frequent and less severe in the PK group compared to the BSA group. Overall, the incidence and severity of ADRs were markedly reduced in the PK group. Pharmacoeconomic analysis demonstrated consistently lower treatment-related costs in the PK group. Both univariate and interaction analyses confirmed the clinical and economic benefits of TDM-guided dosing.</div></div><div><h3>Conclusion</h3><div>TDM-guided docetaxel dosing significantly reduced ADRs and improved cost efficiency in breast cancer chemotherapy. These findings support the implementation of TDM as a superior strategy to traditional BSA-based dosing, with potential to enhance both patient safety and healthcare resource utilization.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107407"},"PeriodicalIF":4.7,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741614","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}
Pub Date : 2025-12-08DOI: 10.1016/j.ejps.2025.107405
Sergi Coll , Claudia Bressan , Núria Monfort , Ana Aldea-Perona , Marcel·lí Carbó , Rosa Ventura
Dexamethasone (DEX) is prohibited in sports competitions when administered by all injectable, oral or rectal routes, and is permitted at all times when administered by all other routes. The present work aimed to assess the urinary excretion profile of DEX after single and multiple oral administrations to verify the suitability of the new minimum reporting level (MRL) of 60 ng/mL established by the World Anti-Doping Agency to distinguish allowed and prohibited administrations. Moreover, the minimum washout period of three days established for out-of-competition treatments with oral glucocorticoids will be evaluated.
DEX was administered to healthy volunteers using two different oral treatments: single administration (4 mg, n = 8 male volunteers) and multiple administrations (2 mg/12 h for 5 days, n = 8 male volunteers). Urine and plasma samples collected before and after administration were analysed using liquid chromatography-tandem mass spectrometry. DEX and 6β‑hydroxy-DEX, were the predominant compounds detected in urine, with peak urinary excretion observed within the first 4 h post-dose. DEX concentrations exceeded the new MRL mainly within 12 h after a single dose, with one volunteer showing levels above this threshold up to 24–36 h. In the multiple-dose study, most of the DEX concentrations remained above 60 ng/mL after the second dose and throughout the dosing period and declined quickly after the final dose. Plasma DEX kinetics was defined by an open bicompartmental model with a first order oral absorption. DEX was detectable up to 48 h post-administration. In the multiple dose study, the steady-state concentrations were reached soon after the first dose, and DEX showed no evidence of accumulation. CORT levels decreased rapidly after both single and multiple administrations due to suppression of the hypothalamic-pituitary-adrenal axis. Recovery times varied among volunteers.
The MRL of 60 ng/mL proved appropriate for distinguishing permitted from prohibited use with a 3-day washout, though further studies on non-systemic routes are recommended to refine sensitivity.
{"title":"Pharmacokinetic profile of dexamethasone in urine and plasma after single and multiple oral administration: Relevance to doping controls","authors":"Sergi Coll , Claudia Bressan , Núria Monfort , Ana Aldea-Perona , Marcel·lí Carbó , Rosa Ventura","doi":"10.1016/j.ejps.2025.107405","DOIUrl":"10.1016/j.ejps.2025.107405","url":null,"abstract":"<div><div>Dexamethasone (DEX) is prohibited in sports competitions when administered by all injectable, oral or rectal routes, and is permitted at all times when administered by all other routes. The present work aimed to assess the urinary excretion profile of DEX after single and multiple oral administrations to verify the suitability of the new minimum reporting level (MRL) of 60 ng/mL established by the World Anti-Doping Agency to distinguish allowed and prohibited administrations. Moreover, the minimum washout period of three days established for out-of-competition treatments with oral glucocorticoids will be evaluated.</div><div>DEX was administered to healthy volunteers using two different oral treatments: single administration (4 mg, <em>n</em> = 8 male volunteers) and multiple administrations (2 mg/12 h for 5 days, <em>n</em> = 8 male volunteers). Urine and plasma samples collected before and after administration were analysed using liquid chromatography-tandem mass spectrometry. DEX and 6β‑hydroxy-DEX, were the predominant compounds detected in urine, with peak urinary excretion observed within the first 4 h post-dose. DEX concentrations exceeded the new MRL mainly within 12 h after a single dose, with one volunteer showing levels above this threshold up to 24–36 h. In the multiple-dose study, most of the DEX concentrations remained above 60 ng/mL after the second dose and throughout the dosing period and declined quickly after the final dose. Plasma DEX kinetics was defined by an open bicompartmental model with a first order oral absorption. DEX was detectable up to 48 h post-administration. In the multiple dose study, the steady-state concentrations were reached soon after the first dose, and DEX showed no evidence of accumulation. CORT levels decreased rapidly after both single and multiple administrations due to suppression of the hypothalamic-pituitary-adrenal axis. Recovery times varied among volunteers.