Pub Date : 2024-07-20DOI: 10.1016/j.ejps.2024.106853
Although older people are the main users of oral medications, few studies are reported on the influence of advanced age on gastric emptying rate of non-caloric liquids. This study aimed at evaluating the gastric emptying of 240 ml water in healthy older and young adults in fasted and fed state conditions using the established method of salivary caffeine kinetics. The gastric emptying of water was evaluated in 12 healthy older volunteers (mean age: 73 ± 6 years) and 12 healthy younger volunteers (mean age: 25 ± 2 years) with the ingestion of a rapid disintegrating tablet containing 20 mg of 13C3-caffeine. The gastric emptying of water was assessed indirectly by calculating the AUC ratios of salivary caffeine concentrations in specific time segments. Comparison of the AUC ratios showed no statistically significant difference between young and older volunteers in both fasted and fed state conditions (p > 0.05). Advanced age itself seems to have no relevant effect on gastric emptying of water in either fasted or fed state conditions and the phenomenon of Magenstrasse appears to follow a similar pattern in healthy older adults as in healthy younger adults.
{"title":"Impact of advanced age on the gastric emptying of water under fasted and fed state conditions","authors":"","doi":"10.1016/j.ejps.2024.106853","DOIUrl":"10.1016/j.ejps.2024.106853","url":null,"abstract":"<div><p>Although older people are the main users of oral medications, few studies are reported on the influence of advanced age on gastric emptying rate of non-caloric liquids. This study aimed at evaluating the gastric emptying of 240 ml water in healthy older and young adults in fasted and fed state conditions using the established method of salivary caffeine kinetics. The gastric emptying of water was evaluated in 12 healthy older volunteers (mean age: 73 ± 6 years) and 12 healthy younger volunteers (mean age: 25 ± 2 years) with the ingestion of a rapid disintegrating tablet containing 20 mg of <sup>13</sup>C<sub>3</sub>-caffeine. The gastric emptying of water was assessed indirectly by calculating the AUC ratios of salivary caffeine concentrations in specific time segments. Comparison of the AUC ratios showed no statistically significant difference between young and older volunteers in both fasted and fed state conditions (<em>p</em> > 0.05). Advanced age itself seems to have no relevant effect on gastric emptying of water in either fasted or fed state conditions and the phenomenon of <em>Magenstrasse</em> appears to follow a similar pattern in healthy older adults as in healthy younger adults.</p></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0928098724001659/pdfft?md5=9a893a28c23fbd91944ee04fab745e7f&pid=1-s2.0-S0928098724001659-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-19DOI: 10.1016/j.ejps.2024.106856
Ulcerative colitis (UC) is a common gastrointestinal problem characterized by the mucosal injury primarily affecting the large intestine. Currently available therapies are not satisfactory as evidenced by high relapse rate and adverse effects. In this study we aimed to develop an effective drug delivery system using reactive oxygen species (ROS)-responsive thioketal nanoparticles (TKNP), to deliver tubastatin A, a potent HDAC6 inhibitor, to the inflamed colon in mice with ulcerative colitis (UC). TKNPs were synthesized by step-growth polymerization from an acetal exchange reaction while TUBA-TKNP was prepared using the single emulsion solvent evaporation technique. Our developed nanoparticle showed release of tubastatin A only in presence of ROS which is found to be highly present at the site of inflamed colon. Oral administration of TUBA-TKNP resulted in the higher accumulation of tubastatin A at the inflamed colon site and decreased the inflammation as evidenced by reduced infiltration of immune cells and decreased level of pro-inflammatory cytokines in TUBA-TKNP treated mice. In summary, our results show the successful localization of tubastatin A at the site of colon inflammation through TUBA-TKNP delivery, as well as resolution of clinical features of UC in mice.
