Dung Nguyen, Xiusheng Miao, Kunal Taskar, Mindy Magee, Pete Gorycki, Katy Moore, Guoying Tai
Fostemsavir is an approved gp120-directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment-experienced adults with multi-drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug-drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co-administered with fostemsavir.
福斯替沙韦是一种已获批准的 gp120 定向附着抑制剂和原药,用于与其他抗逆转录病毒药物(ARVs)联合治疗 1 型人类免疫缺陷病毒感染,适用于对多种药物耐药、不耐受或对当前抗逆转录病毒药物治疗方案存在安全顾虑的重度治疗经验成人。最初的体外研究表明,在测试浓度为100 uM时,fostemsavir的活性分子替米沙韦和其代谢物会抑制有机阳离子转运体(OCT)1、OCT2以及多药和毒素挤压转运体(MATEs),不过,根据食品药品管理局现行的体外药物相互作用(DDI)指南,使用机理静态模型进行的风险评估并未发现对OCTs和MATEs有任何临床相关的抑制作用。然而,EMA 静态模型的预测结果却显示存在 DDI 风险。因此,开发了基于生理学的福斯替沙韦/替米沙韦药代动力学(PBPK)模型,以进一步评估替米沙韦对 OCT 和 MATEs 抑制的 DDI 风险潜力,并预测二甲双胍(一种敏感的 OCT 和 MATEs 底物)暴露量的变化。根据预测,在较宽的替姆沙韦浓度范围内,二甲双胍的浓度不会受到临床相关影响;因此,建议二甲双胍与福斯替沙韦合用时不进行剂量调整。
{"title":"No dose adjustment of metformin or substrates of organic cation transporters (OCT)1 and OCT2 and multidrug and toxin extrusion protein (MATE)1/2K with fostemsavir coadministration based on modeling approaches.","authors":"Dung Nguyen, Xiusheng Miao, Kunal Taskar, Mindy Magee, Pete Gorycki, Katy Moore, Guoying Tai","doi":"10.1002/prp2.1238","DOIUrl":"10.1002/prp2.1238","url":null,"abstract":"<p><p>Fostemsavir is an approved gp120-directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment-experienced adults with multi-drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug-drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co-administered with fostemsavir.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11237172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A drug-drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early-phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three-cycle, self-controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1-hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21-fold based on maximum plasma concentration (Cmax), 8.37-fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC0-t), and 11.22-fold based on area under the curve from zero to infinity (AUC0-∞). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27-fold based on Cmax, ~0.18-fold based on AUC0-t, and ~0.18-fold based on AUC0-∞. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near-maximal CYP3A levels.
{"title":"An open-label study to explore the optimal design of CYP3A drug-drug interaction clinical trials in healthy Chinese people.","authors":"Jingcheng Chen, Jiangshuo Li, Jingxuan Wu, Yuqin Song, Lijun Li, Jianxiong Zhang, Ruihua Dong","doi":"10.1002/prp2.1252","DOIUrl":"10.1002/prp2.1252","url":null,"abstract":"<p><p>A drug-drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early-phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three-cycle, self-controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1-hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21-fold based on maximum plasma concentration (C<sub>max</sub>), 8.37-fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC<sub>0-t</sub>), and 11.22-fold based on area under the curve from zero to infinity (AUC<sub>0-∞</sub>). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27-fold based on C<sub>max</sub>, ~0.18-fold based on AUC<sub>0-t</sub>, and ~0.18-fold based on AUC<sub>0-∞</sub>. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near-maximal CYP3A levels.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In this study, plasma belimumab concentrations were measured over the course of treatment in systemic lupus erythematosus (SLE) patients on belimumab therapy, and intra- and interindividual variations in plasma belimumab concentration were evaluated. A single-center prospective study was conducted at Oita University Hospital to evaluate trough plasma concentrations over the course of treatment in 13 SLE patients treated with intravenous belimumab. Plasma belimumab concentrations were measured by a validated ultra-high performance liquid chromatography with tandem mass spectrometry method. The median age of the patients was 40 (interquartile range: 35-51) years and the median weight was 51.8 (47.0-58.1) kg. A mean of 9.4 (range: 1-13) blood samples was collected per patient at routine visits. The mean (± SD) plasma belimumab concentration was 33.4 ± 11.9 μg/mL in the patient with the lowest concentration and 170.0 ± 16.6 μg/mL in the patient with the highest concentration, indicating a 5-fold difference between patients. On the other hand, the within-patient coefficient of variation ranged from 7.1% to 35.7%, showing no large variations. No significant correlation was observed between plasma belimumab concentration and belimumab dose (mg/kg) (Spearman's rank correlation coefficient = 0.22, p = .54). Examinations of trough plasma belimumab concentrations over the course of treatment in patients with SLE showed small intraindividual variation but large interindividual variation. Plasma belimumab trough concentration varied widely among patients administered the approved dose.
