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The Absorption, Distribution, Metabolism, and Excretion of Binimetinib Following a Single Oral Dose of [14C]Binimetinib 45 mg in Healthy Male Participants.
IF 2.9 4区 医学
Pharmacology Research & Perspectives Pub Date : 2025-02-01 DOI: 10.1002/prp2.70061
Dustin Huynh, Erik Hahn, Micaela B Reddy, Renae Chavira, Lance Wollenberg
{"title":"The Absorption, Distribution, Metabolism, and Excretion of Binimetinib Following a Single Oral Dose of [<sup>14</sup>C]Binimetinib 45 mg in Healthy Male Participants.","authors":"Dustin Huynh, Erik Hahn, Micaela B Reddy, Renae Chavira, Lance Wollenberg","doi":"10.1002/prp2.70061","DOIUrl":"10.1002/prp2.70061","url":null,"abstract":"<p><p>Binimetinib is a MEK1/2 inhibitor particularly active in cells harboring activating mutations in the MAP kinase pathway, especially in BRAF and NRAS. Binimetinib, in combination with encorafenib, has received marketing approval in several jurisdictions for the treatment of patients with BRAF V600E or V600K mutant melanoma. The absorption, distribution, metabolism, and excretion of binimetinib were evaluated by administering a carbon 14-labeled binimetinib 45 mg dose (containing 40 μCi of radiolabeled material) to 6 healthy male participants. A total of 62.3% of the radioactivity was eliminated in the feces, while 31.4% was eliminated in the urine. The overall recovery of radioactivity in the excreta for all 6 participants was 93.6% (3.27%), indicating that good mass balance was achieved. The total percentage of the dose in the excreta of all metabolites containing the N-demethylation clearance of binimetinib by CYP1A2 and CYP2C19 was approximately 17.8%. The contribution of direct glucuronidation to the clearance of binimetinib was estimated to be 61.2% and represented the majority of the clearance. Additionally, excretion of unchanged binimetinib into the urine was estimated to have contributed 6.9% to the overall clearance. Based on study results, binimetinib is at least ≈ 50% absorbed, but based on its PK properties and because its glucuronide conjugates are unstable in the GI tract, absorption is thought to be significantly higher.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70061"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066678","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}
引用次数: 0
HDAC4/5 Inhibitor, LMK-235 Improves Animal Voluntary Movement in MPTP-Induced Parkinson's Disease Model. HDAC4/5抑制剂LMK-235改善mptp诱导的帕金森病模型动物自主运动
IF 2.9 4区 医学
Pharmacology Research & Perspectives Pub Date : 2025-02-01 DOI: 10.1002/prp2.70057
Heejin Lee, Hyun-Jin Kim, Ju-Sik Min, Eunhye Lee, Dong Kyu Choi, Jae-Hyeog Choi, Yohan Seo, Sion Lee, Chun Young Im, Gi Hun Bae, Yoojin Oh, Eun-A Ko, Sung-Cherl Jung, Soong-Hyun Kim, Oh-Bin Kwon
{"title":"HDAC4/5 Inhibitor, LMK-235 Improves Animal Voluntary Movement in MPTP-Induced Parkinson's Disease Model.","authors":"Heejin Lee, Hyun-Jin Kim, Ju-Sik Min, Eunhye Lee, Dong Kyu Choi, Jae-Hyeog Choi, Yohan Seo, Sion Lee, Chun Young Im, Gi Hun Bae, Yoojin Oh, Eun-A Ko, Sung-Cherl Jung, Soong-Hyun Kim, Oh-Bin Kwon","doi":"10.1002/prp2.70057","DOIUrl":"10.1002/prp2.70057","url":null,"abstract":"<p><p>Oxidation of dopamine can cause various side effects, which ultimately leads to cell death and contributes to Parkinson's disease (PD). To counteract dopamine oxidation, newly synthesized dopamine is quickly transported into vesicles via vesicular monoamine transporter 2 (VMAT2) for storage. VMAT2 expression is reduced in patients with PD, and studies have shown increased accumulation of dopamine oxidation byproducts and α-synuclein in animals with low VMAT2 expression. Conversely, animals that overexpress VMAT2 show better protection for dopamine neurons. Based on these findings, this study used histone deacetylase inhibitors (HDACi) to increase VMAT2 expression, reduce dopamine-induced oxidative stress, and evaluate the resulting behavioral improvements in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. LMK-235 not only increased