Frontiers in Veterinary Science
·
2025
·
IF 2.9
Jianping Liang,Can Cui,Wenge Ren,Linglin Li,Linyi Lv,Xianhui Huang,Xiangmei Li
Introduction Tenvermectin (TVM) is a novel avermectin-class drug that has attracted attention for its superior antiparasitic potency, low toxicity, and broad-spectrum activity. However, uncertainty about its interaction with cytochrome P450 enzymes (CYPs) has raised concerns about potential therapeutic failure, increased risk of toxicity, dangerous drug combinations, and prolonged discontinuation periods. Method To address these critical safety concerns, we conducted a systematic comparative study using a highly selective and quantitatively accurate substrate conversion assay to assess and compare the effects of TVM and ivermectin (IVM) on the activities of key CYPs (CYP1A1/2, 2B1, 2C6, 2D2, and 3A1/2). Results TVM induced CYP1A, 2C, 2D and 3A activities only at high therapeutic doses (2.5 mg/kg), and its induction was significantly weaker than that of IVM at all doses tested, with the most pronounced difference for CYP3A1/2. Although TVM had weak inhibitory effects on CYP2B1 and 2D2, at therapeutic concentrations these effects are presumably unlikely to cause clinically significant CYP-mediated drug interactions. Conclusion As the first study to report the effects of TVM on CYP enzyme activity, these findings provide important experimental evidence and a theoretical framework for its clinical safety assessment, development of optimal dosing regimens, and rational polypharmacy strategies.
研究领域:
药理学
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毒理学
·
药物代谢
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临床药理学
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寄生虫学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY
·
2015
·Vol. 121
·期 2
·797-806
·
IF 2.042
Li Wen-Li,Zhou Cai-Rong,Zhang Li
The thermal stability properties and the thermal decomposition kinetics of Ivermectin (IVM) were studied at different heating rates by the thermal gravimetric analysis. The kinetic parameters were calculated by F–W–O, Kissinger and Šatava–Šesták methods, respectively. The results show that the thermal decomposition of IVM under nitrogen atmosphere mainly was consisted of three stages. The thermal decomposition reaction happens mainly in the second and third stages. For the second and third stages, their activation energies ( E ) and pre-exponential factors ( A ) were obtained to be 115.18 kJ mol −1 , 152.46 kJ mol −1 and 7.171 × 10 17 min −1 , 2.410 × 10 15 min −1 , respectively. For the second stage, the thermal decomposition mechanism and integral forms for IVM may be the reaction series, chemical reaction, (1 − α ) −1 − 1, and for the third stage, an Avrami–Erofeev equation of random nuclear producing and growing process which reaction order n is 4, [−ln(1 − α )] 4 . The thermodynamic basic data obtained are available for the exploiting new synthesis method, engineering design and industry production of IVM.
研究领域:
药物化学
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热分析
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动力学
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药物稳定性
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DOI
高影响因子
JOURNAL OF CHROMATOGRAPHIC SCIENCE
·
2023
·
IF 1.3
Chen Yuyang,Huang Xiaofang,Guo Zizheng,Zhang Jingyu,Zhang Lixin,Dai Renke
Ivermectin has been widely used for antiparasitic drug, and has recently shown a broad-spectrum antiviral activity, including anti-Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the pharmacokinetic property of ivermectin has not been fully investigated yet. During the plasma preparation, ~32–46% of ivermectin was found in the precipitation. An Liquid Chromatograph-Mass Spectrometer (LC–MS/MS) method for ivermectin in the whole blood samples from beagle dogs was developed and validated. The specificity, accuracy, precision (intra-day and inter-day), matrix effect, recovery and stability of analyte reported here are satisfied with the criteria of Food and Drug Administration (FDA)-Bioanalysis guideline. The oral administrations pharmacokinetics of ivermectin in beagle dogs under fasting and after high-fat meal were studied, and the following parameters were obtained: fasting Cmax, 104 ± 35 μg·L−1; area under the concentration–time curve (AUC0–∞), 2,555 ± 941 h·μg·L−1; and high-fat meal Cmax, 147 ± 35 μg·L−1; AUC0–∞, 4,198 ± 1,279 h·μg·L−1. When the P-gp inhibitor curcumin was also coadministrated orally, Cmax and AUC0–∞ were found to be 177 ± 57 and 4,213 ± 948 h·μg·L−1, respectively. With the comparison to fasting treatment, coadministration of P-gp inhibitor curcumin resulted in increase of the exposure of ivermectin by 1.6-fold, while the exposure after the high-fat diet versus fasting was increased approximately in 1.4-fold, indicating that alternative absorption might play an important role for increasing the exposure of ivermectin for future clinic applications.
