IMMUNOLOGIC RESEARCH
·
2023
·Vol. 71
·期 3
·356-372
·
IF 4.4
Lamprinou Malamatenia,Sachinidis Athanasios,Stamoula Eleni,Vavilis Theofanis,Papazisis Georgios
COVID-19 is an infectious disease caused by a single-stranded RNA (ssRNA) virus, known as SARS-CoV-2. The disease, since its first outbreak in Wuhan, China, in December 2019, has led to a global pandemic. The pharmaceutical industry has developed several vaccines, of different vector technologies, against the virus. Of note, among these vaccines, seven have been fully approved by WHO. However, despite the benefits of COVID-19 vaccination, some rare adverse effects have been reported and have been associated with the use of the vaccines developed against SARS-CoV-2, especially those based on mRNA and non-replicating viral vector technology. Rare adverse events reported include allergic and anaphylactic reactions, thrombosis and thrombocytopenia, myocarditis, Bell’s palsy, transient myelitis, Guillen-Barre syndrome, recurrences of herpes-zoster, autoimmunity flares, epilepsy, and tachycardia. In this review, we discuss the potential molecular mechanisms leading to these rare adverse events of interest and we also attempt an association with the various vaccine components and platforms. A better understanding of the underlying mechanisms, according to which the vaccines cause side effects, in conjunction with the identification of the vaccine components and/or platforms that are responsible for these reactions, in terms of pharmacovigilance, could probably enable the improvement of future vaccines against COVID-19 and/or even other pathological conditions.
研究领域:
免疫学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Egyptian Journal of Internal Medicine
·
2023
·Vol. 35
·期 1
·1-9
·
IF 0
Muslim Shahnawaz,Mustafa Gulam,Nasrin Nasrin,Firdaus Aaisha,Singh Shambhu Kumar
SARS-CoV-2, the causative agent of COVID-19, claimed multiple lives in a very short span of time. Seeing the urgency of situation, vaccines were developed in hitherto unseen time frame. Vaccines definitely passed the test of safety and efficacy in clinical trials, but post mass vaccination data revealed cases of fatal adverse conditions in the temporal association of vaccination. The temporal association does not guarantee that the fatality is due to vaccination, but at the same time, it does create a concern. To overcome this concern and improve the safety of vaccination, we reviewed literature and collected data of 15 studies comprising of total 22 cases of fatal adverse condition/death in the temporal association of COVID-19 vaccination. Analysis of these data shows that many persons (40.90%) who succumbed were previously healthy individuals. All those who died developed symptoms or were admitted to hospital within a period of 3 weeks after vaccination. 86.36% cases of death took place within a period of 3 weeks after vaccination/presentation/admission/intervention. Complications which lead to death were CVST, thrombocytopenia/thrombosis /VITT, DIC and haemorrhage in 81.18% of cases. 81.81% cases of death were noted in the temporal association with ChAdOx1 nCoV-19 vaccine. 68.18% persons developed symptoms after first dose. Death was more common in females (59.09%), and the most commonly affected age group was 20 to 60 years (86.36%). Knowledge of fatal adverse conditions in the temporal association of vaccination will help to tackle these situations well and improve the safety of vaccination drive further.
研究领域:
免疫学
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流行病学
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公共卫生
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药理学
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转化医学
✓ 已验证
DOI
REGULATORY TOXICOLOGY AND PHARMACOLOGY
·
2015
·
IF 2.031
Dan Wan,Xihong Zhou,Chunyan Xie,Xugang Shu,Xin Wu,Yulong Yin
Iron is an essential trace element that is vital important in various biological process. A deficiency in iron could induce public health problem e.g. anaemia, while an overload could induce ROS production, lipid peroxidation and DNA bases modifications. In the present study, a new iron fortifier was synthesized, and its acute/sub-acute toxicity was investigated. According to the improved Karber's method, the median lethal dose (LD 50 ) of the ferrous N-carbamylglycinate in SD rat was 3.02 g/kg and the 95% confidence intervals were between 2.78 and 3.31 g/kg. No biologically significant or test substance-related differences were observed in body weights, feed consumption, clinical signs, organ weights, histopathology , ophthalmology, hematology, and clinical chemistry parameters in any of the treatment groups of ferrous N-carbamylglycinate at target concentrations corresponding to 150, 300, and 600 mg/kg/day for 28 days. The no observed adverse effect level (NOAEL) for ferrous N-carbamylglycinate was at least 600 mg/kg b.w. day in rats. In addition, no evidence of mutagenicity was found, either in vitro in bacterial reverse mutation assay or in vivo in mice bone marrow micronucleus assay and sperm shape abnormality assay. On the basis of our findings, we conclude that ferrous N-carbamylglycinate is a low-toxic substance with no genotoxicity .
