scholarly journals Exploration of Clinical Breakpoint of Danofloxacin for Glaesserella parasuis in Plasma and in PELF

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 808
Author(s):  
Zihui Xu ◽  
Anxiong Huang ◽  
Xun Luo ◽  
Peng Zhang ◽  
Lingli Huang ◽  
...  
Keyword(s):  
Nonlinear Regression ◽  
Ex Vivo ◽  
Monte Carlo Analysis ◽  
Peak Time ◽  
Cutoff Value ◽  
Cart Analysis ◽  
Concentration Time ◽  
Cutoff Values ◽  
Window Approach

Background: In order to establish the clinical breakpoint (CBP) of danofloxacin against G. parasuis, three cutoff values, including epidemiological cutoff value (ECV), pharmacokinetic-pharmacodynamic (PK-PD) cutoff value (COPD) and clinical cutoff value (COCL), were obtained in the present study. Methods: The ECV was calculated using ECOFFinder base on the MIC distribution of danfloxacin against 347 G. parasuis collected from disease pigs. The COPD was established based on in vivo and ex vivo PK-PD modeling of danofloxacin both in plasma and pulmonary epithelial lining fluid (PELF) using Hill formula and Monte Carlo analysis. The COCL was established based on the relationship between the possibility of cure (POC) and MIC in the clinical trials using the “WindoW” approach, nonlinear regression and CART analysis. Results: The MIC50 and MIC90 of danofloxacin against 347 G. parasuis were 2 μg/mL and 8 μg/mL, respectively. The ECV value was set to 8 μg/mL using ECOFFinder. Concentration-time curves of danofloxacin were fitted with a two-compartment PK model. The PK parameters of the maximum concentration (Cmax) and area under concentration-time curves (AUC) in PELF were 3.67 ± 0.25 μg/mL and 24.28 ± 2.70 h·μg/mL, higher than those in plasma (0.67 ± 0.01 μg/mL and 4.47 ± 0.51 h·μg/mL). The peak time (Tmax) in plasma was 0.23 ± 0.07 h, shorter than that in PELF (1.61 ± 0.15 h). The COPD in plasma and PELF were 0.125 μg/mL and 0.5 μg/mL, respectively. The COCL calculated by WindoW approach, nonlinear regression and CART analysis were 0.125–4 μg/mL, 0.428 μg/mL and 0.56 μg/mL, respectively. The 0.5 μg/mL was selected as eligible COCL. The ECV is much higher than the COPD and COCL, and the clinical breakpoint based on data in plasma was largely different from that of PELF. Conclusions: Our study firstly established three cutoff values of danofloxacin against G. parasuis. It suggested that non-wild-type danofloxacin-resistant G. parasuis may lead to ineffective treatment by danofloxacin.

scholarly journals Exploration of clinical breakpoint of Danofloxacin for Glaesserella parasuis in plasma and in PELF

2021 ◽  
Author(s):  
Zihui Xu ◽  
Anxiong Huang ◽  
Xun Luo ◽  
Peng Zhang ◽  
Lingli Huang ◽  
...  
Keyword(s):  
Nonlinear Regression ◽  
Ex Vivo ◽  
Peak Time ◽  
Time Curve ◽  
Cutoff Value ◽  
Cart Analysis ◽  
Concentration Time ◽  
Cutoff Values ◽  
Window Approach