研究领域:
药理学
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兽医学
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临床医学
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产品关联
DOI
PubMed
高影响因子
eLife
·
2025
·
IF 0
Yi Li,Long Gong,Jing Wu,Wesley Hung,Mei Zhen,Shangbang Gao
Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.
研究领域:
寄生虫学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY
·
2015
·Vol. 124
·期 1
·447-453
·
IF 2.042
Li Wen-li,Zhou Cai-rong,Zhang Li
The specific heat capacity ( C
p ) of ivermectin (IVM) was measured by differential scanning calorimetry (DSC) and expressed as a function of temperature. Moreover, the standard molar combustion enthalpy of IVM was determined to be −26963.6 kJ mol −1 by XRY-1C calorimeter. The standard molar enthalpy of formation was calculated to be −862866.3 kJ mol −1 based on the standard molar combustion enthalpy. The thermodynamic basic data obtained are available for exploiting new synthesis methodology, engineering design and industry production of IVM.
✓ 已验证
DOI
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Zhou Shican,Wu Hang,Ning Wenjuan,Wu Xiao,Xu Xiaoxiao,Ma Yuanqiao,Li Xingwang,Hu Junhong,Wang Chenyu,Wang Junpeng
Colorectal cancer (CRC) is the third most common cancer worldwide and still lacks effective therapy. Ivermectin, an antiparasitic drug, has been shown to possess anti-inflammation, anti-virus, and antitumor properties. However, whether ivermectin affects CRC is still unclear. The objective of this study was to evaluate the influence of ivermectin on CRC using CRC cell lines SW480 and SW1116. We used CCK-8 assay to determine the cell viability, used an optical microscope to measure cell morphology, used Annexin V-FITC/7-AAD kit to determine cell apoptosis, used Caspase 3/7 Activity Apoptosis Assay Kit to evaluate Caspase 3/7 activity, used Western blot to determine apoptosis-associated protein expression, and used flow cytometry and fluorescence microscope to determine the reactive oxygen species (ROS) levels and cell cycle. The results demonstrated that ivermectin dose-dependently inhibited colorectal cancer SW480 and SW1116 cell growth, followed by promoting cell apoptosis and increasing Caspase-3/7 activity. Besides, ivermectin upregulated the expression of proapoptotic proteins Bax and cleaved PARP and downregulated antiapoptotic protein Bcl-2. Mechanism analysis showed that ivermectin promoted both total and mitochondrial ROS production in a dose-dependent manner, which could be eliminated by administering N-acetyl-l-cysteine (NAC) in CRC cells. Following NAC treatment, the inhibition of cell growth induced by ivermectin was reversed. Finally, ivermectin at low doses (2.5 and 5 µM) induced CRC cell arrest. Overall, ivermectin suppressed cell proliferation by promoting ROS-mediated mitochondrial apoptosis pathway and inducing S phase arrest in CRC cells, suggesting that ivermectin might be a new potential anticancer drug therapy for human colorectal cancer and other cancers.
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIODEGRADATION
·
2020
·Vol. 31
·期 4
·275-288
·
IF 2.805
Wang Yuanshan,Gong Meihua,Wang Xianlin,Peng Xiaolun,Wang Yuwei,Guan Jiahui,Cheng Dongyuan,Weng Chunyue,Zheng Yuguo
Ivermectin (IVM) is a widely used antiparasitic agent and acaricide. Despite its high efficiency against nematodes and arthropods, IVM may pose a threat to the environment due to its ecotoxcity. In this study, degradation of IVM by a newly isolated bacterium Aeromonas taiwanensis ZJB-18,044 was investigated. Strain ZJB-18,044 can completely degrade 50 mg/L IVM in 5 d with a biodegradation ability of 0.42 mg/L/h. Meanwhile, it exhibited high tolerance (50 mg/L) to doramectin, emamectin, rifampicin, and spiramycin. It can also efficiently degrade doramectin, emamectin, and spiramycin. The IVM degradation of strain ZJB-18,044 can be inhibited by erythromycin, azithromycin, spiramycin or rifampicin. However, supplement of carbonyl cyanide m -chlorophenylhydrazone, an uncoupler of oxidative phosphorylation, can partially recover the IVM degradation. Moreover, strain ZJB-18,044 cells can pump out excess IVM to maintain a low intracellular IVM concentration. Therefore, the IVM tolerance of strain ZJB-18,044 may be due to the regulation of the intracellular IVM concentration by the activated macrolide efflux pump(s). With the high IVM degradation efficiency, A. taiwanensis ZJB-18,044 may serve as a bioremediation agent for IVM and other macrolides in the environment.