研究领域:
营养学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2023
·Vol. 15
·期 8
·2135
·
IF 5.4
Jia Liu,Peng Sun,Xiaole Qi
Clinically, indobufen is widely used for the treatment of antiplatelet aggregation and anticoagulation. Prior studies have discovered that abnormal platelet function can be promptly restored to normal when the drug is stopped. Herein, through the study of the enzyme reaction kinetics, we demonstrated that the inhibitory effect of indobufen on cyclooxygenase-1 (COX-1) was reversible and non-competitive. Specifically, the cyclooxygenase inhibition experiment showed that the level of 6-keto-PGF1α in the gastric mucosa of the indobufen-treated groups was significantly higher than that of the aspirin group (###p< 0.001), indicating a higher level of PGI2in and a better physiological state of the gastric mucosa. Moreover, the rat gastric ulcer index and mucosal section experiments further confirmed the relief of gastrointestinal irritation and the adverse reaction rate of the indobufen-treated group compared to those of the aspirin group. Furthermore, indobufen was verified to exert reversible inhibitory activity on the heme group of COX-1 and thus reversibly inhibit COX-1 activity. In general, compared with aspirin, the long-term oral administration of indobufen yields a lower risk of gastrointestinal symptoms, such as ulcers.Keywords:indobufen;anticoagulant effect;antiplatelet effect;adverse reaction;COX-1
研究领域:
药理学
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临床医学
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产品关联
DOI
PubMed
高影响因子
CRYSTENGCOMM
·
2023
·Vol. 25
·期 13
·1951-1964
·
IF 3.1
Fan-Zhi Bu,Yue-Ming Yu,Lin-Lin Zhang,Cui-Wei Yan,Zhi-Yong Wu,Yan-Tuan Li
The goal of the present work is to elucidate the ability of protocatechuic acid (PCA) in downregulating the dissolubility property and gain an innovative insights into conquering adverse reactions of the antifungal drug 5-fluorocytosine (FYT) by a salification strategy. The strategy highlights the feature of adjacent 3,4-substituted phenolic groups on PCA molecule that establishes the helical morphology to attain the hydrophobic molecular salt by facilitating proton exchange reaction between PCA and FTY, thus decreasing FYT's dissolution capacity; moreover, it can also play to PCA's strengths with hepatoprotective effect and antifungal potential as a phenolic acid nutrient, all of which benefit in overcoming the adverse drug reactions caused by the fast and inappropriate absorption of FYT. Taking the strategy as a guideline, the first FTY's molecular salt, FTY–PCA, with hydrophobic characteristics has been successfully synthesized and thoroughly characterized by multiple analytical approaches. The single-crystal X-ray diffraction technology verifies that the newly obtained FTY–PCA consists of an unusual hydrophobic triple helix structure (THS) that is dexterously wound by three strands single helix structure (SHS) via robust hydrogen-bonding interplays and electrostatic forces, which endows the ability of concurrent downregulation of the solubility and dissolution rate, with the maximum reduction being, respectively, 31.23% and 60.49% relative to the parent drug FYT. The experimental outcomes are strongly confirmed by relevant theoretical studies. The molecular electrostatic potential confirms that the THS motif constructed by the SHS forms serves a crucial role in reducing the polarity of the molecular salt and complies with the abatement in polarity, attributable to the reinforced hydrogen-bonding energy as per the electron density difference as well as topology analysis of atoms in molecules, thereby clarifying the hydrophobic property of the molecular salt at theoretical levels. Thereby, the current contribution not only exemplifies the first hydrophobic molecular salt of FYT with a rare triple-helical structure, filling the gaps in the application of hydrophobic molecular salt in antifungal drugs, but also supplies some novel insights into the salinization strategy aiming at overcoming the adverse effects caused by the fast and almost entire absorption of some drugs by ameliorating the dissolubility behaviors.