VMAT2 expression at various concentrations in the SH-SY5Y cell line differentiated into dopaminergic cells but also demonstrated effective cytoprotective properties in several toxicity assays. It significantly raised VMAT2 expression in both the striatum and the ventral tegmental area of an MPTP-induced PD model, supporting its role in reversing behavioral abnormalities linked to PD. In addition to these results, coadministration of LMK-235 with L-DOPA, a standard therapy for PD, restored typical behavioral patterns, highlighting the potential of HDACi in alleviating PD symptoms. The expression of VMAT2 induced by LMK-235, an inhibitor of Class IIa histone deacetylases primarily found in the nervous system, aids in sequestering dopamine into vesicles, potentially enhancing cell survival by inhibiting dopamine oxidation. Additionally, upregulation of VMAT2 has been shown to offer effective protection against MPTP-induced toxicity and significantly improve behavioral abnormalities associated with PD. Coadministration with L-DOPA produced the most notable improvement in behavioral outcomes. Altogether, these findings suggest that the overexpression of VMAT2 may offer a promising strategy for developing treatments for PD by mitigating dopaminergic neuron death resulting from dopamine oxidation.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70057"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979430","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}
引用次数: 0
Repurposed Medicines: A Scan of the Non-commercial Clinical Research Landscape. 重新利用药物:非商业临床研究景观的扫描。
IF 2.9 4区 医学
Pharmacology Research & Perspectives Pub Date : 2025-02-01 DOI: 10.1002/prp2.70049
Sola Akinbolade, Ross Fairbairn, Alex Inskip, Rhiannon Potter, Aoife Oliver, Dawn Craig
{"title":"Repurposed Medicines: A Scan of the Non-commercial Clinical Research Landscape.","authors":"Sola Akinbolade, Ross Fairbairn, Alex Inskip, Rhiannon Potter, Aoife Oliver, Dawn Craig","doi":"10.1002/prp2.70049","DOIUrl":"10.1002/prp2.70049","url":null,"abstract":"<p><p>Medicine repurposing is a strategy to identify new uses for the existing medicines for the purpose of addressing areas of unmet medical need. This paper aims to provide horizon scanning intelligence on repurposed medicines that are evaluated by non-commercial organizations such as academia and highlights opportunities for further research to improve patient health outcomes. A scan of the clinical landscape of non-commercially sponsored repurposed medicines is routinely conducted by the NIHR Innovation Observatory (IO). This ongoing project involves a horizon scan of clinical trial registries and the IO's internal horizon scanning Medicines Innovation Database to identify potential candidate medicines used as monotherapy or in combination to treat new indications outside the scope of their licensed indication. In addition to making these data publicly available, the output also supports the NHS England Medicines Repurposing Programme. The snapshot scan reported here (trials completing April 2020-March 2023) identified a total of 528 technologies (meaning, a single product or combination of medicinal products targeting a specific indication in one or more related trials). The technologies were classified according to their characteristics and targeted therapeutic indications as well as revealing the least treated disease conditions. The candidate medicines identified in this scan could potentially receive tailored support toward adoption into practice and policy. The NIHR IO regularly provides this scan as a source of intelligence on repurposed medicines. This provides valuable insights into innovation trends, gaps, and areas of unmet clinical need.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70049"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142838727","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}
引用次数: 0
Are We Estimating the Mean and Variance Correctly in the Presence of Observations Outside of Measurable Range? 在可测量范围之外的观测值存在的情况下,我们对均值和方差的估计是否正确?