</div><div>The MRL of 60 ng/mL proved appropriate for distinguishing permitted from prohibited use with a 3-day washout, though further studies on non-systemic routes are recommended to refine sensitivity.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107405"},"PeriodicalIF":4.7,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721647","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}
Pub Date : 2025-12-08DOI: 10.1016/j.ejps.2025.107403
Luca Morici , Ines Nikolic
Osteoarthritis is the most common degenerative joint disease affecting millions of people in the world and leading to disability. Currently, the only available treatments on the market are symptomatic therapies for pain and inflammation. There are no intra-articular drugs that can restore the cartilage matrix, also known as disease-modifying osteoarthritis drugs (DMOADs). This review focuses on all clinical trials of pro-anabolic DMOADs, which stimulate the regeneration of the cartilage matrix by inducing the differentiation of mesenchymal progenitors into chondrocytes, a process known as chondrogenesis. This review also discussed some pathways of chondrocytes, which boost the transcription of genes involved in the production of extracellular matrix components. Finally, the review also covers some implants in the commercial and clinical phases for cartilage repair.
{"title":"Update on clinical trials of intra-articular disease-modifying osteoarthritis drugs inducing cartilage regeneration","authors":"Luca Morici , Ines Nikolic","doi":"10.1016/j.ejps.2025.107403","DOIUrl":"10.1016/j.ejps.2025.107403","url":null,"abstract":"<div><div>Osteoarthritis is the most common degenerative joint disease affecting millions of people in the world and leading to disability. Currently, the only available treatments on the market are symptomatic therapies for pain and inflammation. There are no intra-articular drugs that can restore the cartilage matrix, also known as disease-modifying osteoarthritis drugs (DMOADs). This review focuses on all clinical trials of pro-anabolic DMOADs, which stimulate the regeneration of the cartilage matrix by inducing the differentiation of mesenchymal progenitors into chondrocytes, a process known as chondrogenesis. This review also discussed some pathways of chondrocytes, which boost the transcription of genes involved in the production of extracellular matrix components. Finally, the review also covers some implants in the commercial and clinical phases for cartilage repair.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107403"},"PeriodicalIF":4.7,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721731","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}
Pub Date : 2025-12-08DOI: 10.1016/j.ejps.2025.107404
Maha F. Emam , Elina Harju , Atte Junnila , Kirsi Mikkonen , Teemu Tomberg , Clare Strachan , Anssi-Pekka Karttunen , Leena Peltonen
The growing demand for personalized medicine requires adaptable dosage forms capable of addressing challenges associated with poorly soluble drugs. Cocrystals offer a powerful strategy to enhance solubility, while semi-solid extrusion (SSE) 3D printing enables flexible, patient-tailored manufacturing. This study establishes a systematic framework for developing oral fast-dissolving films (OFDFs) incorporating indomethacin–nicotinamide (IND–NIC) cocrystals using SSE 3D printing. Critical Material Attributes (CMAs), HPMC–glycerol base, sodium starch glycolate (SSG), and varying cocrystal loadings, were systematically adjusted to evaluate their influence on key ink and film Critical Quality Attributes (CQAs).
All inks displayed desirable shear-thinning behaviour, with IND–NIC cocrystals and SSG synergistically reinforcing the structural network for reliable extrusion and shape fidelity. Solid-state analyses (XRPD, DSC, PLM, Raman microscopy) confirmed preservation of the cocrystal form throughout ink preparation, printing, and short-term storage. The 3D printed OFDFs exhibited uniform thickness, weight, and drug content with minimal variability across batches, and displayed humidity-dependent mechanical behaviour that varied with cocrystal loading.
All formulations achieved rapid drug release, exceeding 80 % IND dissolution within 30 min. Dissolution profiles were consistent across cocrystal loadings and remained statistically equivalent for films printed from inks stored for up to 2 days, as well as for the 3-day redispersed ink, confirming that the structural reinforcement required for printability does not compromise rapid release performance.