{"title":"Evaluation of intra- and inter-individual variations in plasma belimumab concentrations in adult patients with systemic lupus erythematosus.","authors":"Chisato Yoshijima, Yosuke Suzuki, Ryota Tanaka, Hiroyuki Ono, Ayako Oda, Takashi Ozaki, Hirotaka Shibata, Hiroki Itoh, Keiko Ohno","doi":"10.1002/prp2.1255","DOIUrl":"10.1002/prp2.1255","url":null,"abstract":"<p><p>In this study, plasma belimumab concentrations were measured over the course of treatment in systemic lupus erythematosus (SLE) patients on belimumab therapy, and intra- and interindividual variations in plasma belimumab concentration were evaluated. A single-center prospective study was conducted at Oita University Hospital to evaluate trough plasma concentrations over the course of treatment in 13 SLE patients treated with intravenous belimumab. Plasma belimumab concentrations were measured by a validated ultra-high performance liquid chromatography with tandem mass spectrometry method. The median age of the patients was 40 (interquartile range: 35-51) years and the median weight was 51.8 (47.0-58.1) kg. A mean of 9.4 (range: 1-13) blood samples was collected per patient at routine visits. The mean (± SD) plasma belimumab concentration was 33.4 ± 11.9 μg/mL in the patient with the lowest concentration and 170.0 ± 16.6 μg/mL in the patient with the highest concentration, indicating a 5-fold difference between patients. On the other hand, the within-patient coefficient of variation ranged from 7.1% to 35.7%, showing no large variations. No significant correlation was observed between plasma belimumab concentration and belimumab dose (mg/kg) (Spearman's rank correlation coefficient = 0.22, p = .54). Examinations of trough plasma belimumab concentrations over the course of treatment in patients with SLE showed small intraindividual variation but large interindividual variation. Plasma belimumab trough concentration varied widely among patients administered the approved dose.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wei Yin, Pranab Mitra, Veronique Copalu, Thomas C Marbury, Juan Carlos Rondon, Eric J Lawitz, Valerie Lloyd, Mike Baratta, Mahnaz Asgharnejad, Tom Hui, Yasir Khan
This phase 1, open-label, three-arm study (NCT05098054) compared the pharmacokinetics and safety of soticlestat (TAK-935) in participants with hepatic impairment. Participants aged ≥18 to <75 years had moderate (Child-Pugh B) or mild (Child-Pugh A) hepatic impairment or normal hepatic function (matched to hepatic-impaired participants by sex, age, and body mass index). Soticlestat was administered as a single oral 300 mg dose. Pharmacokinetic parameters of soticlestat and its metabolites TAK-935-G (M3) and M-I were assessed and compared by group. The incidence of treatment-emergent adverse events (TEAEs) and other safety parameters were also monitored. The pharmacokinetic analyses comprised 35 participants. Participants with moderate hepatic impairment had lower proportions of bound and higher proportions of unbound soticlestat than participants with mild hepatic impairment and normal hepatic function. Total plasma soticlestat pharmacokinetic parameters (maximum observed concentration [Cmax], area under the concentration-time curve from time 0 to time of last quantifiable concentration [AUClast], and AUC from time 0 to infinity [AUC∞]) were approximately 115%, 216%, and 199% higher with moderate and approximately 45%, 35%, and 30% higher with mild hepatic impairment, respectively, than healthy matched participants. Moderate hepatic impairment decreased the liver's ability to metabolize soticlestat to M-I; glucuronidation to M3 was also affected. Mild hepatic impairment resulted in a lower total plasma M-I exposure, but glucuronidation was unaffected. TEAEs were similar across study arms, mild, and no new safety findings were observed. A soticlestat dose reduction is required for individuals with moderate but not mild hepatic impairment.