IF 2.9 4区 医学
Pharmacology Research & Perspectives Pub Date : 2025-02-01 DOI: 10.1002/prp2.70048
Markéta Janošová, Stanislav Katina, Jozef Hanes
{"title":"Are We Estimating the Mean and Variance Correctly in the Presence of Observations Outside of Measurable Range?","authors":"Markéta Janošová, Stanislav Katina, Jozef Hanes","doi":"10.1002/prp2.70048","DOIUrl":"10.1002/prp2.70048","url":null,"abstract":"<p><p>Laboratory measurements used for safety assessments in clinical trials are subject to the limits of the used laboratory equipment. These limits determine the range of values which the equipment can accurately measure. When observations fall outside the measurable range, this creates a problem in estimating parameters of the normal distribution. It may be tempting to use methods of estimation that are easy to implement, however selecting an incorrect method may lead to biased estimates (under- or overestimation) and change the research outcomes, for example, incorrect result of two-sample test about means when comparing two populations or biased estimation of regression line. In this article, we consider the use of four methods: ignoring unmeasured observations, replacing unmeasured observations with a multiple of the limit, using a truncated normal distribution, and using a normal distribution with censored observations. To compare these methods we designed a simulation study and measured their accuracy in several different situations using relative error <math> <semantics> <mrow> <mfrac> <mrow><mover><mi>μ</mi> <mo>̂</mo></mover> <mo>-</mo> <mi>μ</mi></mrow> <mi>μ</mi></mfrac> </mrow> <annotation>$$ frac{hat{mu}-mu }{mu } $$</annotation></semantics> </math> , ratio <math> <semantics> <mrow> <mfrac><mover><mi>σ</mi> <mo>̂</mo></mover> <mi>σ</mi></mfrac> </mrow> <annotation>$$ frac{hat{sigma}}{sigma } $$</annotation></semantics> </math> , and mean square errors of both parameters. Based on the results of this simulation study, if the amount of observations outside of measurable range is below 40%, we recommend using a normal distribution with censored observations in practice. These recommendations should be incorporated into guidelines for good statistical practice. If the amount of observations outside of measurable range exceeds 40%, we advise not to use the data for any statistical analysis. To illustrate how the choice of method can affect the estimates, we applied the methods to real-life laboratory data.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70048"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872751","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}
引用次数: 0
Part 2: Drug Interactions Involving Cannabis Products in Persons Aged 18 and Over: A Summary of Published Case Reports and Analysis of the FDA Adverse Event Reporting System. 第2部分:18岁及以上人群中涉及大麻产品的药物相互作用:已发表病例报告总结和FDA不良事件报告系统分析。
IF 2.9 4区 医学
Pharmacology Research & Perspectives Pub Date : 2025-02-01 DOI: 10.1002/prp2.70047
Maryann R Chapin, Sandra L Kane-Gill, Xiaotong Li, Kojo Abanyie, Sanya B Taneja, Susan Egbert, Mary F Paine, Richard D Boyce
{"title":"Part 2: Drug Interactions Involving Cannabis Products in Persons Aged 18 and Over: A Summary of Published Case Reports and Analysis of the FDA Adverse Event Reporting System.","authors":"Maryann R Chapin, Sandra L Kane-Gill, Xiaotong Li, Kojo Abanyie, Sanya B Taneja, Susan Egbert, Mary F Paine, Richard D Boyce","doi":"10.1002/prp2.70047","DOIUrl":"10.1002/prp2.70047","url":null,"abstract":"<p><p>The increasing utilization of cannabis products combined with lack of data regarding potential cannabis-prescription drug interactions is concerning. This study aimed to review published case reports and FDA Adverse Event Reporting System (FAERS) spontaneous reports to assess cannabis-drug interactions in persons aged 18 and over. A literature search identified 20 case reports that were each assessed for drug interaction causality using the Drug Interaction Probability Scale. Data collected from the FAERS revealed a greater proportion of reports mentioning serious outcomes, including death, when cannabis was used concomitantly with controlled substances compared to noncontrolled substances. Fisher's exact test showed a statistically significant difference between the controlled and noncontrolled groups (p = 0.043). Overall, these findings emphasize the need for additional research and vigilant monitoring of cannabis use when combined with other medications.