溃疡性结肠炎(UC)是一种常见的胃肠道疾病,其特点是粘膜损伤,主要影响大肠。由于复发率高和不良反应多,目前可用的疗法并不令人满意。在这项研究中,我们旨在开发一种有效的给药系统,利用活性氧(ROS)反应型硫酮纳米颗粒(TKNP)将强效 HDAC6 抑制剂管他汀 A 送入溃疡性结肠炎(UC)小鼠的炎症结肠。TKNP 是通过缩醛交换反应的阶跃生长聚合反应合成的,而 TUBA-TKNP 则是通过单乳液溶剂蒸发技术制备的。我们开发的纳米粒子只有在存在 ROS 的情况下才会释放管他汀 A,而 ROS 在结肠发炎部位的存在率很高。口服 TUBA-TKNP 可使更多的管他汀 A 在结肠发炎部位积聚,并通过减少 TUBA-TKNP 治疗小鼠的免疫细胞浸润和降低促炎细胞因子水平来减轻炎症。总之,我们的研究结果表明,通过 TUBA-TKNP 递送,管他汀 A 成功地在结肠炎症部位定位,并缓解了小鼠 UC 的临床特征。
{"title":"ROS-responsive thioketal nanoparticles delivering system for targeted ulcerative colitis therapy with potent HDAC6 inhibitor, tubastatin A","authors":"","doi":"10.1016/j.ejps.2024.106856","DOIUrl":"10.1016/j.ejps.2024.106856","url":null,"abstract":"<div><p>Ulcerative colitis (UC) is a common gastrointestinal problem characterized by the mucosal injury primarily affecting the large intestine. Currently available therapies are not satisfactory as evidenced by high relapse rate and adverse effects. In this study we aimed to develop an effective drug delivery system using reactive oxygen species (ROS)-responsive thioketal nanoparticles (TKNP), to deliver tubastatin A, a potent HDAC6 inhibitor, to the inflamed colon in mice with ulcerative colitis (UC). TKNPs were synthesized by step-growth polymerization from an acetal exchange reaction while TUBA-TKNP was prepared using the single emulsion solvent evaporation technique. Our developed nanoparticle showed release of tubastatin A only in presence of ROS which is found to be highly present at the site of inflamed colon. Oral administration of TUBA-TKNP resulted in the higher accumulation of tubastatin A at the inflamed colon site and decreased the inflammation as evidenced by reduced infiltration of immune cells and decreased level of pro-inflammatory cytokines in TUBA-TKNP treated mice. In summary, our results show the successful localization of tubastatin A at the site of colon inflammation through TUBA-TKNP delivery, as well as resolution of clinical features of UC in mice.</p></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0928098724001684/pdfft?md5=5f3152d67291c4de48019010d6fc6767&pid=1-s2.0-S0928098724001684-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-19DOI: 10.1016/j.ejps.2024.106858
Protein therapeutics hold immense promise for treating a wide array of diseases. However, their efficacy is often compromised by rapid degradation and clearance. The synthetic smectite clay Laponite emerges as a promising candidate for their sustained delivery. Despite its unique properties allow to load and release proteins mitigating burst release and extending their effects, precise control over Laponite-protein interactions remains challenging since it depends on a complex interplay of factors whose implication is not fully understood yet. The aim of this review article is to shed light on this issue, providing a comprehensive discussion of the factors influencing protein loading and release, including the physicochemical properties of the nanoclay and proteins, pH, dispersion buffer, clay/protein concentration and Laponite degradation. Furthermore, we thoroughly revise the array of bioactive proteins that have been delivered from formulations containing the nanoclay, highlighting Laponite-polymer nanocomposite hydrogels, a promising avenue currently under extensive investigation.
