Tigecycline Interferes with Fibrinogen Polymerization Independent of Peripheral Interactions with the Coagulation System

Tigecycline offers broad anti-bacterial coverage for critically ill patients with complicated infections. A described but less researched side effect is coagulopathy. The aim of this study was to test whether tigecycline interferes with fibrinogen polymerization by peripheral interactions. To study the effect of unmetabolized tigecycline, plasma of healthy volunteers were spiked with increasing concentrations of tigecycline. In a second experimental leg, immortalized human liver cells (HepG2) were treated with the same concentrations to test an inhibitory effect of hepatic tigecycline metabolites. Using standard coagulation tests, only the activated thromboplastin time in humane plasma was prolonged with increasing concentrations of tigecycline. Visualization of the fibrin network using confocal live microscopy demonstrated a qualitative difference in tigecycline treated experiments. Thrombelastometry and standard coagulation tests did not indicate an impairment of coagulation. Although the discrepancy between functional and immunologic fibrinogen levels increased in cell culture assays with tigecycline concentration, fibrinogen levels in spiked plasma samples did not show significant differences determined by functional versus immunologic methods. In our in vitro study, we excluded a direct effect of tigecycline in increasing concentrations on blood coagulation in healthy adults. Furthermore, we demonstrated a rapid loss of mitochondrial activity in hepatic cells with supra-therapeutic tigecycline dosages.

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The Influence of a Knitted Hydrophilic Prosthesis of Blood Vessels on the Activation of Coagulation System—In Vitro Study

Nanomaterials ◽

10.3390/nano11061600 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1600

Author(s):

Maria Szymonowicz ◽

Maciej Dobrzynski ◽

Sara Targonska ◽

Agnieszka Rusak ◽

Zbigniew Rybak ◽

...

Keyword(s):

Blood Vessels ◽

Initial Period ◽

In Vitro Study ◽

Vascular Prosthesis ◽

Coagulation System ◽

Factor Xii ◽

Scanning Calorimetry ◽

Vascular Prostheses ◽

Control Value

The replacement of affected blood vessels of the polymer material can cause imbalances in the blood haemostatic system. Changes in blood after the implantation of vascular grafts depend not only on the chemical composition but also on the degree of surface wettability. The Dallon® H unsealed hydrophilic knitted vascular prosthesis double velour was assessed at work and compare with hydrophobic vascular prosthesis Dallon®. Spectrophotometric studies were performed in the infrared and differential scanning calorimetry, which confirmed the effectiveness of the process of modifying vascular prostheses. Determination of the parameters of coagulation time of blood after contact in vitro with Dallon® H vascular prosthesis was also carried out. Prolongation of activated thromboplastin time, decreased activity of factor XII, IX and VIII, were observed. The prolonged thrombin and fibrinogen were reduced in the initial period of the experiment. The activity of plasminogen and antithrombin III and protein C were at the level of control value. The observed changes in the values of determined parameters blood coagulation do not exceed the range of referential values for those indexes. The observed changes are the result of considerable blood absorptiveness by the prosthesis of blood vessels and their sealing.

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In vitro study on the effect of cornin on the activity of cytochrome P450 enzymes

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03309-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qun Zhang ◽

Zengqiang Qu ◽

Yanqing Zhou ◽

Jin Zhou ◽

Junwei Yang ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Interaction ◽

Liver Microsomes ◽

In Vitro Study ◽

Inhibitory Effect ◽

Dependent Manner ◽

Cytochrome P450 Enzymes ◽

Drug Drug Interaction ◽

Dose Dependent

Abstract Background Cornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin. Methods Cornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Results Cornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 9.20, 22.91, and 14.28 μM, respectively (p < 0.05). Cornin inhibited the activity of CYP3A4 non-competitively with the Ki value of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with the Ki value of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with the KI/Kinact value of 6.40/0.055 min− 1·μM− 1. Conclusions The inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.

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Thrombin activatable fibrinolysis inhibitor (TAFI) affects fibrinolysis in a plasminogen activator concentration-dependent manner

Thrombosis and Haemostasis ◽

10.1160/th03-06-0377 ◽

2004 ◽

Vol 91 (03) ◽

pp. 473-479 ◽

Cited By ~ 15

Author(s):

Ana Guimarães ◽

Dingeman Rijken

Keyword(s):

