Aspirin therapy: An attempt to explain the events of prothrombotic complications after treatment discontinuation

2010 ◽  
Vol 103 (01) ◽  
pp. 171-180 ◽  
Author(s):  
Omar Aguejouf ◽  
Vanessa Desplat ◽  
Francisco Eizayaga ◽  
Christian Doutremepuich
Keyword(s):  
Thrombotic Event ◽  
Selective Inhibition ◽  
In Vivo Model ◽  
High Dose ◽  
Vascular Events ◽  
Thrombotic Risk ◽  
Drug Eluting ◽  
Normal Rat ◽  
Cox 2

SummaryAspirin remains the most widely used drug for prevention of vascular events. Recent observational epidemiological evidence has raised the concern that aspirin withdrawal for treatment non-compliance, surgery or side effects can carry an increased thrombotic risk. The delay to the thrombotic event was between 7 to 30 days in most reports and most frequently 7 to 10 days. The mechanism underlying this effect remains poorly understood. Using an in vivo model of laser-induced thrombosis, aspirin injected in one single dose of 100 mg/kg bw has also shown a prothrombotic activity in the rat 8 to 10 days after injection in the normal rat. The hypothesis was made that minimal concentrations of aspirin or ultra-low dose aspirin (ULDA) could induce this effect. ULDA showed prothrombotic properties in the same model of induced thrombosis that were very similar to those described after aspirin withdrawal, but the effect was observed only one hour after aspirin administration. This prothrombotic effect of ULDA is very similar to the effect observed after COX 2 selective inhibition with NS 398. The administration of both the selective COX 2 inhibitor and ULDA did not produce further changes. High-dose ASA counterbalances the lack of COX 2 with an antithrombotic effect. No effect of residual ASA was observed in COX 2 -/- mice, thus confirming the existence of a COX 2 inhibition pathway. COX 2 inhibition produced by residual ASA is the probable cause of ischaemic accidents and drug-eluting stents thrombosis a few days after ASA withdrawal.

Diuretic and natriuretic properties of prestegane B, a mammalian lignan

1987 ◽  
Vol 253 (2) ◽  
pp. R375-R378
Author(s):  
G. E. Plante ◽  
C. Prevost ◽  
A. Chainey ◽  
P. Braquet ◽  
P. Sirois
Keyword(s):  
Glomerular Filtration Rate ◽  
Filtration Rate ◽  
Urine Flow ◽  
In Vivo Model ◽  
Similar Magnitude ◽  
Site Of Action ◽  
Normal Rat ◽  
Natriuretic Effect

The effect of increasing doses of prestegane B, a synthetic lignan, was examined in the anesthetized normal rat, using clearance methodology. Increasing doses of prestegane B 0.5, 1.0, 2.0, and 5.0 mg) were administered intravenously in our separate groups of hydropenic rats. Urine flow increased by 2.8 +/- 0.3, 4.5 +/- 0.5, 7.7 +/- 0.5, and 18.2 +/- 0.8 microliters/min, respectively, above control values. The rise of urinary sodium secretion was of similar magnitude and averaged 0.4 +/- 0.1, 0.8 +/- 0.2, 1.1 +/- 0.3, and 2.4 +/- 0.3 mu eq/min, respectively. No significant change in urinary phosphate excretion was obtained in all groups of rats, and glomerular filtration rate remained constant from control to experimental clearance periods. The natriuretic effect of prestegane B observed in this in vivo model could be related to the inhibition of the Na+-K+-adenosine triphosphate activity demonstrated in vitro in previous studies from our laboratory. The action of this substance is likely to be situated beyond the proximal tubule, since urinary phosphate was not altered. Prestegane B mimics the effects of other endogenous diuretic and natriuretic hormones, but its site of action and its effect on renal hemodynamics are obviously different.

scholarly journals IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2409-2414 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Steven A. Rosenberg
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Selective Inhibition ◽  
High Dose ◽  
Protein Levels ◽  
And Function ◽  
The Impact

