BMC Pharmacology & Toxicology最新文献

{"title":"Rotenone activates the LKB1-AMPK-ULK1 signaling pathway to induce autophagy and apoptosis in rat thoracic aortic endothelial cells.","authors":"Xiaoyu Chang, Zeyuan Li, Mi Tian, Ziwei Deng, Lingqin Zhu, Guanghua Li","doi":"10.1186/s40360-024-00755-5","DOIUrl":"10.1186/s40360-024-00755-5","url":null,"abstract":"<p><strong>Background: </strong>The specific mechanism by which rotenone impacts thoracic aortic autophagy and apoptosis is unknown. We aimed to investigate the regulatory effects of rotenone on autophagy and apoptosis in rat thoracic aortic endothelial cells (RTAEC) via activation of the LKB1-AMPK-ULK1 signaling pathway and to elucidate the molecular mechanisms of rotenone on autophagy and apoptosis in vascular endothelial cells.</p><p><strong>Methods: </strong>In vivo, 60 male SD rats were randomly selected and divided into 5 groups: control (Con), DMSO, 1, 2, and 4 mg/kg groups, respectively. After 28 days of treatment, histopathological and ultrastructural changes in each group were observed using HE and transmission electron microscopy; Autophagy, apoptosis, and LKB1-AMPK-ULK1 pathway-related proteins were detected by Western blot; Apoptosis levels in the thoracic aorta were detected by TUNEL. In vitro, RTAEC were cultured and divided into control (Con), DMSO, 20, 100, 500, and 1000 nM groups. After 24 h of intervention, autophagy, apoptosis, and LKB1-AMPK-ULK1 pathway-related factors were detected by Western blot and qRT-PCR; Flow cytometry to detect apoptosis levels; Autophagy was inhibited with 3-MA and CQ to detect apoptosis levels, and changes in autophagy, apoptosis, and downstream factors were detected by the AMPK inhibitor CC intervention.</p><p><strong>Results: </strong>Gavage in SD rats for 28 days, some degree of damage was observed in the thoracic aorta and heart of the rotenone group, as well as the appearance of autophagic vesicles was observed in the thoracic aorta. TUNEL analysis revealed higher apoptosis in the rotenone group's thoracic aorta; RTAEC cultured in vitro, after 24 h of rotenone intervention, showed increased ROS production and significantly decreased ATP production. The flow cytometry data suggested an increase in the number of apoptotic RTAEC. The thoracic aorta and RTAEC in the rotenone group displayed elevated levels of autophagy and apoptosis, and the LKB1-AMPK-ULK1 pathway proteins were activated and expressed at higher levels. Apoptosis and autophagy were both suppressed by the autophagy inhibitors 3-MA and CQ. The AMPK inhibitor CC reduced autophagy and apoptosis in RTAEC and suppressed the production of the AMPK downstream factors ULK1 and P-ULK1.</p><p><strong>Conclusions: </strong>Rotenone may promote autophagy in the thoracic aorta and RTAEC by activating the LKB1-AMPK-ULK1 signaling pathway, thereby inducing apoptosis.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"25 1","pages":"33"},"PeriodicalIF":2.8,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11118107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086290","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}

{"title":"Anti-pruritic effect of L-carnitine against chloroquine-induced pruritus mediated via nitric oxide pathway.","authors":"Kiran Seemab, Arif-Ullah Khan, Muhammad Imran Khan, Neelum Gul Qazi, Amber Mahmood Minhas, Fawad Ali","doi":"10.1186/s40360-024-00748-4","DOIUrl":"10.1186/s40360-024-00748-4","url":null,"abstract":"<p><strong>Background: </strong>Pruritus, or itching, is a distressing symptom associated with various dermatological and systemic diseases. L-carnitine (βeta hydroxy-γ-tri methyl amino-butyric acid), is a naturally occurring substance, it controls numerous physiological processes. The present research aims to identify L-carnitine for its anti-pruritic effect via nitric oxide-dependent mechanism.</p><p><strong>Methods: </strong>Chloroquine-induced pruritus serves as an experimental model to investigate possible therapeutic interventions. In this study, we evaluated the efficacy of L-carnitine in combating oxidative stress, nitric oxide, and inflammatory cytokines in a chloroquine-induced pruritus model.