Plasminogen Activator ◽

In Vitro Study ◽

Inhibitory Effect ◽

Retardation Factor ◽

Clot Lysis ◽

Dependent Manner ◽

Plasma Clot ◽

Concentration Dependent Manner ◽

Plasmin Inhibitor

SummaryTAFIa was shown to attenuate fibrinolysis. In our in vitro study, we investigated how the inhibitory effect of TAFIa depended on the type and concentration of the plasminogen activator (PA). We measured PA-mediated lysis times of plasma clots under conditions of maximal TAFI activation by thrombin-thrombomodulin in the absence and presence of potato carboxypeptidase inhibitor. Seven different PAs were compared comprising both tPA-related (tPA, TNK-tPA, DSPA), bacterial PA-related (staphylokinase and APSAC) and urokinase-related (tcu-PA and k2tu-PA) PAs. The lysis times and the retardation factor were plotted against the PA concentration. The retardation factor plots were bell-shaped. At low PA concentrations, the retardation factor was low, probably due to the limited stability of TAFIa. At intermediate PA concentrations the retardation factor was maximal (3-6 depending on the PA), with TNK-tPA, APSAC and DSPA exhibiting the strongest effect. At high PA concentrations, the retardation factor was again low, possibly due to inactivation of TAFIa by plasmin or to a complete conversion of glu-plasminogen into lys-plasminogen. Using individual plasmas with a reduced plasmin inhibitor activity (plasmin inhibitor Enschede) the bell-shaped curve of the retardation factor shifted towards lower tPA and DSPA concentrations, but the height did not decrease. In conclusion, TAFIa delays the lysis of plasma clots mediated by all the plasminogen activators tested. This delay is dependent on the type and concentration of the plasminogen activator, but not on the fibrin specificity of the plasminogen activator. Furthermore, plasmin inhibitor does not play a significant role in the inhibition of plasma clot lysis by TAFI.

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Anti-Allergic Potential of Cinnamaldehyde via the Inhibitory Effect of Histidine Decarboxylase (HDC) Producing Klebsiella pneumonia

Molecules ◽

10.3390/molecules25235580 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5580

Author(s):

Lorina I. Badger-Emeka ◽

Promise Madu Emeka ◽

Krishnaraj Thirugnanasambantham ◽

Hairul Islam M. Ibrahim

Keyword(s):

Mast Cell ◽

Cell Activation ◽

Histidine Decarboxylase ◽

Cell Model ◽

In Vitro Study ◽

Inhibitory Effect ◽

Mast Cell Activation ◽

Klebsiella Pneumonia ◽

Immunological Disorder

Allergy is an immunological disorder that develops in response to exposure to an allergen, and histamines mediate these effects via histidine decarboxylase (HDC) activity at the intracellular level. In the present study, we developed a 3D model of Klebsiella pneumoniae histidine decarboxylase (HDC) and analyzed the HDC inhibitory potential of cinnamaldehyde (CA) and subsequent anti-allergic potential using a bacterial and mammalian mast cell model. A computational and in vitro study using K. pneumonia revealed that CA binds to HDC nearby the pyridoxal-5′-phosphate (PLP) binding site and inhibited histamine synthesis in a bacterial model. Further study using a mammalian mast cell model also showed that CA decreased the levels of histamine in the stimulated RBL-2H3 cell line and attenuated the release of β-hexoseaminidase and cell degranulation. In addition, CA treatment also significantly suppressed the levels of pro-inflammatory cytokines TNF-α and IL-6 and the nitric oxide (NO) level in the stimulated mast cells. A gene expression and Western blotting study revealed that CA significantly downregulated the expressions of MAPKp38/ERK and its downstream pro-allergic mediators that are involved in the signaling pathway in mast cell cytokine synthesis. This study further confirms that CA has the potential to attenuate mast cell activation by inhibiting HDC and modifying the process of allergic disorders.

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Demineralization Inhibitory Effects of Highly Concentrated Fluoride Dentifrice and Fluoride Gels/Solutions on Sound Dentin and Artificial Dentin Caries Lesions in vitro

Caries Research ◽

10.1159/000509931 ◽

2020 ◽

pp. 1-14

Author(s):

Daniel Erdwey ◽

Hendrik Meyer-Lueckel ◽

Marcella Esteves-Oliveira ◽

Christian Apel ◽

Richard Johannes Wierichs

Keyword(s):