{"title":"Laponite nanoclays for the sustained delivery of therapeutic proteins","authors":"","doi":"10.1016/j.ejps.2024.106858","DOIUrl":"10.1016/j.ejps.2024.106858","url":null,"abstract":"<div><p>Protein therapeutics hold immense promise for treating a wide array of diseases. However, their efficacy is often compromised by rapid degradation and clearance. The synthetic smectite clay Laponite emerges as a promising candidate for their sustained delivery. Despite its unique properties allow to load and release proteins mitigating burst release and extending their effects, precise control over Laponite-protein interactions remains challenging since it depends on a complex interplay of factors whose implication is not fully understood yet. The aim of this review article is to shed light on this issue, providing a comprehensive discussion of the factors influencing protein loading and release, including the physicochemical properties of the nanoclay and proteins, pH, dispersion buffer, clay/protein concentration and Laponite degradation. Furthermore, we thoroughly revise the array of bioactive proteins that have been delivered from formulations containing the nanoclay, highlighting Laponite-polymer nanocomposite hydrogels, a promising avenue currently under extensive investigation.</p></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0928098724001702/pdfft?md5=7566c70bfd7a85690741302dc1a81f53&pid=1-s2.0-S0928098724001702-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-18DOI: 10.1016/j.ejps.2024.106857
High-altitude polycythemia (HAPC) is a common chronic altitude disease caused by living in low-pressure and low-oxygen environment. At present, there is still no effective cure for HAPC. HIF-2α may play an important role in the development of HAPC in regulating the increased red blood cell excessively induced by HIF-EPO and the blood vessel formation induced by VEGF-VEGFR. Here, we established a rat HAPC model and treated it with the HIF-2α inhibitor PT2385. We mainly evaluated the therapeutic effect of PT2385 on HAPC rats by observing the changes in rat phenotype, tissue and organ damage, red blood cell and hemoglobin content, angiogenesis, lipid peroxidation reaction, and inflammatory factors. The results showed that PT2385 treatment improved the congestion phenotype characteristics, inhibited increased erythrocytes and hemoglobin, reduced blood vessel formation, lipid peroxidation, and inflammation, and reduced tissue and organ damage in HAPC rats. This study preliminarly explains the physiological, pathological, and immunological effects of PT2385 treatment for HAPC. It provides a new idea, a reliable experimental basis, and theoretical support for the clinical prevention and treatment of HAPC.
{"title":"Ameliorating effects of the HIF-2α inhibitor PT2385 on high-altitude polycythemia","authors":"","doi":"10.1016/j.ejps.2024.106857","DOIUrl":"10.1016/j.ejps.2024.106857","url":null,"abstract":"<div><p>High-altitude polycythemia (HAPC) is a common chronic altitude disease caused by living in low-pressure and low-oxygen environment. At present, there is still no effective cure for HAPC. HIF-2α may play an important role in the development of HAPC in regulating the increased red blood cell excessively induced by HIF-EPO and the blood vessel formation induced by VEGF-VEGFR. Here, we established a rat HAPC model and treated it with the HIF-2α inhibitor PT2385. We mainly evaluated the therapeutic effect of PT2385 on HAPC rats by observing the changes in rat phenotype, tissue and organ damage, red blood cell and hemoglobin content, angiogenesis, lipid peroxidation reaction, and inflammatory factors. The results showed that PT2385 treatment improved the congestion phenotype characteristics, inhibited increased erythrocytes and hemoglobin, reduced blood vessel formation, lipid peroxidation, and inflammation, and reduced tissue and organ damage in HAPC rats. This study preliminarly explains the physiological, pathological, and immunological effects of PT2385 treatment for HAPC. It provides a new idea, a reliable experimental basis, and theoretical support for the clinical prevention and treatment of HAPC.</p></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0928098724001696/pdfft?md5=88a94093cf20503cdeef7baad9fc3928&pid=1-s2.0-S0928098724001696-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-17DOI: 10.1016/j.ejps.2024.106855
Resveratrol (RES) has demonstrated advantages as anti-cancer, anti-inflammatory, blood sugar-lowering agent and as cardioprotective agent, among others. Despite RES therapeutic advantages its use in pharmaceutical applications is limited by its low oral bioavailability, mainly due to its poor water solubility. Formulation of poorly water-soluble compound as solid dispersion (SD) converts a crystalline into a more soluble in water amorphous drug. Lyophilization or freeze-drying is a process in which water, an organic solvent, or a co-solvent system is frozen, followed by its removal from the sample, initially by sublimation (primary drying) and then by desorption (secondary drying). This study aimed the development and optimization of a bulk freeze-drying cycle by critical process parameters assessment in each phase to prepare a RES third-generation SD, containing Eudragit E PO as hydrophilic polymer at 1:2 ratio, and Gelucire 44/14 as surfactant at 16 % (w/w) to RES, using a tert-butanol (TBA)/Acetate buffer pH 4.5 (75:25) co-solvent system. A RES third-generation SD with good appearance, not cracked, collapsed, or melted was prepared by an optimized and robust bulk lyophilization process. A physicochemical characterization confirmed the conversion of RES to the amorphous state in the SD and formulation stability after 1 month at 40 °C/75 % RH. Increased solubility and higher dissolution rate compared with pure RES were also obtained.