研究领域:
环境科学
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微生物学
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生物修复
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2022
·
IF 7.419
Yuanqiao Ma,Xiaoxiao Xu,Hang Wu,Changbo Li,Peijie Zhong,Zejin Liu,Chuang Ma,Wenhua Liu,Chenyu Wang,Yijie Zhang,Junpeng Wang
Ivermectin has been proposed as a potential anti-inflammatory drug in addition to its antiparasitic activity. Here we investigated the potential role of ivermectin in the pathogenesis of acute lung injury (ALI) using the lipopolysaccharide (LPS)- or bleomycin (BLM)-induced mice models. Male C57BL/6 mice were given ivermectin orally every day for the remainder of the experiment at doses of 1 or 2 mg/kg after 24 h of LPS or BLM treatment. Ivermectin reversed severe lung injury caused by LPS or BLM challenge, including mortality, changes in diffuse ground-glass and consolidation shadows on lung CT imaging, lung histopathological scores, lung wet/dry ratio, and protein content in the bronchoalveolar lavage fluid (BALF). Furthermore, ivermectin also reduced total lung BALF inflammatory cells, infiltrating neutrophils, myeloperoxidase activity, and plasma TNF-α and IL-6 levels in mice treated with LPS or BLM. Finally, the mechanism study showed that LPS or BLM administration increased JNK, Erk1/2, and p38 MAPK phosphorylation while decreasing IκBα expression, an inhibitor of NF-κB. However, ivermectin increased IκBα expression but blocked elevated phosphorylated JNK and p38 MAPK, not Erk1/2, in both ALI mice. These findings suggested that ivermectin may alleviate ALI caused by LPS or BLM in mice, partly via lowering the inflammatory response, which is mediated at least by the inhibition of MAPK and NF-κB signaling. Collectively, ivermectin might be used to treat acute lung injury/acute respiratory distress syndrome.
研究领域:
药理学
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免疫学
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呼吸病学
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DOI
PubMed
高影响因子
Anti-Cancer Agents in Medicinal Chemistry
·
2024
·Vol. 24
·期 5
·348-357
·
IF 2.6
Fan Ning,Zhang Lixiu,Wang Zhiping,Ding Hui,Yue Zhongjin
Background: Bladder cancer is the most common malignant tumor of the urinary system. Nevertheless, current therapies do not provide satisfactory results. It is imperative that novel strategies should be developed for treating bladder cancer. Objectives: To evaluate the effect of
a broad-spectrum anti-parasitic agent, Ivermectin, on bladder cancer cells in vitro and in vivo. Methods: CCK-8 and EdU incorporation assays were used to evaluate cell proliferation. Apoptosis was detected by flow cytometry, TUNEL assay, and western blotting. Flow cytometry
and DCFH-DA assay were used to analyze the reactive oxygen species (ROS) levels. DNA damage was determined by Neutral COMET assay and γ H2AX expression. Proteins related to apoptosis and DNA damage pathways were determined by WB assay. Xenograft tumor models in nude mice were used to
investigate the anti-cancer effect of Ivermectin in vivo. Results: Our study showed that in vitro and in vivo, Ivermectin inhibited the growth of bladder cancer cells. In addition, Ivermectin could induce apoptosis, ROS production, DNA damage, and activate ATM/P53
pathwayrelated proteins in bladder cancer cells. Conclusion: According to these findings, Ivermectin may be a potential therapeutic candidate against bladder cancer due to its significant anti-cancer effect.
研究领域:
肿瘤学
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药理学
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分子生物学
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
Veterinary Medicine and Science
·
2023
·Vol. 9
·期 3
·1211-1216
·
IF 1.7
Guiyu Li,Xingyuan Cao,Jianwei Liao,Yanming Wei
Tenvermectin (TVM) is a novel 16-membered macrolide compound isolated and purified from the fermentation broth of genetically engineered Streptomyces avermitilis strain MHJ1011 . TVM and ivermectin were administered at the dose of 0.3 mg/kg body weight through a single subcutaneous injection route followed by plasma collectiom and analysis at different time intervals. Plasma concentrations of TVM and IVM were determined by high-performance liquid chromatography with fluorescence detector. Pharmacokinetic analysis was completed using the non-compartmental method with WinNonlin™ 6.4 software. TVM is rapidly absorbed after administration with peak plasma concentrations ( C max , 9.78 ± 2.34 ng/ml) obtained within 6–22 h. AUC 0-last was 586.86 h·ng/ml ± 121.24 h·ng/ml. The mean elimination half-life of TVM ( T 1/2λz ) was 97.99 h ± 46.41 h. The T 1/2λz of IVM was 146.59 h ± 22.26 h in the study. The present study showed that subcutaneous administration of TVM at 0.3 mg/kg body weight (BW) in swine is absorbed more rapidly than IVM in swine. Compared to the pharmacokinetic characteristics of IVM, there was little difference in the half-life of TVM among different individuals. The data will contribute to refining the formulation and dosage regime for TVM administration.