</p><p><strong>Results: </strong>L-carnitine treatment significantly reduced scratching behavior compared to the disease group (^***P < 0.001 vs. chloroquine group), indicating its antipruritic potential. The markers of oxidative stress, GST, GSH, Catalase, and LPO were dysregulated in the disease model, but administration of L-carnitine restored GST, GSH, and Catalase levels and decreased LPO levels (^***P < 0.001 vs. chloroquine group), thereby alleviating oxidative stress. L-carnitine also reduced nitric oxide synthase (NOS) activity, suggesting that it modulates nitric oxide signaling pathways involved in pruritus. In addition, L-carnitine lowered levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), inflammatory marker nuclear factor kappa B (p-NFκB) and also reduces an inflammatory enzyme, cyclooxygenase-2 (COX-2), determined by ELISA (Enzyme-Linked Immunosorbent Assay) (^***P < 0.001 vs. chloroquine group). It downregulates nNOS mRNA expression confirmed by real-time polymerase chain reaction (RT-PCR).</p><p><strong>Conclusion: </strong>These findings highlight the therapeutic effects of L-carnitine in alleviating chloroquine-induced pruritus.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"25 1","pages":"32"},"PeriodicalIF":2.8,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11110330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080149","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}

{"title":"Iron overload induced submandibular glands toxicity in gamma irradiated rats with possible mitigation by hesperidin and rutin.","authors":"Salwa Farid Ahmed, Eman M F El-Maghraby, Maha M Rashad, Dina W Bashir","doi":"10.1186/s40360-024-00744-8","DOIUrl":"10.1186/s40360-024-00744-8","url":null,"abstract":"<p><strong>Background: </strong>Radiation triggers salivary gland damage and excess iron accumulates in tissues induces cell injury. Flavonoids are found in some fruits and are utilized as potent antioxidants and radioprotective agents. This study aimed to evaluate the antioxidant and anti-inflammatory effects of hesperidin and rutin on gamma radiation and iron overload induced submandibular gland (SMG) damage and to evaluate their possible impact on mitigating the alteration in mTOR signaling pathway and angiogenesis.</p><p><strong>Methods: </strong>Forty-eight adult male Wistar albino rats were randomly assigned to six groups: group C received a standard diet and distilled water; group H received hesperidin at a dose of 100 mg/kg; four times a week for four weeks; group U received rutin at a dose of 50 mg/kg; three times a week for three weeks; group RF received a single dose (5 Gy) of gamma radiation followed by iron at a dose of 100 mg/kg; five times a week for four weeks; group RFH received radiation and iron as group RF and hesperidin as group H; group RFU received radiation and iron as group RF and rutin as group U. SMG specimens from all groups were removed at the end of the experiment; and some were used for biochemical analysis, while others were fixed for histological and immunohistochemical examination.</p><p><strong>Results: </strong>In the RF group, several genes related to antioxidants (Nrf-2 and SOD) and DNA damage (BRCA1) were significantly downregulated, while several genes related to inflammation and angiogenesis (TNFα, IL-1β and VEGF) and the mTOR signaling pathway (PIK3ca, AKT and mTOR) were significantly upregulated. Acinar cytoplasmic vacuolation, nuclear pyknosis, and interacinar hemorrhage with distinct interacinar spaces were observed as histopathological changes in SMGs. The duct system suffered significant damage, eventually degenerating entirely as the cells were shed into the lumina. VEGF and NF-κB were also significantly overexpressed. Hesperidin and rutin cotreatment generated partial recovery as indicated by significant upregulation of Nrf-2, SOD and BRCA1 and considerable downregulation of TNF-α, IL-1β, VEGF, PIK3ca, AKT, and mTOR. Although some acini and ducts continued to deteriorate, most of them had a normal appearance. There was a notable decrease in the expression of VEGF and NF-κB.</p><p><strong>Conclusions: </strong>In γ-irradiated rats with iron overload, the administration of hesperidin and rutin may mitigate salivary gland damage.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"25 1","pages":"22"},"PeriodicalIF":2.9,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10900593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982327","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}