{"title":"Phase 1 pharmacokinetic and safety study of soticlestat in participants with mild or moderate hepatic impairment or normal hepatic function.","authors":"Wei Yin, Pranab Mitra, Veronique Copalu, Thomas C Marbury, Juan Carlos Rondon, Eric J Lawitz, Valerie Lloyd, Mike Baratta, Mahnaz Asgharnejad, Tom Hui, Yasir Khan","doi":"10.1002/prp2.1213","DOIUrl":"10.1002/prp2.1213","url":null,"abstract":"<p><p>This phase 1, open-label, three-arm study (NCT05098054) compared the pharmacokinetics and safety of soticlestat (TAK-935) in participants with hepatic impairment. Participants aged ≥18 to <75 years had moderate (Child-Pugh B) or mild (Child-Pugh A) hepatic impairment or normal hepatic function (matched to hepatic-impaired participants by sex, age, and body mass index). Soticlestat was administered as a single oral 300 mg dose. Pharmacokinetic parameters of soticlestat and its metabolites TAK-935-G (M3) and M-I were assessed and compared by group. The incidence of treatment-emergent adverse events (TEAEs) and other safety parameters were also monitored. The pharmacokinetic analyses comprised 35 participants. Participants with moderate hepatic impairment had lower proportions of bound and higher proportions of unbound soticlestat than participants with mild hepatic impairment and normal hepatic function. Total plasma soticlestat pharmacokinetic parameters (maximum observed concentration [C<sub>max</sub>], area under the concentration-time curve from time 0 to time of last quantifiable concentration [AUC<sub>last</sub>], and AUC from time 0 to infinity [AUC<sub>∞</sub>]) were approximately 115%, 216%, and 199% higher with moderate and approximately 45%, 35%, and 30% higher with mild hepatic impairment, respectively, than healthy matched participants. Moderate hepatic impairment decreased the liver's ability to metabolize soticlestat to M-I; glucuronidation to M3 was also affected. Mild hepatic impairment resulted in a lower total plasma M-I exposure, but glucuronidation was unaffected. TEAEs were similar across study arms, mild, and no new safety findings were observed. A soticlestat dose reduction is required for individuals with moderate but not mild hepatic impairment.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11239955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141591011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Samrita Mondal, Richa Rathor, Som Nath Singh, Geetha Suryakumar
The burden of growing concern about the dysregulation of metabolic processes arises due to complex interplay between environment and nutrition that has great impact on genetics and epigenetics of an individual. Thereby, any abnormality at the level of food intake regulating hormones may contribute to the development of metabolic diseases in any age group due to malnutrition, overweight, changing lifestyle, and exposure to extreme environments such as heat stress (HS), cold stress, or high altitude (HA). Hormones such as leptin, adiponectin, ghrelin, and cholecystokinin regulate appetite and satiety to maintain energy homeostasis. Leptin, an adipokine and a pleiotropic hormone, play major role in regulating the food intake, energy gain and energy expenditure. Using in silico approach, we have identified the major genes (LEP, LEPR, JAK2, STAT3, NPY, POMC, IRS1, SOCS3) that play crucial role in leptin signaling pathway. Further, eight miRNAs (hsa-miR-204-5p, hsa-miR-211-5p, hsa-miR-30, hsa-miR-3163, hsa-miR-33a-3p, hsa-miR-548, hsa-miR-561-3p, hsa-miR-7856-5p) from TargetScan 8.0 database were screened out that commonly target these genes. The role of these miRNAs should be explored as they might play vital role in regulating the appetite, energy metabolism, metabolic diseases (obesity, type 2 diabetes, cardiovascular diseases, inflammation), and to combat extreme environments. The miRNAs regulating leptin signaling and appetite may be useful for developing novel therapeutics for metabolic diseases.