白藜芦醇(RES)具有抗癌、抗炎、降血糖和保护心脏等多种优势。尽管白藜芦醇具有治疗优势,但其口服生物利用度较低,这主要是由于其水溶性较差,因此限制了其在制药领域的应用。将水溶性较差的化合物配制成固体分散体(SD),可将结晶状药物转化为更易溶于水的无定形药物。冻干或冷冻干燥是将水、有机溶剂或助溶剂系统冷冻,然后通过升华(一次干燥)和解吸(二次干燥)将其从样品中去除的过程。本研究旨在通过对每个阶段的关键工艺参数进行评估,开发和优化批量冷冻干燥循环,以制备 RES 第三代 SD,其中 Eudragit E PO 作为亲水性聚合物,与 RES 的比例为 1:2;Gelucire 44/14 作为表面活性剂,与 RES 的比例为 16%(重量比),使用叔丁醇(TBA)/醋酸盐缓冲液 pH 4.5(75:25)共溶剂系统。通过优化和稳健的散装冻干工艺,制备出了外观良好、无裂纹、无塌陷、无熔化的 RES 第三代 SD。理化表征结果表明,RES 在 SD 中转化为无定形状态,在 40⁰C/75% RH 条件下放置 1 个月后,制剂保持稳定。与纯 RES 相比,溶解度和溶解速率均有所提高。
{"title":"Freeze-drying cycle optimization of an amorphous solid dispersion of resveratrol","authors":"","doi":"10.1016/j.ejps.2024.106855","DOIUrl":"10.1016/j.ejps.2024.106855","url":null,"abstract":"<div><p>Resveratrol (RES) has demonstrated advantages as anti-cancer, anti-inflammatory, blood sugar-lowering agent and as cardioprotective agent, among others. Despite RES therapeutic advantages its use in pharmaceutical applications is limited by its low oral bioavailability, mainly due to its poor water solubility. Formulation of poorly water-soluble compound as solid dispersion (SD) converts a crystalline into a more soluble in water amorphous drug. Lyophilization or freeze-drying is a process in which water, an organic solvent, or a co-solvent system is frozen, followed by its removal from the sample, initially by sublimation (primary drying) and then by desorption (secondary drying). This study aimed the development and optimization of a bulk freeze-drying cycle by critical process parameters assessment in each phase to prepare a RES third-generation SD, containing Eudragit E PO as hydrophilic polymer at 1:2 ratio, and Gelucire 44/14 as surfactant at 16 % (w/w) to RES, using a <em>tert</em>-butanol (TBA)/Acetate buffer pH 4.5 (75:25) co-solvent system. A RES third-generation SD with good appearance, not cracked, collapsed, or melted was prepared by an optimized and robust bulk lyophilization process. A physicochemical characterization confirmed the conversion of RES to the amorphous state in the SD and formulation stability after 1 month at 40 °C/75 % RH. Increased solubility and higher dissolution rate compared with pure RES were also obtained.</p></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0928098724001672/pdfft?md5=3247a5e24e8f280c344b437aeb97a107&pid=1-s2.0-S0928098724001672-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-15DOI: 10.1016/j.ejps.2024.106852
Preincubation with inhibitor in organic anion transporting polypeptide (OATP) in vitro assays may increase the inhibition potency of inhibitors compared to conventional inhibition assays with only short inhibitor coincubation with substrate. The decrease in IC50 may affect prediction of drug-drug interactions (DDI) involving these transporters and inhibitors. Only few drugs, however, have been assessed for the preincubation-dependent inhibition of the OATP2B1 transporter. Therefore, we studied the effect of preincubation on OATP2B1 inhibition with five known OATP2B1 inhibitors (atorvastatin, erlotinib, ezetimibe, ticagrelor and simeprevir) in HEK293 cells transiently overexpressing OATP2B1. IC50 values were determined with and without inhibitor preincubation for 20 min with three different OATP2B1 substrates (dibromofluorescein, DBF; 5-carboxyfluorescein, 5-CF; estrone sulfate). Atorvastatin, ezetimibe, and simeprevir displayed more than 2-fold lower IC50 values after preincubation with at least one of the tested substrates. Altogether, 4 out of 15 inhibitor/substrate combinations exhibited more than 2-fold potentiation of IC50 after inhibitor preincubation. In addition, preincubation by itself, without inhibitor present with the substrate, resulted in more than 50% inhibition of OATP2B1-mediated uptake of DBF and/or 5-CF by atorvastatin, ticagrelor and simeprevir. Thus, erlotinib was the only inhibitor with no indication of potentiation of inhibition by preincubation with any of the tested substrates. In conclusion, preincubation resulted in inhibitor- and substrate-dependent inhibition of OATP2B1. These results support the conclusion that to reduce the risk of false negative DDI prediction, preincubation should be considered also in OATP2B1 inhibition assays.