{"title":"Pharmacokinetics and bioequivalence evaluation of two oral formulations of cotrimoxazole tablets in healthy Chinese volunteers under fasting conditions.","authors":"Xu Zuo, Xin Zhao, Jinjin Shi, Tiandong Zhang","doi":"10.1186/s40360-024-00743-9","DOIUrl":"10.1186/s40360-024-00743-9","url":null,"abstract":"<p><p>This bioequivalence study was conducted to evaluate two oral formulations of cotrimoxazole tablets in healthy Chinese subjects. All 26 subjects recruited to this study were randomly and evenly classified into two groups and received a single dose (sulfamethoxazole: 400 mg and trimethoprim: 80 mg) of test cotrimoxazole tablets (generic drug) or reference cotrimoxazole tablets (branded drug). After a 7-day washout period, these subjects received one dose of reference drug or test drug. Blood samples were collected from participants before and up to 48 h after dosing to assess the concentration of sulfamethoxazole (SMX) and trimethoprim (TMP) in plasma and a plasma concentration-time curve was drawn. Then, the pharmacokinetics parameters were calculated accordingly. Our data revealed that there were no significant differences observed in the maximum plasma concentration (Cmax), area under the curve from time 0 to the last measurable concentration (AUC0-t), and area under the curve from time 0 to infinity (AUC0-∞) between the two formulations. For SMX, the 90% confidence intervals (CI) of the geometric mean ratio for Cmax, AUC0-t, and AUC0-∞ were 104.03-113.92%, 100.46-103.70%, and 100.41-103.81%, respectively. Similarly, for Trimethoprim (TMP), the 90% CI ranged from 98.54 to 106.95% for Cmax, from 99.31 to 107.68% for AUC0-t, and from 99.49 to 107.55% for AUC0-∞. Importantly, all these 90% CI values fell within the range of 80.00-125.00%, indicating that the test drug is bioequivalent to the reference drug. Furthermore, throughout the entire trial, no suspected serious adverse events were reported, indicating the safety profile of the newly developed generic cotrimoxazole. In summary, our study demonstrates that the newly developed generic formulation of cotrimoxazole is bioequivalent to the branded formulation under fasting conditions.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"25 1","pages":"23"},"PeriodicalIF":2.9,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10900551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982328","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}

{"title":"The effect of oral supplementation of Paricalcitol on C-reactive protein levels in chronic kidney disease patients: GRADE-assessed systematic review and dose-response meta-analysis of data from randomized controlled trials.","authors":"Seyyed Mostafa Arabi, Mostafa Shahraki-Jazinaki, Mahla Chambari, Leila Sadat Bahrami, Sara Sabeti, Mohammaed Ibrahim Mohaildeen Gubari, Basil D Roufogalis, Amirhossein Sahebkar","doi":"10.1186/s40360-024-00740-y","DOIUrl":"10.1186/s40360-024-00740-y","url":null,"abstract":"<p><strong>Background: </strong>Previous studies investigating the effect of oral supplementation of paricalcitol on reactive protein levels in chronic kidney disease (CKD) patients reported inconsistent findings. In this systematic review and meta-analysis, we have analyzed and interpreted the results obtained from previous randomized clinical trials on the effect of paricalcitol on C-reactive protein in CKD patients in the literature.</p><p><strong>Methods: </strong>MEDLINE, SciVerse Scopus, and Clarivate Analytics Web of Science databases were searched until January 2023 and related articles were obtained through a careful screening process allowing extraction of required data from selected articles. The effect size was calculated using a random effect model and weighted mean differences (WMD) and 95% confidence intervals (CI). Heterogeneity among studies was evaluated using Cochran's Q test and I².