Overall, this work provides mechanistic insight into the formulation–process–performance relationships governing SSE 3D printing of cocrystal-loaded OFDFs and highlights the potential of this green, low-temperature platform for decentralized, patient-centric manufacturing of fast-dissolving dosage forms.
{"title":"Mechanistic insights into semi-solid extrusion 3D printing of indomethacin-nicotinamide cocrystal-loaded oral fast-dissolving films","authors":"Maha F. Emam , Elina Harju , Atte Junnila , Kirsi Mikkonen , Teemu Tomberg , Clare Strachan , Anssi-Pekka Karttunen , Leena Peltonen","doi":"10.1016/j.ejps.2025.107404","DOIUrl":"10.1016/j.ejps.2025.107404","url":null,"abstract":"<div><div>The growing demand for personalized medicine requires adaptable dosage forms capable of addressing challenges associated with poorly soluble drugs. Cocrystals offer a powerful strategy to enhance solubility, while semi-solid extrusion (SSE) 3D printing enables flexible, patient-tailored manufacturing. This study establishes a systematic framework for developing oral fast-dissolving films (OFDFs) incorporating indomethacin–nicotinamide (IND–NIC) cocrystals using SSE 3D printing. Critical Material Attributes (CMAs), HPMC–glycerol base, sodium starch glycolate (SSG), and varying cocrystal loadings, were systematically adjusted to evaluate their influence on key ink and film Critical Quality Attributes (CQAs).</div><div>All inks displayed desirable shear-thinning behaviour, with IND–NIC cocrystals and SSG synergistically reinforcing the structural network for reliable extrusion and shape fidelity. Solid-state analyses (XRPD, DSC, PLM, Raman microscopy) confirmed preservation of the cocrystal form throughout ink preparation, printing, and short-term storage. The 3D printed OFDFs exhibited uniform thickness, weight, and drug content with minimal variability across batches, and displayed humidity-dependent mechanical behaviour that varied with cocrystal loading.</div><div>All formulations achieved rapid drug release, exceeding 80 % IND dissolution within 30 min. Dissolution profiles were consistent across cocrystal loadings and remained statistically equivalent for films printed from inks stored for up to 2 days, as well as for the 3-day redispersed ink, confirming that the structural reinforcement required for printability does not compromise rapid release performance.</div><div>Overall, this work provides mechanistic insight into the formulation–process–performance relationships governing SSE 3D printing of cocrystal-loaded OFDFs and highlights the potential of this green, low-temperature platform for decentralized, patient-centric manufacturing of fast-dissolving dosage forms.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107404"},"PeriodicalIF":4.7,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721582","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}
This study aimed to examine the relationship between Phosphodiesterase 4 (PDE4) and Aquaporin-5 (AQP5) under Lipopolysaccharide (LPS) induced-inflammatory condition.
Methods
Inflammatory Acute lung injury (ALI) was induced by intratracheal LPS (5 mg/kg) administration. Rolipram (intraperitoneal) was used as PDE4 inhibiting agent at three different doses (1, 3 and 5 mg/kg) in rat groups. 24 h after LPS administration lung tissues obtained and following analyses performed. AQP5, Phosphodiesterase 4D (PDE4D), Cyclic adenosine monophosphate (cAMP) levels were evaluated for determination of the relationship between these parameters. Also Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α), Nuclear factor kappa B (NF-κB), Mitogen-activated protein kinase (MAPK) levels were evaluated as ALI markers.
Results
LPS-induced ALI resulted in increased PDE4 enzyme and inflammatory marker levels (IL-6, TNF-α, NF-κB and MAPK) and decreased AQP5 and cAMP levels. Inhibition of PDE4 enzyme to increase cAMP levels by Rolipram resulted in increased AQP5 expression and decreased inflammatory condition and in lung tissues. These results were supported by histopathological and immunhistochemical results.
Conclusion
The fact that this study observed a decreases PDE4 expression and increases in AQP5 expression upon Rolipram administration might indicate a close relationship of these two parameters in inflammatory lung disease.