研究领域:
兽医学
·
药理学
·
寄生虫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
World Journal of Clinical Oncology
·
2024
·
IF 2.6
Yang Song,Hao-Jun Zhang,Xia Song,Jie Geng,Hong-Yi Li,Li-Zhong Zhang,Bo Yang,Xue-Chun Lu
BACKGROUND Multiple myeloma (MM) is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow. The translocation, (t)(4;14), results in high-risk MM with limited treatment alternatives. Thus, there is an urgent need for identification and validation of potential treatments for this MM subtype. Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets. AIM To elucidate the molecular basis and search for potential effective drugs of t(4;14) MM subtype by employing a comprehensive approach. METHODS The transcriptional signature of t(4;14) MM was sourced from the Gene Expression Omnibus. Two datasets, {"type":"entrez-geo","attrs":{"text":"GSE16558","term_id":"16558"}} GSE16558 and {"type":"entrez-geo","attrs":{"text":"GSE116294","term_id":"116294"}} GSE116294 , which included 17 and 15 t(4;14) MM bone marrow samples, and five and four normal bone marrow samples, respectively. After the differentially expressed genes were identified, the Cytohubba tool was used to screen for hub genes. Then, the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Using the STRING database and Cytoscape, protein–protein interaction networks and core targets were identified. Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis, respectively. RESULTS In this study, a total of 258 differentially expressed genes with enriched functions in cancer pathways, namely cytokine receptor interactions, nuclear factor (NF)-κB signaling pathway, lipid metabolism, atherosclerosis, and Hippo signaling pathway, were identified. Ten hub genes ( cd45, vcam1, ccl3, cd56, app, cd48, btk, ccr2, cybb, and cxcl12 ) were identified. Nine drugs, including ivermectin, deforolimus, and isoliquiritigenin, were predicted by the Connectivity Map database to have potential therapeutic effects on t (4;14) MM. In molecular docking, ivermectin showed strong binding affinity to all 10 identified targets, especially cd45 and cybb . Ivermectin inhibited t(4;14) MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro. Furthermore, ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14) MM cells. CONCLUSION Collectively, the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14) MM diagnosis and treatment, with ivermectin emerging as a potential therapeutic alternative.
研究领域:
肿瘤学
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药理学
·
分子生物学
·
生物信息学
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
PeerJ
·
2018
·
IF 2.118
Xiangchun Ruan,Xiuge Gao,Ying Gao,Lin Peng,Hui Ji,Dawei Guo,Shanxiang Jiang
Sustained-release formulations of ivermectin (IVM) are useful for controlling parasitic diseases in animals. In this work, an IVM bolus made from microcrystalline cellulose (MCC), starch and low-substituted hydroxypropyl cellulose (LS-HPC) was optimized by response surface methodology. The bolus was dissolved in a cup containing 900 mL of dissolution medium at 39.5 °C, under with stirring at 100 rpm. A quadratic model was formulated using analysis of variance according to the dissolution time. The optimized formulation of the bolus contained 8% MCC, 0.5% starch, and 0.25% LS-HPC. The length, width, and height of the prepared IVM bolus were 28.12 ± 0.14, 16.1 ± 0.13, and 13.03 ± 0.05 mm, respectively. The bolus weighed 11.4842 ± 0.1675 g (with a density of 1.95 g/cm 3 ) and contained 458.26 ± 6.68 mg of IVM. It exhibited in vitro sustained-release for over 60 days, with a cumulative amount and percentage of released IVM of 423.72 ± 5.48 mg and 92.52 ± 1.20%, respectively. The Korsmeyer–Peppas model provided the best fit to the dissolution release kinetics, exhibiting an R 2 value close to 1 and the lowest Akaike Information Criterion among different models. The parameter n (0.5180) of the Korsmeyer–Peppas model was between 0.45 and 0.89. It was demonstrated that the release mechanism of the IVM bolus followed a diffusive erosion style.
研究领域:
药剂学
·
兽医学
·
药物递送
·
生物药剂学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）