</p><p><strong>Results: </strong>Amongst the 182 articles obtained from the initial search, 4 studies (6 arms) were finally included in the meta-analysis. Pooled analysis shows that C-reactive protein levels significantly decrease after oral supplementation with paricalcitol (WMD: -2.55 mg/L, 95% CI (-4.99 to -0.11; P = 0.04). The studies used in this meta-analysis showed significant heterogeneity (I² = 66.3% and P = 0.01).</p><p><strong>Conclusion: </strong>Oral paricalcitol supplementation in CKD patients can significantly reduce C-reactive protein levels, which may prevent CKD progression.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"25 1","pages":"19"},"PeriodicalIF":2.8,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10885610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139939587","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}

{"title":"Pharmacovigilance study of BCR-ABL1 tyrosine kinase inhibitors: a safety analysis of the FDA adverse event reporting system.","authors":"Dehua Zhao, Xiaoqing Long, Jisheng Wang","doi":"10.1186/s40360-024-00741-x","DOIUrl":"10.1186/s40360-024-00741-x","url":null,"abstract":"<p><strong>Background: </strong>With the increased use of BCR-ABL1 tyrosine kinase inhibitors (TKIs) in cancer patients, adverse events (AEs) have garnered considerable interest. We conducted this pharmacovigilance study to evaluate the AEs of BCR-ABL1 TKIs in cancer patients using the Food and Drug Administration Adverse Event Reporting System (FAERS) database.</p><p><strong>Methods: </strong>To query AE reports from the FAERS database, we used OpenVigil 2.1. Descriptive analysis was then employed to describe the characteristics of TKIs-associated AE reports. We also utilized the disproportionality analysis to detect safety signals by calculating the proportional reporting ratio (PRR) and reporting odds ratios (ROR).</p><p><strong>Results: </strong>From the FAERS database, a total of 85,989 AE reports were retrieved, with 3,080 significant AE signals identified. Specifically, imatinib, nilotinib, dasatinib, bosutinib, and ponatinib had significant AE signals of 1,058, 813, 232, 186, and 791, respectively. These significant signals were further categorized into 26 system organ classes (SOCs). The AE signals of imatinib and ponatinib were primarily associated with general disorders and administration site conditions. On the other hand, nilotinib, dasatinib, and bosutinib were mainly linked to investigations, respiratory, thoracic and mediastinal disorders, and gastrointestinal disorders, respectively. Notably, new signals of 245, 278, 47, 55, and 253 were observed in imatinib, nilotinib, dasatinib, bosutinib, and ponatinib, respectively.</p><p><strong>Conclusions: </strong>The results of this study demonstrated that AE signals differ among the five BCR-ABL1 TKIs. Furthermore, each BCR-ABL1 TKI displayed several new signals. These findings provide valuable information for clinicians aiming to reduce the risk of AEs during BCR-ABL1 TKI treatment.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"25 1","pages":"20"},"PeriodicalIF":2.9,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10885429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139939586","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}

{"title":"New tricks for old drugs- praziquantel ameliorates bleomycin-induced pulmonary fibrosis in mice.","authors":"Yanjun Zeng, Rui Hu, Wei Ma, Ying Ding, Yi Zhou, Xin Peng, Lixin Feng, Qingmei Cheng, Ziqiang Luo","doi":"10.1186/s40360-024-00737-7","DOIUrl":"10.1186/s40360-024-00737-7","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary fibrosis is a chronic progressive disease with complex pathogenesis, short median survival time, and high mortality. There are few effective drugs approved for pulmonary fibrosis treatment. This study aimed to evaluate the effect of praziquantel (PZQ) on bleomycin (BLM)-induced pulmonary fibrosis.</p><p><strong>Methods: </strong>In this study, we investigated the role and mechanisms of PZQ in pulmonary fibrosis in a murine model induced by BLM. Parameters investigated included survival rate, lung histopathology, pulmonary collagen deposition, mRNA expression of key genes involved in pulmonary fibrosis pathogenesis, the activity of fibroblast, and M2/M1 macrophage ratio.