研究领域:
药学
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化学
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产品关联
DOI
高影响因子
Pharmaceuticals
·
2024
·Vol. 17
·期 1
·141
·
IF 4.3
Jiahui Zhang,Junxiang Wang,Lingfan Chen,Xiangbin Yu,Shuihua Zhang,Yue Yu
Levamisole (LVM) is considered an immunomodulatory agent that has the potential to treat various cancer and inflammation diseases. However, there is still much debate surrounding the toxicokinetic and toxicological information of LVM. Therefore, it is crucial to assess its toxicity to provide useful data for future human LVM risk assessments. In this study, a barrier environment was established under the guidance of good laboratory practice (GLP) at the Fujian Center for New Drug Safety Evaluation. Male beagle dogs were orally administered with 5, 15, and 30 mg/kg of LVM daily for four weeks. Toxicity assessment was based on various factors such as mortality, clinical signs, food and water consumption, body weight, body temperature, electrocardiogram, ophthalmological examination, hematology, serum biochemistry, organ/body coefficients, histopathological study, and toxicokinetic analysis. The results of this study showed that LVM did not exhibit any significant toxicological effects on beagle dogs at the exposure levels tested. A no observed adverse effect level (NOAEL) of LVM was set at 30 mg/kg/day for male beagle dogs, which is equivalent to a 12-fold clinical dose in humans. Moreover, the repeated exposure to LVM for four weeks did not lead to any bioaccumulation. These findings provide valuable insights for future human LVM risk assessments.Keywords:levamisole;repeated dose toxicity;toxicokinetics;NOAEL;beagle dogs
研究领域:
药理学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
·
2022
·Vol. 15
·期 9
·1104
·
IF 5.215
Yin Huang,Fang Yang,Linling Guo,Yan Xu,Xiaxia Yu,Zunjian Zhang,Yuxin Zhang
Doxorubicin (DOX) is an essential component in chemotherapy, and Astragali Radix (AR) is a widely used tonic herbal medicine. The combination of DOX and AR offers widespread, well-documented advantages in treating cancer, e.g., reducing the risk of adverse effects. This study mainly aims to uncover the impact of AR on DOX disposition in vivo. Rats received a single intravenous dose of 5 mg/kg DOX following a single-dose co-treatment or multiple-dose pre-treatment of AR (10 g/kg × 1 or × 10). The concentrations of DOX in rat plasma and six tissues, including heart, liver, lung, kidney, spleen, and skeletal muscle, were determined by a fully validated LC-MS/MS method. A network-based approach was further employed to quantify the relationships between enzymes that metabolize and transport DOX and the targets of nine representative AR components in the human protein–protein interactome. We found that short-term (≤10 d) AR administration was ineffective in changing the plasma pharmacokinetics of DOX in terms of the area under the concentration–time curve (AUC, 1303.35 ± 271.74 μg/L*h versus 1208.74 ± 145.35 μg/L*h,p> 0.46), peak concentrations (Cmax, 1351.21 ± 364.86 μg/L versus 1411.01 ± 368.38 μg/L,p> 0.78), and half-life (t1/2, 31.79 ± 5.12 h versus 32.05 ± 6.95 h,p> 0.94), etc. Compared to the isotype control group, DOX concentrations in six tissues slightly decreased under AR pre-administration but only showed statistical significance (p< 0.05) in the liver. Using network analysis, we showed that five of the nine representative AR components were not localized to the vicinity of the DOX disposition-associated module. These findings suggest that AR may mitigate DOX-induced toxicity by affecting drug targets rather than drug disposition.Keywords:Adriamycin;drug disposition;combination therapy;LC-MS/MS;network
研究领域:
药理学
·
肿瘤学
·
中药学
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分析化学