Abstract Interleukin-2 (IL-2) is historically known as a T-cell growth factor. Accumulating evidence from knockout mice suggests that IL-2 is crucial for the homeostasis and function of CD4+CD25+ regulatory T cells in vivo. However, the impact of administered IL-2 in an immune intact host has not been studied in rodents or humans. Here, we studied the impact of IL-2 administration on the frequency and function of human CD4+CD25hi T cells in immune intact patients with melanoma or renal cancer. We found that the frequency of CD4+CD25hi T cells was significantly increased after IL-2 treatment, and these cells expressed phenotypic markers associated with regulatory T cells. In addition, both transcript and protein levels of Foxp3, a transcription factor exclusively expressed on regulatory T cells, were consistently increased in CD4 T cells following IL-2 treatment. Functional analysis of the increased number of CD4+CD25hi T cells revealed that this population exhibited potent suppressive activity in vitro. Collectively, our results demonstrate that administration of high-dose IL-2 increased the frequency of circulating CD4+CD25hi Foxp3+ regulatory T cells. Our findings suggest that selective inhibition of IL-2-mediated enhancement of regulatory T cells may improve the therapeutic effectiveness of IL-2 administration. (Blood. 2006;107:2409-2414)

scholarly journals Development and Validation of Endovascular Chemotherapy Filter Device for Removing High-Dose Doxorubicin: Preclinical Study

2014 ◽  
Vol 8 (4) ◽  
Author(s):  
Anand S. Patel ◽  
Maythem Saeed ◽  
Erin J. Yee ◽  
Jeffrey Yang ◽  
Gregory J. Lam ◽  
...  
Keyword(s):  
Flow Model ◽  
Vena Cava ◽  
High Capacity ◽  
Ion Exchange Resin ◽  
In Vivo Model ◽  
High Dose ◽  
Single Pass ◽  
Porcine Serum

To develop a novel endovascular chemotherapy filter (CF) able to remove excess drug from the blood during intra-arterial chemotherapy delivery (IAC), thus preventing systemic toxicities and thereby enabling higher dose IAC. A flow circuit containing 2.5 mL of ion-exchange resin was constructed. Phosphate-buffered saline (PBS) containing 50 mg doxorubicin (Dox) was placed in the flow model with the hypothesis that doxorubicin would bind rapidly to resin. To simulate IAC, 50 mg of doxorubicin was infused over 10 min into the flow model containing resin. Similar testing was repeated with porcine serum. Doxorubicin concentrations were measured over 60 min and compared to controls (without resin). Single-pass experiments were also performed. Based on these experiments, an 18F CF was constructed with resin in its tip. In a pilot porcine study, the device was deployed under fluoroscopy. A control hepatic doxorubicin IAC model (no CF placed) was developed in another animal. A second CF device was created with a resin membrane and tested in the infrarenal inferior vena cava (IVC) of a swine. In the PBS model, resin bound 76% of doxorubicin in 10 min, and 92% in 30 min (P < 0.001). During IAC simulation, 64% of doxorubicin bound in 10 min and 96% in 60 min (P < 0.001). On average, 51% of doxorubicin concentration was reduced during each pass in single pass studies. In porcine serum, 52% of doxorubicin bound in 10 min, and 80% in 30 min (P < 0.05). CF device placement and administration of IAC were successful in three animals. No clot was present on the resin within the CF following the in vivo study. The infrarenal IVC swine study demonstrated promising results with up to 85% reduction in peak concentration by the CF device. An endovascular CF device was developed and shown feasible in vitro. An in vivo model was established with promising results supporting high-capacity rapid doxorubicin filtration from the blood that can be further evaluated in future studies.

scholarly journals Cardiovascular Biology of Prostanoids and Drug Discovery

2020 ◽  
Vol 40 (6) ◽  
pp. 1454-1463 ◽  
Author(s):  
Liyuan Zhu ◽  
Yuze Zhang ◽  
Ziyi Guo ◽  
Miao Wang
Keyword(s):  
De Novo ◽  
Thrombotic Event ◽  
Prostaglandin E ◽  
Bioactive Lipids ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
Ep Receptor ◽  
Clinical Responses ◽  
Cardiovascular Biology ◽  
Cox 2