</p><p><strong>Results: </strong>We found that PZQ improved the survival rate of mice and reduced the body weight loss induced by BLM. Histological examination showed that PZQ significantly inhibited the infiltration of inflammatory cells, collagen deposition, and hydroxyproline content in BLM-induced mice. Besides, PZQ reduced the expression of TGF-β and MMP-12 in vivo and inhibited the proliferation of fibroblast induced by TGF-β in vitro. Furthermore, PZQ affected the balance of M2/M1 macrophages.</p><p><strong>Conclusions: </strong>Our study demonstrated that PZQ could ameliorate BLM-induced pulmonary fibrosis in mice by affecting the balance of M2/M1 macrophages and suppressing the expression of TGF-β and MMP-12. These findings suggest that PZQ may act as an effective anti-fibrotic agent for preventing the progression of pulmonary fibrosis.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"25 1","pages":"18"},"PeriodicalIF":2.8,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10868045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139734381","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}

{"title":"Safinamide, an inhibitor of monoamine oxidase, modulates the magnitude, gating, and hysteresis of sodium ion current.","authors":"Te-Yu Hung, Sheng-Nan Wu, Chin-Wei Huang","doi":"10.1186/s40360-024-00739-5","DOIUrl":"10.1186/s40360-024-00739-5","url":null,"abstract":"<p><strong>Background: </strong>Safinamide (SAF), an α-aminoamide derivative and a selective, reversible monoamine oxidase (MAO)-B inhibitor, has both dopaminergic and nondopaminergic (glutamatergic) properties. Several studies have explored the potential of SAF against various neurological disorders; however, to what extent SAF modulates the magnitude, gating, and voltage-dependent hysteresis [Hys_(V)] of ionic currents remains unknown.</p><p><strong>Methods: </strong>With the aid of patch-clamp technology, we investigated the effects of SAF on voltage-gated sodium ion (Na_V) channels in pituitary GH3 cells.</p><p><strong>Results: </strong>SAF concentration-dependently stimulated the transient (peak) and late (sustained) components of voltage-gated sodium ion current (I_Na) in pituitary GH₃ cells. The conductance-voltage relationship of transient I_Na [I_Na(T)] was shifted to more negative potentials with the SAF presence; however, the steady-state inactivation curve of I_Na(T) was shifted in a rightward direction in its existence. SAF increased the decaying time constant of I_Na(T) induced by a train of depolarizing stimuli. Notably, subsequent addition of ranolazine or mirogabalin reversed the SAF-induced increase in the decaying time constant. SAF also increased the magnitude of window I_Na induced by an ascending ramp voltage V_ramp. Furthermore, SAF enhanced the Hys_(V) behavior of persistent I_Na induced by an upright isosceles-triangular V_ramp. Single-channel cell-attached recordings indicated SAF effectively increased the open-state probability of Na_V channels. Molecular docking revealed SAF interacts with both MAO and Na_V channels.</p><p><strong>Conclusion: </strong>SAF may interact directly with Na_V channels in pituitary neuroendocrine cells, modulating membrane excitability.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"25 1","pages":"17"},"PeriodicalIF":2.8,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10851555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139705997","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}