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系统生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
REGULATORY TOXICOLOGY AND PHARMACOLOGY
·
2023
·
IF 3.4
Lang Yan,Jingjing Mao,Wenjing Shi,Lijun Ren,Jinfeng Li,Bijiang Geng,Haoneng Wang,Jiqianzhu Zhang,Yijun Tian,Bin Zhang,Fangyuan Gao,Xiaofang Zhang,Jikuai Chen,Jiangbo Zhu
In this study, the toxicity of ferric oxide nanoparticles (Fe 2 O 3 NPs) administered through gavage to Sprague Dawley (SD) rats for 94 d, consecutively and the recovery after Fe 2 O 3 NPs withdrawal for 30 d were evaluated. The vehicle control group, low-, medium-, and high-dose groups were administered with the vehicle (0.5% sodium carboxymethyl cellulose [CMC-Na]), 125, 250, and 500 mg/kg of Fe 2 O 3 NPs, respectively, administered every morning for 94 d. There was no significant difference in the body weight, food intake, hematological, blood biochemical, and urine indices of SD rats in each administration group and the control group (P > 0.05). There was no significant difference in organ weight, organ indices, and the coefficient of the visceral brain between the SD rats in the different dosage groups and the SD rats in the vehicle control group (P > 0.05). Histopathological observations showed that there was no correlation between the pathological lesions of the organs observed in this study and the dose of Fe 2 O 3 NPs (P > 0.05). The no-observed-adverse-effect level (NOAEL) dose of Fe 2 O 3 NPs was initially determined to be 500 mg/kg administered to SD rats through oral gavage for 94 d, consecutively, followed by recovery after Fe 2 O 3 NPs withdrawal for 30 d.
研究领域:
毒理学
·
纳米医学
·
实验动物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Ming-Li Sun,Jun-Min Dong,Chen Liu,Pu Li,Chao Zhang,Jie Zhen,Wei Chen
Background A phase II clinical trial of metformin (MET) for the treatment of doxorubicin (DOX)-induced cardiotoxicity (NCT02472353) failed. Objectives The aims of this study were to confirm MET-mediated protection against DOX-induced cardiotoxicity and its mechanism using H9C2 cells, and to establish a Wistar rat model of DOX-induced cardiotoxicity. Subsequently, Wistar rats were utilized to identify clinically relevant indicators for evaluating MET-mediated protection against DOX-induced cardiotoxicity, thereby facilitating early transition towards successful clinical trials. Methods MET-mediated protection was assessed using cell viability and cytotoxicity experiments. Additionally, intramitochondrial reactive oxygen species (ROS) levels were measured using an ROS fluorescent probe (dihydroethidium) to confirm the oxidative stress mechanism. Eighteen Wistar rats were randomly allocated to the control, DOX, and DOX+MET groups; and the body weight, adverse drug reactions (ADRs), myocardial injury, cardiac function, oxidative stress, and histopathology of heart tissues were compared between groups. Results H9C2 cells treated with MET/Dexrazoxane demonstrated dose-dependent protection against DOX-induced cardiotoxicity. The fluorescence intensity of H9C2 cells suggested DOX-induced cardiomyocyte toxicity and MET-mediated protection against DOX-induced cardiotoxicity. In vivo experiments confirmed that a rat model of DOX-induced cardiotoxicity was successfully established, but MET-mediated protection against DOX-induced cardiotoxicity was not demonstrated. This was attributed to insufficient energy intake because of ADRs, such as vomiting. Conclusions We confirmed the MET-mediated protection against DOX-induced cardiomyocyte toxicity and its mechanism involving the inhibition of oxidative stress in vitro experiments. It is imperative to investigate the optimal conditions for MET-mediated protection against DOX-induced cardiotoxicity in vivo or clinical trials.