Prostanoids are a group of bioactive lipids that are synthesized de novo from membrane phospholipid-released arachidonic acid and have diverse functions in normal physiology and disease. NSAIDs (non-steroidal anti-inflammatory drugs), which are among the most commonly used medications, ameliorate pain, fever, and inflammation by inhibiting COX (cyclooxygenase), which is the rate-limiting enzyme in the biosynthetic cascade of prostanoids. The use of NSAIDs selective for COX-2 inhibition increases the risk of a thrombotic event (eg, myocardial infarction and stroke). All NSAIDs are associated with an increased risk of heart failure. Substantial variation in clinical responses to aspirin exists and is associated with cardiovascular risk. Limited clinical studies suggest the involvement of prostanoids in vascular restenosis in patients who received angioplasty intervention. mPGES (microsomal PG [prostaglandin] E synthase)-1, an alternative target downstream of COX, has the potential to be therapeutically targeted for inflammatory disease, with diminished thrombotic risk relative to selective COX-2 inhibitors. mPGES-1–derived PGE 2 critically regulates microcirculation via its receptor EP (receptor for prostanoid E) 4. This review summarizes the actions and associated mechanisms for modulating the biosynthesis of prostanoids in thrombosis, vascular remodeling, and ischemic heart disease as well as their therapeutic relevance.

scholarly journals Inhibition of cyclo-oxigenase-2 activity does not abolish the anabolic effect of prostaglandin E2 in vivo or in vitro

2002 ◽  
Vol 174 (1) ◽  
pp. 127-135 ◽  
Author(s):  
M Weinreb ◽  
A Kelner ◽  
S Keila
Keyword(s):  
Bone Formation ◽  
Bone Tissue ◽  
Receptor Expression ◽  
Male Rats ◽  
Nodule Formation ◽  
High Dose ◽  
Anabolic Effect ◽  
Cox 2

It was previously reported that the expression of cyclo-oxigenase-2 (COX-2) is induced by prostaglandin E(2) (PGE(2)) in vitro in an osteogenic cell line and organ culture, suggesting an autoamplification mechanism. In this study, we first tested whether this phenomenon also occurs in bone tissue in vivo and found that a single anabolic dose of PGE(2) (5 mg/kg) induced (between 30 and 120 min) in rat tibiae, an increase in the mRNA level of COX-2 (2.5- to 9-fold) but not that of COX-1. Secondly, to test whether COX-2 activity in generating endogenous prostaglandins (PGs) is required for the in vivo anabolic properties of PGE(2), young male rats were injected daily with either vehicle (8% ethanol) or 5 mg/kg PGE(2) for 21 days. PGE(2)-injected rats received, 45 min prior to PGE(2), either dimethyl sulphoxide (as vehicle) or one of two doses of NS-398, a selective COX-2 inhibitor: a low dose (3 mg/kg) or a high dose (10 mg/kg). PGE(2) increased bone formation (measured as cancellous mineralizing surface, mineral apposition rate and bone formation rate) and bone mass (measured as cancellous bone area and surface and cortical width). None of these increases was suppressed by pre-administration of NS-398. In contrast, the high dose of NS-398 effectively suppressed an increase in rat hind-paw volume induced by a local carrageenan injection. Furthermore, since COX-2 inactivation may affect PG receptor expression, we found that pre-administration of NS-398 did not abolish the induction in EP(4) receptor mRNA levels, caused by PGE(2) in rat bone tissue. For in vitro testing, rat femoral bone marrow stromal cell cultures were initiated and were incubated in the absence or presence of PGE(2) at 100 nM (as an inducer) and with increasing concentrations of NS-398 (10(-8) M to 10(-5) M) for 21 days, after which time mineralized (Von-Kossa positive) nodules were counted. PGE(2) increased nodule formation as previously reported; however, NS-398 reduced nodule formation in both control and PGE(2)-treated cultures to the same extent. We conclude that while the level of COX-2 mRNA is increased in vivo by administration of PGE(2), inhibition of its activity (i.e. generation of endogenous PGs) does not abolish the anabolic effect of PGE(2).