{"title":"miRNA and leptin signaling in metabolic diseases and at extreme environments.","authors":"Samrita Mondal, Richa Rathor, Som Nath Singh, Geetha Suryakumar","doi":"10.1002/prp2.1248","DOIUrl":"10.1002/prp2.1248","url":null,"abstract":"<p><p>The burden of growing concern about the dysregulation of metabolic processes arises due to complex interplay between environment and nutrition that has great impact on genetics and epigenetics of an individual. Thereby, any abnormality at the level of food intake regulating hormones may contribute to the development of metabolic diseases in any age group due to malnutrition, overweight, changing lifestyle, and exposure to extreme environments such as heat stress (HS), cold stress, or high altitude (HA). Hormones such as leptin, adiponectin, ghrelin, and cholecystokinin regulate appetite and satiety to maintain energy homeostasis. Leptin, an adipokine and a pleiotropic hormone, play major role in regulating the food intake, energy gain and energy expenditure. Using in silico approach, we have identified the major genes (LEP, LEPR, JAK2, STAT3, NPY, POMC, IRS1, SOCS3) that play crucial role in leptin signaling pathway. Further, eight miRNAs (hsa-miR-204-5p, hsa-miR-211-5p, hsa-miR-30, hsa-miR-3163, hsa-miR-33a-3p, hsa-miR-548, hsa-miR-561-3p, hsa-miR-7856-5p) from TargetScan 8.0 database were screened out that commonly target these genes. The role of these miRNAs should be explored as they might play vital role in regulating the appetite, energy metabolism, metabolic diseases (obesity, type 2 diabetes, cardiovascular diseases, inflammation), and to combat extreme environments. The miRNAs regulating leptin signaling and appetite may be useful for developing novel therapeutics for metabolic diseases.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11253706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141627339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J Butauskaite, A Zumbakyte, L Aukstikalne, J Pancere, S Zukaitiene, E Karinauske
As the population continues to age, the occurrence of chronic illnesses and comorbidities that often necessitate the use of polypharmacy has been on the rise. Polypharmacy, among other factors that tend to coincide with chronic diseases, such as obesity, impaired kidney and liver function, and older age, can increase the risk of medication errors (MEs). Our study aims to evaluate the prevalence of MEs in the Internal medicine, Cardiology, and Neurology departments at the secondary-level university hospital. We conducted a prospective observational study of 145 patients' electronic or paper-based data of inpatient prescriptions and patients' pharmacokinetic risk factors, such as an impairment of renal and/or hepatic function, weight, and age. All included patients collectively received 1252 prescribed drugs. The median (Q1; Q3) number of drugs per patient was 8 (7;10). At least one ME was identified in 133 out of the 145 patients, indicating a significantly higher prevalence than hypothesized (91.7% vs. 50%; p < .001). There was moderate, positive correlation between the quantity of prescribed drugs and the number of MEs, meaning that the more drugs are prescribed, the higher the number of identified MEs (Spearman's ρ = 0.428; p < .001). These findings suggest that there is a need for continuous medication education activity for prescribing physicians, continuous evaluation of prescription appropriateness to objectively identify the MEs and to contribute to more rational patient treatment.