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70047"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885387","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}
引用次数: 0
A549 Alveolar Carcinoma Spheroids as a Cytotoxicity Platform for Carboxyl- and Amine-Polyethylene Glycol Gold Nanoparticles. 羧基和胺-聚乙二醇金纳米颗粒作为肺泡癌球体的细胞毒性平台。
IF 2.9 4区 医学
Pharmacology Research & Perspectives Pub Date : 2025-02-01 DOI: 10.1002/prp2.70051
Melissa Petzer, Seth-Frerich Fobian, Mary Gulumian, Vanessa Steenkamp, Werner Cordier
{"title":"A549 Alveolar Carcinoma Spheroids as a Cytotoxicity Platform for Carboxyl- and Amine-Polyethylene Glycol Gold Nanoparticles.","authors":"Melissa Petzer, Seth-Frerich Fobian, Mary Gulumian, Vanessa Steenkamp, Werner Cordier","doi":"10.1002/prp2.70051","DOIUrl":"10.1002/prp2.70051","url":null,"abstract":"<p><p>Gold nanoparticles (AuNPs) present with unique physicochemical features and potential for functionalization as anticancer agents. Three-dimensional spheroid models can be used to afford greater tissue representation due to their heterogeneous phenotype and complex molecular architecture. This study developed an A549 alveolar carcinoma spheroid model for cytotoxicity assessment and mechanistic evaluation of functionalized AuNPs. A549 spheroids were generated using an agarose micro-mold and were characterized (morphology, acid phosphatase activity, protein content) over 21 culturing days. The 72-h cytotoxicity of carboxyl-polyethylene glycol- (PCOOH-) and amine-polyethylene glycol- (PNH<sub>2</sub>-) functionalized AuNPs against Day 7 spheroids was assessed by determining spheroid morphology, acid phosphatase activity, protein content, caspase-3/7 activity, and cell cycle kinetics. Spheroids remained stable over the experimental period. Although the A549 spheroids' volume increased while remaining viable over the culturing period, structural integrity decreased from Day 14 onwards. The PCOOH-AuNPs lacked cytotoxicity at a maximum concentration of 1.2 × 10<sup>12</sup> nanoparticles/mL with no prominent alteration to the cellular processes investigated, while the PNH<sub>2</sub>-AuNPs (at a maximum of 4.5 × 10<sup>12</sup> nanoparticles/mL) displayed dose- and time-dependent cytotoxicity with associated loss of spheroid compactness, debris formation, DNA fragmentation, and a 75% reduction in acid phosphatase activity. Differentiation between cytotoxic and non-cytotoxic AuNPs was achieved, with preliminary elucidation of cytotoxicity endpoints. The PNH<sub>2</sub>-AuNPs promote cytotoxicity by modulating cellular kinetics while destabilizing the spheroid ultrastructure. The model serves as a proficient platform for more in-depth elucidation of NP cytotoxicity at the preclinical investigation phase.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70051"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896376","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}
引用次数: 0
Intravitreal Administration of Avacincaptad Pegol in a Nonhuman Primate Model of Dry Age-Related Macular Degeneration. 非人类灵长类干性年龄相关性黄斑变性模型玻璃体内注射无活性Pegol。
IF 2.9 4区 医学
Pharmacology Research & Perspectives Pub Date : 2025-02-01 DOI: 10.1002/prp2.70052
Rintaro Fujii, Mayumi Matsushita, Yoshitaka Itani, Aldric Hama, Takahiro Natsume, Hiroyuki Takamatsu