scholarly journals Confirming the Effects of Qinghuayin against Chronic Atrophic Gastritis and a Preliminary Observation of the Involved Inflammatory Signaling Pathways: An In Vivo Study

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Sihan Li ◽  
Minghan Huang ◽  
Qin Chen ◽  
Shunan Li ◽  
Xin Wang ◽  
...  
Keyword(s):  
Atrophic Gastritis ◽  
Signaling Pathways ◽  
Chronic Atrophic Gastritis ◽  
Preliminary Observation ◽  
High Dose ◽  
Inflammatory Signaling ◽  
Necrosis Factor Alpha ◽  
Messenger Ribonucleic Acid ◽  
Cox 2

Background.Qinghuayin (QHY) is a Chinese formula that is widely used in the treatment of chronic atrophic gastritis (CAG). This study was planned with the following objectives:(1)confirming the efficacy of QHY in a rat model of CAG and(2)performing a preliminary observation of the changes in several inflammatory signaling pathways potentially involved in the QHY mechanisms.Methods.A total of 33 rats were used in this study; they were divided into the control (n = 12) and model (n = 21) groups. QHY was administrated to both the groups. We assessed the pathological manifestations and the serum tumor necrosis factor alpha (TNF-α) level as markers of efficacy. We also performed a preliminary observation of the changes in the protein and messenger ribonucleic acid (mRNA) expression of toll-like receptors 4 (TLR4), MyD88, NF-κB, and COX-2.Results.The pathological changes induced in the rats by the establishment of the CAG models were recovered by low and high doses of QHY. Their serum TNF-αlevel also reduced following low- and high-dose QHY treatment. Protein and mRNA expressions of TLR4, MyD88, NF-κB, and COX-2 were upregulated by the establishment of CAG models and downregulated by the administration of low- and high-dose QHY.Conclusions. Our data confirm the efficacy of QHY as an adjuvant therapy, based on the theories in traditional Chinese medicine. The preliminary observations indicate that the downregulation of the enhanced inflammatory signaling pathways might be crucial QHY mechanisms that need further verification.

scholarly journals Thrombotic Risk Detection in Patients with Polycythemia Vera: The Predictive Role of DNMT3A/TET2/ASXL1 Mutations

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 934 ◽  
Author(s):  
Adrián Segura-Díaz ◽  
Ruth Stuckey ◽  
Yanira Florido ◽  
Jesús María González-Martín ◽  
Juan Francisco López-Rodríguez ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Myeloproliferative Neoplasms ◽  
Thrombotic Event ◽  
Primary Myelofibrosis ◽  
Case Control ◽  
Vascular Events ◽  
Thrombotic Risk ◽  
Initial Cohort ◽  
Predictive Role ◽  
Next Generation Sequencing Ngs

The development of thrombotic events is common among patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We studied the influence of pathogenic mutations frequently associated with myeloid malignancies on thrombotic events using next-generation sequencing (NGS) in an initial cohort of 68 patients with myeloproliferative neoplasms (MPN). As expected, the presence of mutations in DNMT3A, TET2, and ASXL1 (DTA genes) was positively associated with age for the whole cohort (p = 0.025, OR: 1.047, 95% CI: 1.006–1.090). Also, while not related with events in the whole cohort, DTA mutations were strongly associated with the development of vascular events in PV patients (p = 0.028). To confirm the possible association between the presence of DTA mutation and thrombotic events, we performed a case-control study on 55 age-matched patients with PV (including 12 PV patients from the initial cohort, 25 with event vs. 30 no event). In the age-matched case-control PV cohort, the presence of ≥1 DTA mutation significantly increased the risk of a thrombotic event (OR: 6.333, p = 0.0024). Specifically, mutations in TET2 were associated with thrombotic events in the PV case-control cohort (OR: 3.56, 95% CI: 1.15–11.83, p = 0.031). Our results suggest that pathogenic DTA mutations, and particularly TET2 mutations, may be an independent risk factor for thrombosis in patients with PV. However, the predictive value of TET2 and DTA mutations in ET and PMF was inconclusive and should be determined in a larger cohort.