{"title":"Large variation in anti-factor Xa levels with nadroparin as thromboprophylaxis in COVID-19 and non-COVID-19 critically ill patients.","authors":"Monique M R de Maat, Henk J van Leeuwen, Lian Roovers, Sabine J G M Ahlers, Jolanda Lambers, Marcel M C Hovens","doi":"10.1186/s40360-024-00733-x","DOIUrl":"10.1186/s40360-024-00733-x","url":null,"abstract":"<p><strong>Purpose: </strong>Critically ill COVID-19 and non-COVID-19 patients receive thromboprophylaxis with the LMWH nadroparin. Whether a standard dosage is adequate in attaining the target anti-FXa levels (0.20-0.50 IU/ml) in these groups is unknown.</p><p><strong>Methods: </strong>This study was a prospective, observational study in the ICU of a large general teaching hospital in the Netherlands. COVID-19 and non-COVID-19 patients admitted to the ICU who received LMWH in a prophylactic dosage of 2850 IU, 5700 IU or 11400 IU subcutaneously were eligible for the study. Anti-FXa levels were determined 4 h after administration. Relevant laboratory parameters, prespecified co-variates and clinical data were extracted from the electronic health record system. The primary goal was to evaluate anti-FXa levels in critically ill patients on a prophylactic dosage of nadroparin. The second goal was to investigate whether covariates had an influence on anti-FXa levels.</p><p><strong>Results: </strong>A total of 62 patients were included in the analysis. In the COVID-19 group and non-COVID-19 group, 29 (96%) and 12 patients (38%) reached anti-FXa levels above 0.20 IU/ml, respectively. In the non-COVID-19 group, 63% of the patients had anti-FXA levels below the target range. When adjusted for nadroparin dosage a significant relation was found between body weight and the anti-FXa level (p = 0.013).</p><p><strong>Conclusion: </strong>A standard nadroparin dosage of 2850 IU sc in the critically ill patient is not sufficient to attain target anti-FXa levels in the majority of the studied patient group. We suggest a standard higher dosage in combination with body-weight dependent dosing as it leads to better exposure to nadroparin.</p><p><strong>Clinical trials registration: </strong>Retrospectively registered, ClinicalTrials.gov ID NTC 05926518 g, date of registration 06/01/23, unique ID 2020/1725.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"25 1","pages":"16"},"PeriodicalIF":2.9,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10848501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139696880","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}

{"title":"Lipidomics reveals serum lipid metabolism disorders in CTD-induced liver injury.","authors":"Shan Li, Xiaotong Duan, Yixin Zhang, Cancan Zhao, Ming Yu, Xiaofei Li, Xiaomei Li, Jianyong Zhang","doi":"10.1186/s40360-024-00732-y","DOIUrl":"10.1186/s40360-024-00732-y","url":null,"abstract":"<p><strong>Background: </strong>Cantharidin (CTD), the main toxic component of Mylabris, has been extensively used for tumor treatment in recent years. CTD-induced liver toxicity has attracted significant interest in clinic.</p><p><strong>Methods: </strong>In this study, biochemical parameters and liver pathological changes were analyzed after CTD was administered to mice by gavage. Subsequently, a lipidomic approach was used to investigate serum lipid metabolism disorders, and the mechanism underlying CTD-induced liver injury in mice was explored.</p><p><strong>Results: </strong>The results showed that the levels of TC and LDL-C were significantly increased after CTD intervention. Besides, pathological results showed inflammatory cell infiltration and hepatocyte necrosis in the liver. Furthermore, lipidomics found that a total of 18 lipid metabolites were increased and 40 were decreased, including LPC(20:4), LPC(20:3), PC(22:6e/2:0), PE(14:0e/21:2), PC(18:2e/22:6), glycerophospholipids, CE(16:0), CE(18:0) Cholesterol esters and TAG(12:0/12:0/22:3), TAG(16:1/16:2/20:4), TAG(18:1/18:1/20:0), TAG(16:2/18:2/18:2), TAG(18:0/18:0/20:0), TAG(13:1/19:0/19:0) glycerolipids. Metabolic pathway analysis found that glycerophospholipid, glycerol ester and glycosylphosphatidylinositol (GPI)-anchored biosynthetic metabolic pathways were dysregulated and the increase in PE caused by glycophoric metabololism and GPI may be the source of lipid metabolism disorders caused by CTD. Overall, the present study provided new insights into the mechanism of CTD-induced liver injury and increased drug safety during clinical application.</p>","PeriodicalId":9023,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"25 1","pages":"10"},"PeriodicalIF":2.9,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10790540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139471897","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}