研究领域:
药理学
·
心脏病学
·
毒理学
·
细胞生物学
·
动物模型
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2016
·
IF 7.441
Qin Wang,Jiayu Jiang,Wenfei Chen,Hao Jiang,Zhirong Zhang,Xun Sun
Glucocorticoid (GC) is the cornerstone therapy of rheumatoid arthritis , but high doses are associated with serious adverse effects. In an effort to improve the efficacy of low-dose GC therapy, we developed a micelle system for targeted delivery to inflamed joints and validated the approach in a rat model of arthritis. Micelles loaded with dexamethasone (Dex) self-assembled from the amphipathic poly (ethylene glycol)-block–poly (εcaprolactone) (PCL–PEG) polymer via film dispersion, and they were injected intravenously at a dose of only 0.8 mg/kg into rats with adjuvant-induced arthritis. The micelles persisted for a relatively long time in the circulation, and they accumulated preferentially in inflamed joints. Micelle-delivered Dex potently reduced joint swelling, bone erosion, and inflammatory cytokine expression in both joint tissue and serum. PCL–PEG micelles caused only moderate adverse effects on body weight, lymphocyte count and blood glucose concentration, and they weakly activated the host complement system. These results suggest that encapsulating Dex in PCL–PEG micelles may allow for safe and effective low-dose GC therapy targeting inflammatory disorders.
研究领域:
药理学
·
风湿病学
·
纳米技术
·
炎症
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Bo Wang,Jiquan Shen,Xinggao Wang,Ruixing Hou
Previous study has indicated that Celastrol (Cel) has various physiological and pharmacological effects, including antibacterial, antioxidant, pro-apoptotic, anticancer and anti-rheumatoid arthritis (RA) effects. However, low water solubility, low oral bioavailability, narrow treatment window, and high incidence of systemic adverse reactions still limit the further clinical application of Cel. Here, aiming at effectively overcome those shortcomings of Cel to boost its beneficial effects for treating RA, we developed the leukosome (LEUKO) coated biomimetic nanoparticles (NPs) for the targeted delivery of Cel to arthritis injury area in RA. LEUKO were synthesized using membrane proteins purified from activated J774 macrophage. LEUKO and Cel-loaded LEUKO (Cel@LEUKO) were characterized using dynamic light scattering and transmission electron microscopy. Our results demonstrated that Cel@LEUKO can inhibit the inflammatory response of lipopolysaccharide (LPS) induced mouse monocyte macrophage leukemia cells (RAW264.7 cells) and human rheumatoid arthritis synovial fibroblasts (MH7A) cells through the inhibition of reactive oxygen species (ROS)-NF-κB pathway. In addition, research has shown that LEUKO effectively targets and transports Cel to the inflammatory site of RA, increased drug concentration in affected areas, reduced systemic toxicity of Cel, and reduced clinical symptoms, inflammatory infiltration, bone erosion, and serum inflammatory factors in collagen-induced arthritis (CIA) rats.
研究领域:
药理学
·
纳米技术
·
炎症
·
风湿病学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Shuaijun Li,Caiting Meng,Qian Hao,Luyao Dai,Jiahong Shi,Ji Xu,Xin Zhou,Sitong Zhao,Jinfan Yang,Huafeng Kang,Yuzhu Hou,Mingzhen Zhang,Xiaobin Ma,Mingqian Tan,Hao Wu
Immune checkpoint blockade (ICB) therapy has emerged as a promising approach in clinical oncology. For brain metastases, the presence of the robust blood–brain barrier (BBB) and potential immune-related adverse events (irAEs) pose significant challenges. Here, a multistage-responsive antibody-delivery strategy is developed for non-small cell lung cancer (NSCLC) brain metastases, with the ultra-pH sensitivity borate bonds. The antibody-delivery nanoformulation (MB-aPDL1) is able to maintain the “silent state” in health tissue, cross the BBB/BTB by the GLUT1-mediated transcytosis, release the functionalized aPDL1 responsively, and promote the aPDL1 tumor-anchoring. In the in vivo tumor region, the MB-aPDL1 rapidly releases the activated BPA 6 -aPDL1, which successfully anchors to the tumor cells and improves the efficiency of ICB therapy. The two in vivo ICB therapy studies show a significant tumor growth inhibition from the MB-aPDL1 with an encouraging cure rate of 20% for the NSCLC brain metastases, due to enhanced immune response in tumor, commendably with less behavioral adverse reactions and liver damage. Taken together, this antibody-delivery strategy holds substantial potential for application in clinical treatment of brain metastases.
研究领域:
肿瘤学
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药理学
·
生物医学工程
·
神经科学
·
免疫学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）