Background: To establish the clinical breakpoint (CBP) of danofloxacin to G. parasuis, three cutoff values, including epidemiological cutoff value (ECV), pharmacodynamic cutoff value (COPD) and clinical cutoff value (COCL), was obtained in the present study. Methods: The ECV was calculated using ECOFFinder base on MIC distribution of 347 G. parasuis collected from disease pigs. The COPD was established base on in vivo and ex vivo pharmacokinetic (PK)-pharmacodynamic (PD) modeling of danofloxacin both in plasma and pulmonary epithelial lining fluid (PELF) using Hill formula and Monte Carlo analysis. The COCL was established based on the relationship between possibility of cure (POC) and MIC in the clinical trials using 'WindoW' approach, nonlinear regression and CART analysis. Results: The MIC50 and MIC90 of danofloxacin against 347 G. parasuis were 2 μg/mL and 8 μg/mL, respectively. The ECV value was set up as 8 μg/mL using ECOFFinder. Concentration-time curve of danofloxacin indicated a two-compartment model for PK analysis. The PK parameters of the maximum concentration (Cmax) and area under concentration-time curve (AUC) in PELF were 3.67 ± 0.25 μg/mL and 24.28 ± 2.70 h·μg/mL, higher than those in plasma (0.67 ± 0.01μg/mL and 4.47 ± 0.51 h·μg/mL). The peak time (Tmax) in plasma was 0.23 ± 0.07 h, shorter than that in PELF (1.61 ± 0.15 h). The COPD in plasma and PELF were 0.125 μg/mL and 0.5 μg/mL, respectively. The COCL calculated by WindoW approach, nonlinear regression and CART analysis were 0.125~4 μg/mL, 0.428 μg/mL and 0.56 μg/mL, respectively. The 0.5 μg/mL was selected as eligible COCL. The ECV is much higher than the COPD and COCL, and the clinical breakpoint based on data in plasma was large different with that of in PELF. Conclusions: Our study firstly established three cutoff values of danofloxacin against G. parasuis. It suggested that epidemiological danofloxacin-resistant G. parasuis may lead to the ineffective treatment by danofloxacin.

scholarly journals PHARMACODYNAMICS EFFECT OF METHYLPREDNISOLONE TABLETS ON THE SERUM CONCENTRATION OF ANNEXIN A1: IN VIVO COMPARATIVE STUDY BETWEEN GENERIC AND INNOVATOR DRUG

2019 ◽  
Vol 12 (1) ◽  
pp. 414
Author(s):  
Hansen Nasif ◽  
Henny Lucida ◽  
Yanwirasti Yanwirasti ◽  
Yufri Aldi ◽  
Yori Yuliandra
Keyword(s):  
Serum Concentration ◽  
Peak Concentration ◽  
Peak Time ◽  
Annexin A1 ◽  
Onset Of Action ◽  
Time Curve ◽  
Concentration Time ◽  
Significant Difference ◽  
Generic Products

Objective: The aims of this study were to investigate the comparative pharmacodynamics effect of methylprednisolone (MP) innovator, MP branded generic, and MP generic products to the serum concentration of annexin A1 (AnxA1).Methods: It was conducted by two-way crossover design in male rabbits. AnxA1 was measured at 0, 0.5, 1, 2, 3, 5, 7, and 9 h after the administration of the drugs. The peak concentration (Cmax), the time at which the peak concentration was achieved (Tmax), and the area under the plasma concentration-time curve (AUC) were also determined.Results: The highest concentration and widest AUC of AnxA1 were obtained in MP innovator drug. MP innovator and branded generic reaches the peak time (Tmax) at the third 3rd h, while the MP generic reaches the peak time at the 5th h. The results showed that there was no significant difference in the serum concentration of AnxA1 between MP tablets after analyzed with a one-way analysis of variance.Conclusion: It could be concluded that the innovator drug of MP tablet gave the same effect on the serum concentration of AnxA1 than its generic counterparts, but an onset of action MP innovator and branded generic is faster than the generic product.

scholarly journals Healthy Strut Coverage After Coronary Stent Implantation

2020 ◽  
Vol 13 (5) ◽  
Author(s):  
Hiroyuki Jinnouchi ◽  
Fumiyuki Otsuka ◽  
Yu Sato ◽  
Rahul R. Bhoite ◽  
Atsushi Sakamoto ◽  
...  
Keyword(s):  
Predictive Value ◽  
Ex Vivo ◽  
Smooth Muscles ◽  
Cross Sectional ◽  
Cutoff Value ◽  
Neointimal Thickness ◽  
Cutoff Values ◽  
Coronary Stent Implantation ◽  
Stent Strut ◽  
Oct Imaging