{"title":"Preincubation-dependent inhibition of organic anion transporting polypeptide 2B1","authors":"","doi":"10.1016/j.ejps.2024.106852","DOIUrl":"10.1016/j.ejps.2024.106852","url":null,"abstract":"<div><p>Preincubation with inhibitor in organic anion transporting polypeptide (OATP) <em>in vitro</em> assays may increase the inhibition potency of inhibitors compared to conventional inhibition assays with only short inhibitor coincubation with substrate. The decrease in IC<sub>50</sub> may affect prediction of drug-drug interactions (DDI) involving these transporters and inhibitors. Only few drugs, however, have been assessed for the preincubation-dependent inhibition of the OATP2B1 transporter. Therefore, we studied the effect of preincubation on OATP2B1 inhibition with five known OATP2B1 inhibitors (atorvastatin, erlotinib, ezetimibe, ticagrelor and simeprevir) in HEK293 cells transiently overexpressing OATP2B1. IC<sub>50</sub> values were determined with and without inhibitor preincubation for 20 min with three different OATP2B1 substrates (dibromofluorescein, DBF; 5-carboxyfluorescein, 5-CF; estrone sulfate). Atorvastatin, ezetimibe, and simeprevir displayed more than 2-fold lower IC<sub>50</sub> values after preincubation with at least one of the tested substrates. Altogether, 4 out of 15 inhibitor/substrate combinations exhibited more than 2-fold potentiation of IC<sub>50</sub> after inhibitor preincubation. In addition, preincubation by itself, without inhibitor present with the substrate, resulted in more than 50% inhibition of OATP2B1-mediated uptake of DBF and/or 5-CF by atorvastatin, ticagrelor and simeprevir. Thus, erlotinib was the only inhibitor with no indication of potentiation of inhibition by preincubation with any of the tested substrates. In conclusion, preincubation resulted in inhibitor- and substrate-dependent inhibition of OATP2B1. These results support the conclusion that to reduce the risk of false negative DDI prediction, preincubation should be considered also in OATP2B1 inhibition assays.</p></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0928098724001647/pdfft?md5=c6b886bfd069318fc6c73a10feddb776&pid=1-s2.0-S0928098724001647-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-14DOI: 10.1016/j.ejps.2024.106851
Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), is an effective drug in treating patients infected with human immunodeficiency virus (HIV). Previous population pharmacokinetics (PPK) studies have showed the large variabilities in PK of TFV. Furthermore, limited information was known in Chinese populations. Therefore, the aim of this study was to characterize PPK of TDF in Chinese and identify factors that may affect its PK. TFV concentrations (n = 552) from 30 healthy subjects and 162 HIV-infected Chinese adult patients were pooled for PPK analysis by a nonlinear mixed-effects method. The PK of TFV was adequately described as a two-compartment model with first order absorption and elimination. The typical apparent clearance (CL/F) of TFV in 70-kg adults was 137 L/h, higher than that reported in Caucasians and Blacks (45.8–93 L/h). Estimated glomerular filtration rate was identified to be a significant factor influencing CL/F. Monte Carlo simulation showed that the exposure of standard dosing regimen of TDF 300 mg every 24 h in Chinese people with mild renal impairment (60 to 90 ml/min/1.73 m2) was close to that in individuals with normal renal function (90 mL/min). Dose adjustment is not required for patients with mild renal impairment. Our study might offer new clues for optimal dosing strategies in Chinese patients with HIV-infected.