scholarly journals Neurotoxicity evaluation of meloxicam in the alternative in vivo model, Caenorhabditis elegans

2020 ◽  
Vol 8 (8) ◽  
pp. 319-325
Author(s):  
Juliana Cyrillo Guimarães da Silva ◽  
Cassiana Bigolin ◽  
Laura Cé da Silva ◽  
Thalia Emmanoella Sebulsqui Saraiva ◽  
Julia Machado Menezes ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
In Vivo Model ◽  
High Dose ◽  
Neurological Effect ◽  
Inflammatory Processes ◽  
The Central Nervous System ◽  
Acute Neurotoxicity ◽  
Low Toxicity ◽  
Inflammatory Drugs

Inflammatory processes cause changes in the permeability of the blood brain barrier. Non-steroidal anti-inflammatory drugs (NSAID) are most commonly used to treat these inflammatory processes, including meloxicam, and they can reach the central nervous system (CNS) and cause neurotoxicity. Since there are no studies evaluating the neurotoxicity of NSAID in alternative models of toxicity, the aim of this study was to evaluate the acute neurotoxicity (through nematodes changes in behavior) of meloxicam in an alternative in vivo model, Caenorhabditis elegans, as well as, to determine meloxicam toxicity through LD50 and development assessments. Meloxicam LD50 was high (50.03 mg/mL) and only the highest dose (100 mg/mL) caused a decrease in the nematode body size, indicating low toxicity in this alternative model. Besides, a neurological effect was observed only in the highest dose. Meloxicam showed neurotoxicity only at a very high dose, suggesting low potential to cause toxicity in the CNS. However, further studies are necessary to evaluate meloxicam neurotoxicity.

scholarly journals Combination of Trans-Resveratrol and ε-Viniferin Induces a Hepatoprotective Effect in Rats with Severe Acute Liver Failure via Reduction of Oxidative Stress and MMP-9 Expression

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3677
Author(s):  
João C. Fernandes ◽  
Elizângela G. Schemitt ◽  
Juliana Da Silva ◽  
Norma P. Marroni ◽  
Ana Lima ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Biological Activities ◽  
Treated Group ◽  
Protective Role ◽  
Hepatoprotective Effect ◽  
In Vivo Model ◽  
Sod Activity ◽  
Cox 2

Stilbenes are a major grapevine class of phenolic compounds, known for their biological activities, including anti-inflammatory and antioxidant, but never studied in combination. We aimed to evaluate the effect of trans-resveratrol + ε-viniferin as an antioxidant mixture and its role in inflammatory development an in vivo model of severe acute liver failure induced with TAA. Trans-resveratrol + trans-ε-viniferin (5 mg/kg each) was administered to Wistar rats. Resveratrol + ε-viniferin significantly decreased TBARS and SOD activity and restored CAT and GST activities in the treated group. This stilbene combination reduced the expression of TNFα, iNOS, and COX-2, and inhibited MMP-9. The combination of resveratrol + ε-viniferin had a hepatoprotective effect, reducing DNA damage, exhibiting a protective role on the antioxidant pathway by altering SOD, CAT, and GST activities; by downregulating TNFα, COX-2, and iNOS; and upregulating IL-10. Our results suggested that adding viniferin to resveratrol may be more effective in hepatoprotection than resveratrol alone, opening a new perspective on using this stilbene combination in functional diets.

Sign in / Sign up

Export Citation Format

Share Document