In Vitro Study ◽

Inhibitory Effect ◽

Negative Effects ◽

Dentin Caries ◽

Before And After ◽

Amine Fluoride ◽

Ph Cycling ◽

Fluoride Dentifrice ◽

Caries Lesions

Objectives: The aim of this in vitro study was to compare the demineralization inhibitory effect of gels/solutions used in combination with either standard or highly fluoridated dentifrices on sound dentin as well as on artificial dentin caries-like lesions. Methods: Bovine dentin specimens (n = 240) with two different surfaces each (sound [ST] and artificial caries lesion [DT]) were prepared and randomly allocated to twelve groups. Weekly interventions during pH-cycling (28 days, 6 × 120 min demineralization/day) were: the application of gels/solutions containing amine fluoride/sodium fluoride (12,500 ppm F [ppm]; pH = 4.4; AmF); NaF (12,500 ppm; pH = 6.6; NaF1); NaF (12,500 ppm; pH = 6.3; NaF2); silver diamine fluoride (14,200 ppm; pH = 8.7; SDF); acidulated phosphate fluoride (12,500 ppm; pH = 3.8; APF), and no intervention (standard control; S). Furthermore, half of the specimens in each group were brushed (10 s; twice per day) with dentifrice slurries containing either 1,450 ppm (e.g., AmF1450) or 5,000 ppm (e.g., AmF5000). Differences in integrated mineral loss (ΔΔZ) and lesion depth (ΔLD) were calculated between values before and after pH-cycling using transversal microradiography. Results: After pH-cycling Ss showed significantly increased ΔZDT and LDDT values, indicating further demineralization. In contrast, except for one, all groups including fluoride gels/solutions showed significantly decreased ΔZDT values. Additional use of most fluoride gels/solutions significantly enhanced mineral gain, mainly in the surface area; however, acidic gels/solutions seemed to have negative effects on lesion depths. Significance: Under the present pH-cycling conditions the highly fluoridated dentifrice significantly reduced caries progression and additional application of nearly all of the fluoride gels/solutions resulted in remineralization. However, there was no difference in the remineralizing capacity of fluoride gels/solutions when used in combination with either standard or highly fluoridated dentifrices.

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Inhibitory effect of Salvadora persica extract (Miswak) on collagen degradation in demineralized dentin: In vitro study

Journal of Dental Sciences ◽

10.1016/j.jds.2020.05.025 ◽

2021 ◽

Vol 16 (1) ◽

pp. 208-213

Author(s):

Sahar Khunkar ◽

Ilnaz Hariri ◽

Ehab Alsayed ◽

Amal Linjawi ◽

Sawsan Khunkar ◽

...

Keyword(s):

In Vitro Study ◽

Inhibitory Effect ◽

Collagen Degradation ◽

Vitro Study ◽

Salvadora Persica ◽

Demineralized Dentin

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Extended Half-Life Factor VIII/Factor IX Products: Assay Discrepancies and Implications for Hemophilia Management

Hämostaseologie ◽

10.1055/a-1282-2251 ◽

2020 ◽

Vol 40 (S 01) ◽

pp. S15-S20

Author(s):

Jens Müller ◽

Georg Goldmann ◽

Natascha Marquardt ◽

Bernd Pötzsch ◽

Johannes Oldenburg

Keyword(s):

Factor Viii ◽

Half Life ◽

In Vitro Study ◽

Factor Ix ◽

University Hospital ◽

Spiked Plasma ◽

Structural Differences ◽

The University ◽

Life Factor

AbstractDue to structural differences between extended half-life (EHL) factor VIII (FVIII) or FIX products and equivalent plasma wild-type molecules used for assay calibration, reagent-dependent discrepancies during monitoring of FVIII- and FIX-replacement therapies with EHL products have been described. To assess the performance of available one-stage clotting and chromogenic substrate assays on the Siemens Atellica COAG 360 analyzer, an in vitro study using spiked plasma samples was performed. The described results confirm previously described findings and allowed allocation of each EHL product to an appropriate assay. In addition, corresponding EHL product–specific analytes were defined within the order entry system of the University Hospital Bonn. The requirement of product-specific FVIII and FIX assays complicates patient monitoring and demonstrates the need for both continuous education and communication between treating physicians and the coagulation laboratory.

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Inhibitory Effect of Resveratrol on the Pharmacokinetics of Ticagrelor in Vivo and Vitro

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0512 ◽

2021 ◽

Author(s):

Peng Wang ◽

Xiao-Xia Hu ◽

Ying-hui Li ◽

Nan-Yong Gao ◽

Guo-quan Chen ◽

...

Keyword(s):

Rat Liver ◽

Liver Microsomes ◽

In Vitro Study ◽

Inhibitory Effect ◽

Control Group ◽

Rat Liver Microsomes ◽

Sprague Dawley ◽

Group B

This study was to evaluate the effect of resveratrol on the pharmacokinetics of ticagrelor in rats and the metabolism of ticagrelor in human CYP3A4 and liver microsomes. Eighteen Sprague-Dawley rats were randomly divided into three groups: group A (control group), group B (50mg/kg resveratrol), and group C (150mg/kg resveratrol ). After 30 minutes administration of resveratrol, a single dose of ticagrelor (18mg/kg) was administered orally. The vitro experiment was performed to examine the influence of resveratrol on ticagrelor metabolism in CYP3A4*1, human, and rat liver microsomes. Serial biological samples were assayed by validated UHPLC-MS/MS methods. In vivo study, the AUC and Cmax of ticagrelor in group B and C appeared to be significantly higher than the control group, while Vz/F and CLz/F of ticagrelor in group B and C were significantly decreased. In vitro study, resveratrol exhibited an inhibitory effect on CYP3A4*1, human and rat liver microsomes. The IC50 values of resveratrol were 56.75μM，69.07μM and 14.22μM, respectively. Our results indicated that resveratrol had a inhibitory effect on the metabolism of ticagrelor in vitro and vivo. It should be paid more attention to the clinical combination of resveratrol with ticagrelor and ticagrelor plasma concentration should be monitored to avoid the occurrence of adverse reaction.

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