Background: Struts have been considered as covered when tissue overlying the struts is >0 μm by optical coherence tomography (OCT). However, there is no confirmatory study to validate this definition by histology which is the gold standard. The aim of the present study was to assess the appropriate cutoff value of neointimal thickness of stent strut coverage by OCT with histology confirmation. Methods: We performed ex vivo OCT imaging of human coronary arteries with stents at autopsy. A total of 46 stents in 39 vessels from 25 patients were examined in this study, and a total of 165 cross-sectional images were co-registered with histology to determine the optimal cutoff value for strut coverage by OCT which was defined as luminal endothelial cells with 2 abluminal layers of smooth muscles cells and matrix. Considering the resolution of OCT is 10 to 20 μm, the cutoff values were assessed at ≥20, ≥40, and ≥60 μm. Results: A total of 2235 struts were reviewed by histology, 1216 were considered as well-matched struts which were analyzed in this study. By histology, 160 struts were identified as uncovered, while 1056 struts were covered. The OCT assessment without consideration of neointimal thickness yielded a poor specificity of 37.5% and sensitivity 100%. Of 3 cutoff values, the cutoff value of ≥40 μm yielded the best sensitivity (99.3%), specificity (91.0%), positive predictive value (98.6%), and negative predictive value (95.6%) as compared with ≥20 and ≥60 μm. Conclusions: Neointimal thickness ≥40 μm by OCT yielded the most accurate cutoff value to identify stent strut coverage validated by histology.

scholarly journals PHARMACODYNAMICS EFFECT OF METHYLPREDNISOLONE TABLETS ON THE SERUM CONCENTRATION OF ANNEXIN A1: IN VIVO COMPARATIVE STUDY BETWEEN GENERIC AND INNOVATOR DRUG

2019 ◽  
Vol 12 (1) ◽  
pp. 414
Author(s):  
Hansen Nasif ◽  
Henny Lucida ◽  
Yanwirasti Yanwirasti ◽  
Yufri Aldi ◽  
Yori Yuliandra
Keyword(s):  
Serum Concentration ◽  
Peak Concentration ◽  
Peak Time ◽  
Annexin A1 ◽  
Onset Of Action ◽  
Time Curve ◽  
Concentration Time ◽  
Significant Difference ◽  
Generic Products

Objective: The aims of this study were to investigate the comparative pharmacodynamics effect of methylprednisolone (MP) innovator, MP branded generic, and MP generic products to the serum concentration of annexin A1 (AnxA1).Methods: It was conducted by two-way crossover design in male rabbits. AnxA1 was measured at 0, 0.5, 1, 2, 3, 5, 7, and 9 h after the administration of the drugs. The peak concentration (Cmax), the time at which the peak concentration was achieved (Tmax), and the area under the plasma concentration-time curve (AUC) were also determined.Results: The highest concentration and widest AUC of AnxA1 were obtained in MP innovator drug. MP innovator and branded generic reaches the peak time (Tmax) at the third 3rd h, while the MP generic reaches the peak time at the 5th h. The results showed that there was no significant difference in the serum concentration of AnxA1 between MP tablets after analyzed with a one-way analysis of variance.Conclusion: It could be concluded that the innovator drug of MP tablet gave the same effect on the serum concentration of AnxA1 than its generic counterparts, but an onset of action MP innovator and branded generic is faster than the generic product.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Antithrombotic Effects and Bleeding Time Prolongation with Synthetic Platelet GPIIb/llla Inhibitors in Animal Models of Platelet-Mediated Thrombosis

1994 ◽  
Vol 71 (01) ◽  
pp. 095-102 ◽  
Author(s):  
Désiré Collen ◽  
Hua Rong Lu ◽  
Jean-Marie Stassen ◽  
Ingrid Vreys ◽  
Tsunehiro Yasuda ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bolus Injection ◽  
Cell Injury ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Thrombotic Occlusion ◽  
Antithrombotic Effects

SummaryCyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-a-aspartyl-cyclic (1→5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-arginyl-glycyl-L-α-aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1→9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor.The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID50) of approximately 20 μg/kg, ex vivo ADP-induccd platelet aggregation with ID50 of 10 μg/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 ± 9 to 1,100 ± 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 μg/kg, ex vivo platelet aggregation with an ID50 of 50 μg/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 μg/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induccd ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 ± 0.4 to 12 ± 2 min. Infusion of 300 μg/kg of TP9201 over 60 min completely prevented thrombotic occlusion, inhibited ex vivo platelet aggregation, but was not associated with prolongation of the template bleeding time.TP9201, unlike G4120, inhibits in vivo platelet-mediated thrombus formation without associated prolongation of the template bleeding time.

Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl
Keyword(s):  
Ex Vivo ◽  
High Dose ◽  
Platelet Aggregability ◽  
Adrenoceptor Agonist ◽  
Dose Infusion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

In Vivo Effect of Suloctidil as an Antiplatelet Agent

1979 ◽  
Vol 41 (03) ◽  
pp. 465-474 ◽  
Author(s):  
Marcia R Stelzer ◽  
Thomas S Burns ◽  
Robert N Saunders
Keyword(s):  
Ex Vivo ◽  
Antiplatelet Agent ◽  
Ratio Method ◽  
Platelet Aggregate ◽  
Permanent Effect ◽  
Platelet Aggregates ◽  
5 Ht Uptake ◽  
High Doses

SummaryThe relationship between the effects of suloctidil in vivo as an antiplatelet agent and in vitro as a modifier of platelet serotonin (5-HT) parameters was investigated. Suloctidil was found to be effective in reducing platelet aggregates formation in the retired breeder rat as determined using the platelet aggregate ratio method (PAR) with an ED50 of 16.1 mg/kg 24 hours post administration. In contrast to the hypothesis that 5-HT depletion is involved in the anti-aggregatory mechanism of suloctidil, no correlation was found between platelet 5- HT content and this antiplatelet activity. Reduction of platelet 5-HT content required multiple injections of high doses (100 mg/kg/day) of suloctidil. Suloctidil administration for 8 days at 100 mg/kg/day, which lowered platelet 5-HT content by 50%, resulted in no permanent effect on ex vivo platelet 5-HT uptake or thrombin-induced release, nor alteration in the plasma 5-HT level. However, these platelets exhibited a short-lived, significant increase in percent leakage of 5-HT after 30 minutes of incubation. Therefore, suloctidil treatment at high doses may with time result in platelet 5-HT depletion, however this effect is probably not related to the primary anti-aggregatory activity of the drug.

Studies on the Haemostatic Defect in a Complicated Syndrome

1995 ◽  
Vol 74 (05) ◽  
pp. 1244-1251 ◽  
Author(s):  
H Stormorken ◽  
H Holmsen ◽  
R Sund ◽  
K S Sakariassen ◽  
T Hovig ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Bleeding Tendency ◽  
Clot Retraction ◽  
Abnormal Finding ◽  
Shear Rates ◽  
Perfusion Chamber ◽  
Coagulant Activity ◽  
5 Ht Uptake ◽  
And Storage

SummaryThe Stormorken syndrome is a multifacetted syndrome including a bleeding tendency. No deviations were found in the coagulation- or fibrinolytic systems. Platelet number was low normal, and size abnormal, whereas EM findings were unremarkable. Survival time was half normal. Clot retraction was initially rapid, but clearly decreased, whereas prothrombin consumption was also initially rapid, but complete. Membrane GP’s were normal, so was AA metabolism, PI-cycle, granule storage and secretion, and c-AMP function, whereas 5-HT uptake and storage was decreased. Optical platelet aggregation was low normal with all physiological agonists. The only clearly abnormal finding was that coagulant activity was present on non stimulated platelets at the same level as kaolin-stimulated normal platelets. This indicated a platelet abnormality which should lead to a thrombogenic, not to a haemorrhagic trait. This paradox may have its origin in rheology, because when challenged with in vivo shear rates in an ex vivo perfusion chamber, platelet cohesion was abnormally low. Further studies to better delineate the membrane abnormality are underway.

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