{"title":"The relationship between PDE4 and AQP5 in lung tissue under inflammatory conditions: An experimental study","authors":"Ayse Bozkurt , Zafer Bayraktutan , Erdem Toktay , Adem Kara , Zekai Halici , Elif Cadirci","doi":"10.1016/j.ejps.2025.107400","DOIUrl":"10.1016/j.ejps.2025.107400","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to examine the relationship between Phosphodiesterase 4 (PDE4) and Aquaporin-5 (AQP5) under Lipopolysaccharide (LPS) induced-inflammatory condition.</div></div><div><h3>Methods</h3><div>Inflammatory Acute lung injury (ALI) was induced by intratracheal LPS (5 mg/kg) administration. Rolipram (intraperitoneal) was used as PDE4 inhibiting agent at three different doses (1, 3 and 5 mg/kg) in rat groups. 24 h after LPS administration lung tissues obtained and following analyses performed. AQP5, Phosphodiesterase 4D (PDE4D), Cyclic adenosine monophosphate (cAMP) levels were evaluated for determination of the relationship between these parameters. Also Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α), Nuclear factor kappa B (NF-κB), Mitogen-activated protein kinase (MAPK) levels were evaluated as ALI markers.</div></div><div><h3>Results</h3><div>LPS-induced ALI resulted in increased PDE4 enzyme and inflammatory marker levels (IL-6, TNF-α, NF-κB and MAPK) and decreased AQP5 and cAMP levels. Inhibition of PDE4 enzyme to increase cAMP levels by Rolipram resulted in increased AQP5 expression and decreased inflammatory condition and in lung tissues. These results were supported by histopathological and immunhistochemical results.</div></div><div><h3>Conclusion</h3><div>The fact that this study observed a decreases PDE4 expression and increases in AQP5 expression upon Rolipram administration might indicate a close relationship of these two parameters in inflammatory lung disease.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107400"},"PeriodicalIF":4.7,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721652","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}
Pub Date : 2025-12-07DOI: 10.1016/j.ejps.2025.107399
Charles E. Amankwa , Biddut DebNath , Arlene Abraham , Olivia Young , Sudershan R Gondi , Michael J Forster , Ritu A. Shetty , Suchismita Acharya
Background
Cocaine- and methamphetamine (METH)-induced mitochondrial dysfunction and oxidative stress are key contributors to the neuropathology of psychostimulant addiction. These effects are often accompanied by epigenetic alterations, mitochondrial damage, and the accumulation of reactive oxygen species (ROS). Methionine synthase (MS) plays a critical role in epigenetic regulation and neuronal survival and may offer neuroprotection against psychostimulant-induced toxicity. We hypothesize that SA-31, a novel thiourea-based analog of TEMPOL, will attenuate cocaine or METH induced decrease in antioxidant, anti-inflammatory, and MS activities in neuronal cells.
Methods
SA-31 was synthesized and characterized via 1H NMR and mass spectrometry. Human SH-SY5Y dopaminergic neural cells were exposed to tert‑butyl hydrogen peroxide (TBHP), cocaine hydrochloride, or methamphetamine (METH), with or without co-treatment with SA-31 for 24 h. Cell viability was measured using MTT assays. MS activity, IL-1β, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase levels were assessed via ELISA. Mitochondrial function was evaluated using Seahorse-based oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) assays.
Results
SA-31 (10–100 µM) significantly protected cells from TBHP-, cocaine-, and METH-induced cytotoxicity. TBHP and METH reduced MS activity, which was significantly restored by SA-31. The compound also reversed cocaine-induced reductions in SOD, GPx, and catalase and lowered pro-inflammatory IL-1β levels. Additionally, SA-31 (1–100 µM) enhanced mitochondrial respiration and glycolytic activity.
Conclusion
These findings suggest that SA-31 confers neuroprotection by enhancing MS activity, upregulating antioxidant defenses, and improving mitochondrial function. Further studies in rodent models of addiction are planned to evaluate its therapeutic potential for psychostimulant use disorders and related neurodegenerative conditions.