{"title":"Do Chinese HIV-infected adult patients with altered renal function need to adjust tenofovir disoproxil fumarate dosage? A population pharmacokinetics analysis","authors":"","doi":"10.1016/j.ejps.2024.106851","DOIUrl":"10.1016/j.ejps.2024.106851","url":null,"abstract":"<div><p>Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), is an effective drug in treating patients infected with human immunodeficiency virus (HIV). Previous population pharmacokinetics (PPK) studies have showed the large variabilities in PK of TFV. Furthermore, limited information was known in Chinese populations. Therefore, the aim of this study was to characterize PPK of TDF in Chinese and identify factors that may affect its PK. TFV concentrations (<em>n</em> = 552) from 30 healthy subjects and 162 HIV-infected Chinese adult patients were pooled for PPK analysis by a nonlinear mixed-effects method. The PK of TFV was adequately described as a two-compartment model with first order absorption and elimination. The typical apparent clearance (CL/F) of TFV in 70-kg adults was 137 L/h, higher than that reported in Caucasians and Blacks (45.8–93 L/h). Estimated glomerular filtration rate was identified to be a significant factor influencing CL/F. Monte Carlo simulation showed that the exposure of standard dosing regimen of TDF 300 mg every 24 h in Chinese people with mild renal impairment (60 to 90 ml/min/1.73 m<sup>2</sup>) was close to that in individuals with normal renal function (90 mL/min). Dose adjustment is not required for patients with mild renal impairment. Our study might offer new clues for optimal dosing strategies in Chinese patients with HIV-infected.</p></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0928098724001635/pdfft?md5=50d332bbe800739e369b869d5e12d989&pid=1-s2.0-S0928098724001635-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1016/j.ejps.2024.106850
Farnoosh Ebrahimi, Han Xu, Evert Fuenmayor, Ian Major
Additive manufacturing (AM) enables the production of complex, lightweight, and customized components with superior quality. Selecting the right materials considering their thermal properties, printability, and layer adhesion is crucial in melting-based AM techniques. This study investigates Droplet Deposition Modelling (DDM), an innovative material extrusion process that utilizes thermoplastic granules. DDM is distinguished by its shorter manufacturing times and a wider range of materials, setting it apart from traditional material extrusion methods such as fused filament fabrication. We investigated the printability and part quality in DDM using two common pharmaceutical excipients: Polyvinylpyrrolidone/vinyl acetate 6:4 (PVP/VA), which is highly brittle, and Polycaprolactone (PCL), known for its low solubility and role in controlled drug release. Different ratios of PVP/VA and PCL were compounded via hot melt extrusion (HME) and used in DDM to study the impact of ingredient content on printability and part quality, employing geometrical models to assess material compatibility and printability. The study revealed that increasing PVP/VA content leads to higher viscosity, reduced flowability, and uneven deposition, with formulations of 80% and 100% PVP/VA showing poor processability. In contrast, formulations with 60% and 40% PVP/VA exhibited smooth processing and compatibility with DDM. We identified processing temperature and Drop Aspect Ratio (DAR) as key factors influencing material printability and part quality. Elevated processing temperatures and reduced DAR were found to increase interface temperatures, reduce diffusion, and potentially cause the 'elephant feet' issue. Additionally, smaller droplet sizes and material characteristics, such as higher interfacial tension in PCL, could lead to coalescence. Our findings highlight the complexities in optimizing DDM processing parameters and material blends, underscoring the need for careful formulation design to achieve high-quality 3D printed products.
{"title":"Material Compatibility and Processing Challenges in Droplet Deposition Modelling Additive Manufacturing: A Study on Pharmaceutical Excipients Polyvinylpyrrolidone/vinyl acetate (PVP/VA) and Polycaprolactone (PCL)","authors":"Farnoosh Ebrahimi, Han Xu, Evert Fuenmayor, Ian Major","doi":"10.1016/j.ejps.2024.106850","DOIUrl":"10.1016/j.ejps.2024.106850","url":null,"abstract":"<div><p>Additive manufacturing (AM) enables the production of complex, lightweight, and customized components with superior quality. Selecting the right materials considering their thermal properties, printability, and layer adhesion is crucial in melting-based AM techniques. This study investigates Droplet Deposition Modelling (DDM), an innovative material extrusion process that utilizes thermoplastic granules. DDM is distinguished by its shorter manufacturing times and a wider range of materials, setting it apart from traditional material extrusion methods such as fused filament fabrication. We investigated the printability and part quality in DDM using two common pharmaceutical excipients: Polyvinylpyrrolidone/vinyl