{"title":"Intravitreal Administration of Avacincaptad Pegol in a Nonhuman Primate Model of Dry Age-Related Macular Degeneration.","authors":"Rintaro Fujii, Mayumi Matsushita, Yoshitaka Itani, Aldric Hama, Takahiro Natsume, Hiroyuki Takamatsu","doi":"10.1002/prp2.70052","DOIUrl":"10.1002/prp2.70052","url":null,"abstract":"<p><p>The lack of effective treatments for dry age-related macular degeneration (AMD) is in part due to a lack of a preclinical animal model that recapitulates features of the clinical state including macular retinal pigment epithelium (RPE) degeneration, also known as geographic atrophy (GA). A nonhuman primate model of GA was developed and its responsiveness to an approved treatment, avacincaptad pegol (ACP), a complement C5 inhibitor, was evaluated. Intravitreal (ivt) administration of sodium iodate (SI) into one eye of male Macaca fascicularis leads to retinal areas (mm<sup>2</sup>) of hyper- or hypo-autofluorescence. Qualitative changes to the retinal structure over time were observed with spectral domain optical coherence tomography (OCT). Six days after SI administration, prior to treatment, mean (± SEM) GA of all eyes was 8.2 ± 1.8 mm<sup>2</sup>. Following randomization to treatment groups, either vehicle or ACP was ivt injected and treatment was continued every 4 weeks, for a total of four treatments. Sixteen weeks after SI administration, the GA area in vehicle-treated eyes was 18.9 ± 6.6 mm<sup>2</sup>, whereas GA in ACP-treated eyes was 11.4 ± 4.0 mm<sup>2</sup>, a reduction by about 36%. Increased, followed by decreased, overall macular thickness was observed with OCT over time following SI administration. Treatment with ACP did not change alter macular thickness thinning. Geographic atrophy-like lesions that expand over time are observed following SI administration. The current macaque model could be utilized to further explore the mechanism of dry AMD and to develop more novel therapeutics.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70052"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896377","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}
引用次数: 0
A Clinical Practice-Based Comparison of Conventional and Individualized Dosing Strategies for Therapeutic Enoxaparin.
IF 2.9 4区 医学
Pharmacology Research & Perspectives Pub Date : 2025-02-01 DOI: 10.1002/prp2.70039
Anthony Damiani, Viviane De Menezes Caceres, Greg Roberts, Jessica Coddo, Nicholas Scarfo, Desmond B Willliams, Vinosshini Tharmathurai, Rami Tadros, Stephen Fitzgerald, Alice O'Connell, Amrit Kaur Sandhu, Andrew Vanlint, Arduino A Mangoni, Dirk Hofmann, Hosam Bony, Jeff Faunt, Jir Ping Boey, Nicholas Farinola, Rachel Wells, Stephen Hedger, Udul Hewage, Yogesh Sharma, Zuhair Jabbar, Josephine Thomas, Katerina Flabouris, Toby Gilbert, Campbell Thompson, Patrick Russell
{"title":"A Clinical Practice-Based Comparison of Conventional and Individualized Dosing Strategies for Therapeutic Enoxaparin.","authors":"Anthony Damiani, Viviane De Menezes Caceres, Greg Roberts, Jessica Coddo, Nicholas Scarfo, Desmond B Willliams, Vinosshini Tharmathurai, Rami Tadros, Stephen Fitzgerald, Alice O'Connell, Amrit Kaur Sandhu, Andrew Vanlint, Arduino A Mangoni, Dirk Hofmann, Hosam Bony, Jeff Faunt, Jir Ping Boey, Nicholas Farinola, Rachel Wells, Stephen Hedger, Udul Hewage, Yogesh Sharma, Zuhair Jabbar, Josephine Thomas, Katerina Flabouris, Toby Gilbert, Campbell Thompson, Patrick Russell","doi":"10.1002/prp2.70039","DOIUrl":"10.1002/prp2.70039","url":null,"abstract":"<p><p>To understand differences in anti-factor-Xa levels produced by two different dosing strategies (conventional and individualized) for therapeutic enoxaparin in a cohort of hospital inpatients. A multicenter, retrospective cohort study over a two- and a half-year period for inpatients with stable renal function and on therapeutic enoxaparin. Anti-factor-Xa levels were taken 3-5 h after enoxaparin administration and a minimum of 48 h of dosing. The final analysis included 278 patients from five hospitals: conventional dosing was used for 141, while 137 were given an unconventional dose, that is, individualized for their renal function and weight. Out-of-range levels were frequent (35% to 40% of all inpatients). After adjustment for age, renal function, and body mass index (BMI), the conventional group was more