{"title":"Protective effects of SA-31 in a psychostimulant-induced neurotoxicity model using SH-SY5Y cells","authors":"Charles E. Amankwa , Biddut DebNath , Arlene Abraham , Olivia Young , Sudershan R Gondi , Michael J Forster , Ritu A. Shetty , Suchismita Acharya","doi":"10.1016/j.ejps.2025.107399","DOIUrl":"10.1016/j.ejps.2025.107399","url":null,"abstract":"<div><h3>Background</h3><div>Cocaine- and methamphetamine (METH)-induced mitochondrial dysfunction and oxidative stress are key contributors to the neuropathology of psychostimulant addiction. These effects are often accompanied by epigenetic alterations, mitochondrial damage, and the accumulation of reactive oxygen species (ROS). Methionine synthase (MS) plays a critical role in epigenetic regulation and neuronal survival and may offer neuroprotection against psychostimulant-induced toxicity. We hypothesize that SA-31, a novel thiourea-based analog of TEMPOL, will attenuate cocaine or METH induced decrease in antioxidant, anti-inflammatory, and MS activities in neuronal cells.</div></div><div><h3>Methods</h3><div>SA-31 was synthesized and characterized via <sup>1</sup>H NMR and mass spectrometry. Human SH-SY5Y dopaminergic neural cells were exposed to tert‑butyl hydrogen peroxide (TBHP), cocaine hydrochloride, or methamphetamine (METH), with or without co-treatment with SA-31 for 24 h. Cell viability was measured using MTT assays. MS activity, IL-1β, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase levels were assessed via ELISA. Mitochondrial function was evaluated using Seahorse-based oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) assays.</div></div><div><h3>Results</h3><div>SA-31 (10–100 µM) significantly protected cells from TBHP-, cocaine-, and METH-induced cytotoxicity. TBHP and METH reduced MS activity, which was significantly restored by SA-31. The compound also reversed cocaine-induced reductions in SOD, GPx, and catalase and lowered pro-inflammatory IL-1β levels. Additionally, SA-31 (1–100 µM) enhanced mitochondrial respiration and glycolytic activity.</div></div><div><h3>Conclusion</h3><div>These findings suggest that SA-31 confers neuroprotection by enhancing MS activity, upregulating antioxidant defenses, and improving mitochondrial function. Further studies in rodent models of addiction are planned to evaluate its therapeutic potential for psychostimulant use disorders and related neurodegenerative conditions.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107399"},"PeriodicalIF":4.7,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713845","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}
Pub Date : 2025-12-06DOI: 10.1016/j.ejps.2025.107401
Malte Bøgh Senniksen , Justus Johann Lange , Wiebke Saal , Patrick O’Dwyer , Martin Kuentz , Brendan T. Griffin , Susanne Page , Jennifer Dressman , Nicole Wyttenbach
Poor aqueous solubility and thereby poor and/or variable bioavailability of drug candidates is frequently overcome by developing enabling formulations such as amorphous solid dispersions (ASDs). This study proposes a systematic, miniaturized approach to evaluate the ASD developability of an active pharmaceutical ingredient (API) based on i) assessment of glass forming ability ii) assessment of the supersaturation potential of the neat API by supersaturation/permeation testing, iii) selection of an appropriate ASD carrier system using high-throughput dissolution screening of ASD films and iv) performing high-throughput dissolution/permeation testing of ASD films. The model drug candidate, RO6897779, exhibited good glass forming ability. Eight pharmaceutical polymers (CAP, Eudragit® E, Eudragit® L100, HPMC 100LV, HPMCAS-M, PVP K25, PVP VA64, and Soluplus®) were screened as ASD carriers by high-throughput dissolution testing at drug loads of 20, 30 and 40 % [w/w]. Due to poor performance of the binary systems, ternary ASDs containing Soluplus® were prepared at surfactant loads of 4, 6 and 8 % [w/w] and subsequently, high-throughput dissolution/permeation studies were conducted on selected compositions. The composition containing RO6897779 at a drug load of 20 % in Soluplus®[w/w] with the addition of 6 % [w/w] SDS yielded the best performance, but was inferior to the permeation of supersaturated neat RO6897779. Further studies should be conducted to assess the ability of this four-step, miniaturized approach to predict optimal ASD formulations over a broad range of API physicochemical properties.