acetate 6:4 (PVP/VA), which is highly brittle, and Polycaprolactone (PCL), known for its low solubility and role in controlled drug release. Different ratios of PVP/VA and PCL were compounded via hot melt extrusion (HME) and used in DDM to study the impact of ingredient content on printability and part quality, employing geometrical models to assess material compatibility and printability. The study revealed that increasing PVP/VA content leads to higher viscosity, reduced flowability, and uneven deposition, with formulations of 80% and 100% PVP/VA showing poor processability. In contrast, formulations with 60% and 40% PVP/VA exhibited smooth processing and compatibility with DDM. We identified processing temperature and Drop Aspect Ratio (DAR) as key factors influencing material printability and part quality. Elevated processing temperatures and reduced DAR were found to increase interface temperatures, reduce diffusion, and potentially cause the 'elephant feet' issue. Additionally, smaller droplet sizes and material characteristics, such as higher interfacial tension in PCL, could lead to coalescence. Our findings highlight the complexities in optimizing DDM processing parameters and material blends, underscoring the need for careful formulation design to achieve high-quality 3D printed products.</p></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0928098724001623/pdfft?md5=04fabcdc811701ef0daa34fb9a03f368&pid=1-s2.0-S0928098724001623-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-09DOI: 10.1016/j.ejps.2024.106849
Elsayed A. Elmorsy , Sameh Saber , Rabab S. Hamad , Mustafa Ahmed Abdel-Reheim , Attalla F. El-kott , Mohammed A. AlShehri , Kareem Morsy , Sally Negm , Mahmoud E. Youssef
Doxorubicin (DOX) is an anthracycline chemotherapy drug widely employed in the treatment of various cancers, known for its potent antineoplastic properties but often associated with dose-dependent cardiotoxicity, limiting its clinical use. This review explores the complex molecular details that determine the heart-protective effectiveness of carvedilol in relation to cardiotoxicity caused by DOX. The harmful effects of DOX on heart cells could include oxidative stress, DNA damage, iron imbalance, disruption of autophagy, calcium imbalance, apoptosis, dysregulation of topoisomerase 2-beta, arrhythmogenicity, and inflammatory responses. This review carefully reveals how carvedilol serves as a strong protective mechanism, strategically reducing each aspect of cardiac damage caused by DOX. Carvedilol's antioxidant capabilities involve neutralizing free radicals and adjusting crucial antioxidant enzymes. It skillfully manages iron balance, controls autophagy, and restores the calcium balance essential for cellular stability. Moreover, the anti-apoptotic effects of carvedilol are outlined through the adjustment of Bcl-2 family proteins and activation of the Akt signaling pathway. The medication also controls topoisomerase 2-beta and reduces the renin-angiotensin-aldosterone system, together offering a thorough defense against cardiotoxicity induced by DOX. These findings not only provide detailed understanding into the molecular mechanisms that coordinate heart protection by carvedilol but also offer considerable potential for the creation of targeted treatment strategies intended to relieve cardiotoxicity caused by chemotherapy.
{"title":"Mechanistic insights into carvedilol's potential protection against doxorubicin-induced cardiotoxicity","authors":"Elsayed A. Elmorsy , Sameh Saber , Rabab S. Hamad , Mustafa Ahmed Abdel-Reheim , Attalla F. El-kott , Mohammed A. AlShehri , Kareem Morsy , Sally Negm , Mahmoud E. Youssef","doi":"10.1016/j.ejps.2024.106849","DOIUrl":"10.1016/j.ejps.2024.106849","url":null,"abstract":"<div><p>Doxorubicin (DOX) is an anthracycline chemotherapy drug widely employed in the treatment of various cancers, known for its potent antineoplastic properties but often associated with dose-dependent cardiotoxicity, limiting its clinical use. This review explores the complex molecular details that determine the heart-protective effectiveness of carvedilol in relation to cardiotoxicity caused by DOX. The harmful effects of DOX on heart cells could include oxidative stress, DNA damage, iron imbalance, disruption of autophagy, calcium imbalance, apoptosis, dysregulation of topoisomerase 2-beta, arrhythmogenicity, and inflammatory responses. This review carefully reveals how carvedilol serves as a strong protective mechanism, strategically reducing each aspect of cardiac damage caused by DOX. Carvedilol's antioxidant capabilities involve neutralizing free radicals and adjusting crucial antioxidant enzymes. It skillfully manages iron balance, controls autophagy, and restores the calcium balance essential for cellular stability. Moreover, the anti-apoptotic effects of carvedilol are outlined through the adjustment of Bcl-2 family proteins and activation of the Akt signaling pathway. The medication also controls topoisomerase 2-beta and reduces the renin-angiotensin-aldosterone system, together offering a thorough defense against cardiotoxicity induced by DOX. These findings not only provide detailed understanding into the molecular mechanisms that coordinate heart protection by carvedilol but also offer considerable potential for the creation of targeted treatment strategies intended to relieve cardiotoxicity caused by chemotherapy.</p></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0928098724001611/pdfft?md5=b70513aba450b9837ab3ef848162c935&pid=1-s2.0-S0928098724001611-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-08DOI: 10.1016/j.ejps.2024.106848