{"title":"High prevalence of medication errors in a secondary-level Lithuanian hospital: A prospective cross-sectional observational study.","authors":"J Butauskaite, A Zumbakyte, L Aukstikalne, J Pancere, S Zukaitiene, E Karinauske","doi":"10.1002/prp2.1246","DOIUrl":"10.1002/prp2.1246","url":null,"abstract":"<p><p>As the population continues to age, the occurrence of chronic illnesses and comorbidities that often necessitate the use of polypharmacy has been on the rise. Polypharmacy, among other factors that tend to coincide with chronic diseases, such as obesity, impaired kidney and liver function, and older age, can increase the risk of medication errors (MEs). Our study aims to evaluate the prevalence of MEs in the Internal medicine, Cardiology, and Neurology departments at the secondary-level university hospital. We conducted a prospective observational study of 145 patients' electronic or paper-based data of inpatient prescriptions and patients' pharmacokinetic risk factors, such as an impairment of renal and/or hepatic function, weight, and age. All included patients collectively received 1252 prescribed drugs. The median (Q1; Q3) number of drugs per patient was 8 (7;10). At least one ME was identified in 133 out of the 145 patients, indicating a significantly higher prevalence than hypothesized (91.7% vs. 50%; p < .001). There was moderate, positive correlation between the quantity of prescribed drugs and the number of MEs, meaning that the more drugs are prescribed, the higher the number of identified MEs (Spearman's ρ = 0.428; p < .001). These findings suggest that there is a need for continuous medication education activity for prescribing physicians, continuous evaluation of prescription appropriateness to objectively identify the MEs and to contribute to more rational patient treatment.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11291557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bonifasius Siyuka Singu, Clarissa Hildegard Pieper, Roger Karel Verbeeck, Ene I Ette
Sepsis is a common disease with high morbidity and mortality among newborns in intensive care units world-wide. Gram-negative bacillary bacteria are the major source of infection in neonates. Gentamicin is the most widely used aminoglycoside antibiotic in empiric therapy against early-onset sepsis. However, therapy failure may result due to various factors. The purpose of this study was to identify predictors of gentamicin therapy failure in neonates with sepsis. This was a prospective cross-sectional study at the Neonatal Intensive Care Unit at Windhoek Central Hospital over a period of 5 months in 2019. Neonates received intravenous gentamicin 5 mg/kg/24 h in combination with either benzylpenicillin 100 000 IU/kg/12 h or ampicillin 50 mg/kg/8 h. Logistic regression modeling was performed to determine the predictors of treatment outcomes. 36% of the 50 neonates were classified as having gentamicin treatment failure. Increasing treatment duration by 1 day resulted in odds of treatment failure increasing from 1.0 to 2.41. Similarly, one unit increase in CRP increases odds of gentamicin treatment failure by 49%. The 1 kg increase in birthweight reduces the log odds of treatment failure by 6.848, resulting in 99.9% decrease in the odds of treatment failure. One unit increase in WBC reduces odds of gentamicin treatment failure by 27%. Estimates of significant predictors of treatment failure were precise, yielding odds ratios that were within 95% confidence interval. This study identified the following as predictors of gentamicin therapy failure in neonates: prolonged duration of treatment, elevated C-reactive protein, low birthweight, and low white blood cell count.