likely to experience above-range levels (> 1.0 IU/mL; OR 2.50 [95% CI 1.38-4.56], p < 0.003) than the individualized group. Individualized dosing was independently associated with higher odds of a below-range anti-Xa level (< 0.5 IU/mL) compared to conventional dosing (OR 2.27 [95% CI 1.07-4.76], p = 0.03). Within the conventional group, above-range levels were significantly and independently associated with decreasing renal function (OR 0.97, 95% CI 0.96-0.99, p = 0.004) and with increasing BMI (OR 1.06, 95% CI 1.01-1.10, p = 0.02). No such associations were seen with an individualized approach. Clinical event rates were low and not different between groups (p > 0.24). Conventional therapeutic dosing of enoxaparin exposed people with obesity or renal impairment to more frequent above-range anti-factor-Xa levels; individualizing the dose could improve this but might expose people to subtherapeutic levels. More research is needed.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70039"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11760983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033061","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}
引用次数: 0
Transfer of the Oral Gonadotropin-Releasing Hormone Receptor Antagonist Relugolix Into Breast Milk of Healthy Lactating Women.
IF 2.9 4区 医学
Pharmacology Research & Perspectives Pub Date : 2025-02-01 DOI: 10.1002/prp2.70067
Darin B Brimhall, Yu-Luan Chen, Sarah Lee, Kazumasa Yoshida, Mike Ufer
{"title":"Transfer of the Oral Gonadotropin-Releasing Hormone Receptor Antagonist Relugolix Into Breast Milk of Healthy Lactating Women.","authors":"Darin B Brimhall, Yu-Luan Chen, Sarah Lee, Kazumasa Yoshida, Mike Ufer","doi":"10.1002/prp2.70067","DOIUrl":"10.1002/prp2.70067","url":null,"abstract":"<p><p>Relugolix is an oral gonadotropin-releasing hormone receptor antagonist that suppresses sex steroid hormones and is approved as monotherapy for prostate cancer and as a fixed-dose combination with estradiol/norethindrone for the treatment of endometriosis and uterine fibroids. The aim of this postmarketing study was to determine the pharmacokinetics and quantify the amount of relugolix excreted into breast milk of healthy lactating women. Following a single, oral dose of 40 mg relugolix, breast milk was sampled over 120 h. Pharmacokinetic parameters were determined, including the cumulative amount of relugolix excreted into breast milk to derive the total infant dose. The safety and tolerability of relugolix were also assessed. Eight healthy lactating women were enrolled and completed the study per protocol. Relugolix was safe and well tolerated based on adverse events and other safety data. It was excreted into breast milk with a median time to peak concentration (t<sub>max</sub>) of 5.81 h and a geometric mean peak concentration (C<sub>max</sub>) of 15.7 ng/mL, similar to corresponding plasma data from previous clinical studies. The mean cumulative amount of relugolix excreted was 0.0051 mg over 24 h and 0.0067 mg over 120 h, corresponding to 0.0128% and 0.0167% of the maternal dose, respectively. The body weight-adjusted relative daily infant dose of approximately 0.25% suggests a 400-fold lower newborn than maternal relugolix exposure. Relevant effects of relugolix on the breastfed child appear unlikely given its limited excretion into breast milk of lactating women but cannot be fully excluded in the absence of infant safety data.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"13 1","pages":"e70067"},"PeriodicalIF":2.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066960","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}
引用次数: 0
From Psychiatry to Oncology: Exploring the Anti-Neoplastic Mechanisms of Aripiprazole and Its Potential Use in Cancer Treatment.
IF 2.9 4区 医学
Pharmacology Research & Perspectives Pub Date : 2025-02-01 DOI: 10.1002/prp2.70076
Liam A O'Callaghan, Ciara B Blum, Katie Powell, Russ Chess-Williams, Catherine McDermott
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