Transdermal drug delivery is suitable for low-molecular-weight drugs with specific lipophilicity, like fentanyl, which is widely used for cancer-induced pain management. However, fentanyl's transdermal therapy displays high intra-individual variability. Factors like skin characteristics at application sites and ambient temperature contribute to this variation. In this study, we developed a physics-based digital twin of the human body to cope with this variability and propose better adapted setups. This twin includes an in-silico skin model for drug penetration, a pharmacokinetic model, and a pharmacodynamic model. Based on the results of our simulations, applying the patch on the flank (side abdominal area) showed a 15.3 % higher maximum fentanyl concentration in the plasma than on the chest. Additionally, the time to reach this maximum concentration when delivered through the flank was 19.8 h, which was 10.3 h earlier than via the upper arm. Finally, this variation led to an 18 % lower minimum pain intensity for delivery via the flank than the chest. Moreover, the impact of seasonal changes on ambient temperature and skin temperature by considering the activity level was investigated. Based on our result, the fentanyl uptake flux by capillaries increased by up to 11.8 % from an inactive state in winter to an active state in summer. We also evaluated the effect of controlling fentanyl delivery by adjusting the temperature of the patch to alleviate the pain to reach a mild pain intensity (rated three on the VAS scale). By implementing this strategy, the average pain intensity decreased by 1.1 points, and the standard deviation for fentanyl concentration in plasma and average pain intensity reduced by 37.5 % and 33.3 %, respectively. Therefore, our digital twin demonstrated the efficacy of controlled drug release through temperature regulation, ensuring the therapy toward the intended target outcome and reducing therapy outcome variability. This holds promise as a potentially useful tool for physicians.
{"title":"Exploring the thermally-controlled fentanyl transdermal therapy to provide constant drug delivery by physics-based digital twins","authors":"","doi":"10.1016/j.ejps.2024.106848","DOIUrl":"10.1016/j.ejps.2024.106848","url":null,"abstract":"<div><p>Transdermal drug delivery is suitable for low-molecular-weight drugs with specific lipophilicity, like fentanyl, which is widely used for cancer-induced pain management. However, fentanyl's transdermal therapy displays high intra-individual variability. Factors like skin characteristics at application sites and ambient temperature contribute to this variation. In this study, we developed a physics-based digital twin of the human body to cope with this variability and propose better adapted setups. This twin includes an <em>in-silico</em> skin model for drug penetration, a pharmacokinetic model, and a pharmacodynamic model. Based on the results of our simulations, applying the patch on the flank (side abdominal area) showed a 15.3 % higher maximum fentanyl concentration in the plasma than on the chest. Additionally, the time to reach this maximum concentration when delivered through the flank was 19.8 h, which was 10.3 h earlier than via the upper arm. Finally, this variation led to an 18 % lower minimum pain intensity for delivery via the flank than the chest. Moreover, the impact of seasonal changes on ambient temperature and skin temperature by considering the activity level was investigated. Based on our result, the fentanyl uptake flux by capillaries increased by up to 11.8 % from an inactive state in winter to an active state in summer. We also evaluated the effect of controlling fentanyl delivery by adjusting the temperature of the patch to alleviate the pain to reach a mild pain intensity (rated three on the VAS scale). By implementing this strategy, the average pain intensity decreased by 1.1 points, and the standard deviation for fentanyl concentration in plasma and average pain intensity reduced by 37.5 % and 33.3 %, respectively. Therefore, our digital twin demonstrated the efficacy of controlled drug release through temperature regulation, ensuring the therapy toward the intended target outcome and reducing therapy outcome variability. This holds promise as a potentially useful tool for physicians.</p></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S092809872400160X/pdfft?md5=06c155dcd7781022e188ba1a3cac13d8&pid=1-s2.0-S092809872400160X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}