{"title":"Predictors of gentamicin therapy failure in neonates with sepsis.","authors":"Bonifasius Siyuka Singu, Clarissa Hildegard Pieper, Roger Karel Verbeeck, Ene I Ette","doi":"10.1002/prp2.1250","DOIUrl":"10.1002/prp2.1250","url":null,"abstract":"<p><p>Sepsis is a common disease with high morbidity and mortality among newborns in intensive care units world-wide. Gram-negative bacillary bacteria are the major source of infection in neonates. Gentamicin is the most widely used aminoglycoside antibiotic in empiric therapy against early-onset sepsis. However, therapy failure may result due to various factors. The purpose of this study was to identify predictors of gentamicin therapy failure in neonates with sepsis. This was a prospective cross-sectional study at the Neonatal Intensive Care Unit at Windhoek Central Hospital over a period of 5 months in 2019. Neonates received intravenous gentamicin 5 mg/kg/24 h in combination with either benzylpenicillin 100 000 IU/kg/12 h or ampicillin 50 mg/kg/8 h. Logistic regression modeling was performed to determine the predictors of treatment outcomes. 36% of the 50 neonates were classified as having gentamicin treatment failure. Increasing treatment duration by 1 day resulted in odds of treatment failure increasing from 1.0 to 2.41. Similarly, one unit increase in CRP increases odds of gentamicin treatment failure by 49%. The 1 kg increase in birthweight reduces the log odds of treatment failure by 6.848, resulting in 99.9% decrease in the odds of treatment failure. One unit increase in WBC reduces odds of gentamicin treatment failure by 27%. Estimates of significant predictors of treatment failure were precise, yielding odds ratios that were within 95% confidence interval. This study identified the following as predictors of gentamicin therapy failure in neonates: prolonged duration of treatment, elevated C-reactive protein, low birthweight, and low white blood cell count.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11301262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hanlim Moon, Dae Young Zang, Min-Hee Ryu, YeonSook Seo, Bitna Oh, Sunjin Hwang, Lee Farrand
{"title":"FDA regulatory considerations for oncology drug development.","authors":"Hanlim Moon, Dae Young Zang, Min-Hee Ryu, YeonSook Seo, Bitna Oh, Sunjin Hwang, Lee Farrand","doi":"10.1002/prp2.1254","DOIUrl":"10.1002/prp2.1254","url":null,"abstract":"","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eric A. Mensah, Noriko Daneshtalab, Reza Tabrizchi
Piezo are mechanosensitive non‐selective cation channels that are suggested to be involved in vascular development and function. The aim of our study was to determine any sex‐specific contributions of the mechanosensitive Piezo 1 channels on blood vessel wall stiffness. Composite Young modulus (CYM) was determined using pressure myograph experimental approach using third‐order mesenteric arteries (intact and denuded) from Dahl salt‐sensitive male and female normotensive and hypertensive rats (n = 6–8). The effects of Piezo 1 agonist (Yoda 1; 10 μM), and antagonist (GsMTx‐4; 2 μM) were studied in intact and denuded vessels. The distribution of Piezo 1 was identified using immunohistochemistry. In intact blood vessels, there were no differences in CYM between the experimental groups, however, removal of the endothelium unmasked significant increases in CYM in normotensive males and female groups compared to hypertensive males. The presence of Yoda 1 did not affect CYM in any groups. In the intact tissues, GsMTx‐4 led to significant increases in CYM in hypertensive females, and normotensive males and females, but not in hypertensive males. In the denuded vessels, GsMTx‐4, produced a significant increase in CYM but only in the female normotensives. Differential expression of Piezo 1 were found in male versus female blood vessels. Our findings support a greater contribution of Piezo 1 mechanoceptors to vascular biomechanics of male hypertensive compared to male normotensive or female groups. The evidence also points to a possible differential vasoregulatory role for Piezo 1 in endothelial versus vascular smooth cells, with a greater contribution in males than females.
{"title":"Involvement of Piezo 1 mechanoceptors in vascular stiffness in isolated small resistance arteries of male and female Dahl salt‐sensitive hypertensive rats","authors":"Eric A. Mensah, Noriko Daneshtalab, Reza Tabrizchi","doi":"10.1002/prp2.1227","DOIUrl":"https://doi.org/10.1002/prp2.1227","url":null,"abstract":"Piezo are mechanosensitive non‐selective cation channels that are suggested to be involved in vascular development and function. The aim of our study was to determine any sex‐specific contributions of the mechanosensitive Piezo 1 channels on blood vessel wall stiffness. Composite Young modulus (CYM) was determined using pressure myograph experimental approach using third‐order mesenteric arteries (intact and denuded) from Dahl