{"title":"High-throughput screening of amorphous solid dispersions: a systematic approach to enhance bioaccessibility of a poorly soluble drug","authors":"Malte Bøgh Senniksen , Justus Johann Lange , Wiebke Saal , Patrick O’Dwyer , Martin Kuentz , Brendan T. Griffin , Susanne Page , Jennifer Dressman , Nicole Wyttenbach","doi":"10.1016/j.ejps.2025.107401","DOIUrl":"10.1016/j.ejps.2025.107401","url":null,"abstract":"<div><div>Poor aqueous solubility and thereby poor and/or variable bioavailability of drug candidates is frequently overcome by developing enabling formulations such as amorphous solid dispersions (ASDs). This study proposes a systematic, miniaturized approach to evaluate the ASD developability of an active pharmaceutical ingredient (API) based on i) assessment of glass forming ability ii) assessment of the supersaturation potential of the neat API by supersaturation/permeation testing, iii) selection of an appropriate ASD carrier system using high-throughput dissolution screening of ASD films and iv) performing high-throughput dissolution/permeation testing of ASD films. The model drug candidate, RO6897779, exhibited good glass forming ability. Eight pharmaceutical polymers (CAP, Eudragit® E, Eudragit® L100, HPMC 100LV, HPMCAS-M, PVP K25, PVP VA64, and Soluplus®) were screened as ASD carriers by high-throughput dissolution testing at drug loads of 20, 30 and 40 % [w/w]. Due to poor performance of the binary systems, ternary ASDs containing Soluplus® were prepared at surfactant loads of 4, 6 and 8 % [w/w] and subsequently, high-throughput dissolution/permeation studies were conducted on selected compositions. The composition containing RO6897779 at a drug load of 20 % in Soluplus®[w/w] with the addition of 6 % [w/w] SDS yielded the best performance, but was inferior to the permeation of supersaturated neat RO6897779. Further studies should be conducted to assess the ability of this four-step, miniaturized approach to predict optimal ASD formulations over a broad range of API physicochemical properties.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107401"},"PeriodicalIF":4.7,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707092","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}
Pub Date : 2025-12-06DOI: 10.1016/j.ejps.2025.107402
Xiaoqing Zhuang , Jenni Virta , Heidi Liljenbäck , Lauri Paasonen , Anu J. Airaksinen , Anne Roivainen , Xiang-Guo Li
Nanofibrillar cellulose (NFC) hydrogel has emerged as a promising implantable material for therapeutic applications. In this study, the relatively longer-lived positron-emitting radionuclide zirconium-89 was chelated to the octadentate deferoxamine (DFO*)-conjugated NFC hydrogel ([89Zr]Zr-DFO*-NFC) to enable longitudinal monitoring of its in vivo fate using positron emission tomography techniques. Following subcutaneous implantation in healthy mice, [89Zr]Zr-DFO*-NFC retained radioactivity at the implant site for at least 14 days, with minimal signal detected in the kidneys, urinary bladder, and overlying skin. In contrast, mice receiving a control formulation of [89Zr]Zr-oxalate mixed with NFC hydrogel showed progressive accumulation of radioactivity in the bones, consistent with known [89Zr]Zr-oxalate distribution patterns, and only limited retention at the implant site by Day 7. These findings demonstrate that [89Zr]Zr-DFO*-NFC hydrogel implants exhibit high in vivo stability with negligible systemic release following subcutaneous implantation, supporting their potential use as safe and traceable biomaterial platforms.
{"title":"Longitudinal monitoring of nanofibrillar cellulose hydrogel medical implants in mice using positron emission tomography","authors":"Xiaoqing Zhuang , Jenni Virta , Heidi Liljenbäck , Lauri Paasonen , Anu J. Airaksinen , Anne Roivainen , Xiang-Guo Li","doi":"10.1016/j.ejps.2025.107402","DOIUrl":"10.1016/j.ejps.2025.107402","url":null,"abstract":"<div><div>Nanofibrillar cellulose (NFC) hydrogel has emerged as a promising implantable material for therapeutic applications. In this study, the relatively longer-lived positron-emitting radionuclide zirconium-89 was chelated to the octadentate deferoxamine (DFO*)-conjugated NFC hydrogel ([<sup>89</sup>Zr]Zr-DFO*-NFC) to enable longitudinal monitoring of its <em>in vivo</em> fate using positron emission tomography techniques. Following subcutaneous implantation in healthy mice, [<sup>89</sup>Zr]Zr-DFO*-NFC retained radioactivity at the implant site for at least 14 days, with minimal signal detected in the kidneys, urinary bladder, and overlying skin. In contrast, mice receiving a control formulation of [<sup>89</sup>Zr]Zr-oxalate mixed with NFC hydrogel showed progressive accumulation of radioactivity in the bones, consistent with known [<sup>89</sup>Zr]Zr-oxalate distribution patterns, and only limited retention at the implant site by Day 7. These findings demonstrate that [<sup>89</sup>Zr]Zr-DFO*-NFC hydrogel implants exhibit high <em>in vivo</em> stability with negligible systemic release following subcutaneous implantation, supporting their potential use as safe and traceable biomaterial platforms.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107402"},"PeriodicalIF":4.7,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707293","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}
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