salt‐sensitive male and female normotensive and hypertensive rats (<jats:italic>n</jats:italic> = 6–8). The effects of Piezo 1 agonist (Yoda 1; 10 μM), and antagonist (GsMTx‐4; 2 μM) were studied in intact and denuded vessels. The distribution of Piezo 1 was identified using immunohistochemistry. In intact blood vessels, there were no differences in CYM between the experimental groups, however, removal of the endothelium unmasked significant increases in CYM in normotensive males and female groups compared to hypertensive males. The presence of Yoda 1 did not affect CYM in any groups. In the intact tissues, GsMTx‐4 led to significant increases in CYM in hypertensive females, and normotensive males and females, but not in hypertensive males. In the denuded vessels, GsMTx‐4, produced a significant increase in CYM but only in the female normotensives. Differential expression of Piezo 1 were found in male versus female blood vessels. Our findings support a greater contribution of Piezo 1 mechanoceptors to vascular biomechanics of male hypertensive compared to male normotensive or female groups. The evidence also points to a possible differential vasoregulatory role for Piezo 1 in endothelial versus vascular smooth cells, with a greater contribution in males than females.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In the treatment of chronic myeloid leukemia (CML), resistance to BCR‐ABL inhibitors makes it difficult to continue treatment and is directly related to life expectancy. Therefore, asciminib was introduced to the market as a useful drug for overcoming drug resistance. While combining molecular targeted drugs is useful to avoid drug resistance, the new BCR‐ABL inhibitor asciminib and conventional BCR‐ABL inhibitors should be used as monotherapy in principle. Therefore, we investigated the synergistic effect and mechanism of the combination of asciminib and imatinib. We generated imatinib‐resistant cells using the human CML cell line K562, examined the effects of imatinib and asciminib exposure on cell survival using the WST‐8 assay, and comprehensively analyzed genetic variation related to drug resistance using RNA‐seq and real‐time PCR. A synergistic effect was observed when imatinib and asciminib were combined with or without imatinib resistance. Three genes, GRRP1, ESPN, and NOXA1, were extracted as the sites of action of asciminib. Asciminib in combination with BCR‐ABL inhibitors may improve the therapeutic efficacy of conventional BCR‐ABL inhibitors and prevent the development of resistance. Its dosage may be effective even at minimal doses that do not cause side effects. Further verification of this mechanism of action is needed. Additionally, cross‐resistance between BCR‐ABL inhibitors and asciminib may occur, which needs to be clarified through further validation as soon as possible.
{"title":"Asciminib, a novel allosteric inhibitor of BCR‐ABL1, shows synergistic effects when used in combination with imatinib with or without drug resistance","authors":"Naoki Okamoto, Kenta Yagi, Sayaka Imawaka, Mayu Takaoka, Fuka Aizawa, Takahiro Niimura, Mitsuhiro Goda, Koji Miyata, Kei Kawada, Yuki Izawa‐Ishizawa, Satoshi Sakaguchi, Keisuke Ishizawa","doi":"10.1002/prp2.1214","DOIUrl":"https://doi.org/10.1002/prp2.1214","url":null,"abstract":"In the treatment of chronic myeloid leukemia (CML), resistance to BCR‐ABL inhibitors makes it difficult to continue treatment and is directly related to life expectancy. Therefore, asciminib was introduced to the market as a useful drug for overcoming drug resistance. While combining molecular targeted drugs is useful to avoid drug resistance, the new BCR‐ABL inhibitor asciminib and conventional BCR‐ABL inhibitors should be used as monotherapy in principle. Therefore, we investigated the synergistic effect and mechanism of the combination of asciminib and imatinib. We generated imatinib‐resistant cells using the human CML cell line K562, examined the effects of imatinib and asciminib exposure on cell survival using the WST‐8 assay, and comprehensively analyzed genetic variation related to drug resistance using RNA‐seq and real‐time PCR. A synergistic effect was observed when imatinib and asciminib were combined with or without imatinib resistance. Three genes, GRRP1, ESPN, and NOXA1, were extracted as the sites of action of asciminib. Asciminib in combination with BCR‐ABL inhibitors may improve the therapeutic efficacy of conventional BCR‐ABL inhibitors and prevent the development of resistance. Its dosage may be effective even at minimal doses that do not cause side effects. Further verification of this mechanism of action is needed. Additionally, cross‐resistance between BCR‐ABL inhibitors and asciminib may occur, which needs to be clarified through further validation as soon as possible.","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":null,"pages":null},"PeriodicalIF":2.6,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}