Effects of clopidogrel on horses with experimentally induced endotoxemia

Watts, Ashlee E.; Ness, Sally L.; Divers, Thomas J.; Fubini, Susan L.; Frye, Amelia H.; Stokol, Tracy; Cummings, Kevin J.; Brooks, Marjory B.

doi:10.2460/ajvr.75.8.760

Cited by 16 publications

(20 citation statements)

References 50 publications

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“…Furthermore, there were no statistical significant differences in cytokine responses between ticagrelor-and clopidogrel-treated subjects. Animal studies evaluating the role of P2Y 12 inhibition in various models of inflammation are sparse and have yielded conflicting results, showing pro-inflammatory (33), anti-inflammatory (34,35), or no effects (36). Our results are in contrast with the scarcely available human data, as a single dose of ticagrelor reduced platelet-leukocyte interaction and ex vivo cytokine responses (21), and ticagrelor and clopidogrel reduced pro-inflammatory cytokine levels during human endotoxaemia (22).…”

Section: Kiers Et Al Effects Of Anti-platelet Therapy On Inflammationcontrasting

confidence: 65%

A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia

Kiers¹,

Heijden²,

Ede³

et al. 2017

Thromb Haemost

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The use of acetylsalicylic acid (ASA) is associated with improved outcome in patients with sepsis, and P2Y inhibitors have been suggested to also have immunomodulatory effects. Therefore, we evaluated the effects of clinically relevant combinations of antiplatelet therapy on the immune response in experimental endotoxaemia in humans in vivo. Forty healthy subjects were randomised to seven days of placebo, placebo with ASA, ticagrelor and ASA, or clopidogrel and ASA treatment. Systemic inflammation was elicited at day seven by intravenous administration of Escherichia coli endotoxin. ASA treatment profoundly augmented the plasma concentration of pro-inflammatory cytokines, but did not affect anti-inflammatory cytokines. Addition of either P2Y antagonist to ASA did not affect any of the circulating cytokines, except for an attenuation of the ASA-induced increase in TNFα by ticagrelor. Systemic inflammation increased plasma adenosine, without differences between groups, and although P2Y inhibition impaired platelet reactivity, there was no correlation with cytokine responses.

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Section: Kiers Et Al Effects Of Anti-platelet Therapy On Inflammationcontrasting

confidence: 65%

A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia

Kiers¹,

Heijden²,

Ede³

et al. 2017

Thromb Haemost

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“…This effect is presumably caused by the synthesis and release of pro-inflammatory substances, which could inhibit the normal gastrointestinal muscular activity, reduce the threshold for painful stimuli, and/or reduce gastrointestinal blood flow. As a consequence of these possible effects of LPS, it may be surmised that endotoxaemia can increase the likelihood that a donkey Some in vivo experiments have been conducted in horses and ponies using physiological amounts of E. coli O55:B5 endotoxin at doses of 20-30 ng/kg (Moore et al 2007;Toth et al 2008;McGovern et al 2013;Watts et al 2014) or 0.1 µg/kg (Rosa et al 2003), which were given via slow i.v. infusion.…”

Section: Discussionmentioning

confidence: 99%

The influence of experimentally-induced endotoxaemia on clinical variables and markers of systemic inflammation in donkeys (Equus asinus)

El-Ashker¹,

El-Sebaei²,

Aamer³

2017

Vet. Med. - Czech

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ABSTRACT:In view of the frequent involvement of endotoxins in the pathogenesis of equine diseases, the present study set out to gain preliminary insight into the challenge caused by lipopolysaccharide (LPS) exposure in donkeys and into the responses of animals to LPS challenge. To the best of our knowledge, this is the first study to determine the susceptibility and response of donkeys to LPS administration and the first to describe the extent to which donkeys can tolerate a state of endotoxaemia. For this purpose, 18 clinically healthy, native breed donkeys were randomly allocated into three groups of equal size. The first and second groups received E. coli O55:B5 endotoxin at a dose rate of 20 ng/kg (Low dose group), and 5.0 µg/kg (High dose group), respectively, after dilution in 500 ml of 0.9% normal saline, while the third group (Control) received 500 ml of 0.9% isotonic saline solution. Blood samples were drawn from each animal before exposure to LPS and hourly for 6 h subsequently to measure the circulating levels of inflammatory cytokines as well as the cellular response. All animals were clinically monitored throughout the study period. Following LPS exposure, donkeys in both treated groups had quite different temporal patterns of clinical manifestations. The high dose of LPS yielded a statistically significant (P < 0.001 and P < 0.001, respectively) increase in heart rate, and respiratory rate, as well as hypothermia and poor outcome compared with animals receiving the low dose. The severity of colic was, in general, mild in donkeys receiving the low dose of LPS, while the signs were overt in those receiving the high dose. Donkeys of both treated groups exhibited marked cellular alterations and up-regulation of tumour necrosis factor alpha, interleukin (IL)-12 and IL-10 with a marginal increase in the values of serum amyloid A compared with controls (P < 0.05). The results described herein demonstrate that donkeys can respond to even a physiological dose of E. coli O55:B5 endotoxin, while a high dose can elicit overt clinical alterations and marked inflammatory responses. Further studies with an extended follow-up time are needed to verify and generalise the obtained findings and to evaluate novel medications to minimise the deleterious consequences of endotoxaemia in equine patients.

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“…Experimental LPS infusion induces pronounced hematologic changes in horses. Neutrophil nadirs occur 1‐2 hours after bolus LPS infusions, followed by neutrophilia 4,5 . The lymphocyte counts decrease gradually, with nadirs after 5 hours 4,6 .…”

Section: H N Pgm Hematology Saa + Ironmentioning

confidence: 99%

“…In spontaneous diseases, however, LPS exposure is a more gradual, prolonged process than when one dose is administered on a single occasion. Furthermore, most studies have monitored immediate and short‐term responses (6‐24 hours) after LPS challenge 5‐9 . A study looking at the long‐lasting effects of LPS insult, which likely resemble clinical endotoxemia and the associated kinetic changes, is thus warranted.…”

Section: H N Pgm Hematology Saa + Ironmentioning

confidence: 99%

Hematologic, prostaglandin F_2α‐metabolite, serum amyloid A, and serum iron changes in horses with experimentally induced endotoxemia

Lilliehöök

Bröjer

Nostell

et al. 2020

Veterinary Clinical Pathol

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Background: Endotoxemia is a common and severe disease of horses. Most previous studies have monitored changes caused by a bolus dose of endotoxin over short time periods. Objectives: We aimed to describe inflammatory responses to endotoxin with inflammatory and hematologic markers monitored over a longer time than has been performed in the past using more prolonged endotoxin exposures. Methods: Escherichia coli O55:B5 endotoxin was administered as a 6-hour continuous intravenous infusion of lipopolysaccharide (LPS) to eight horses. Blood cell counts, and prostaglandin F 2α-metabolite (PGM), serum amyloid A (SAA), and serum total iron concentrations were monitored for up to 3 or 6 days. Results: An immediate and severe decrease in neutrophils and monocytes occurred in all horses, which subsequently changed to a moderate to strong neutrophilia and monocytosis that persisted for more than 78 hours postinfusion (PI) of LPS. Lymphocyte and eosinophil numbers decreased gradually and then normalized after 66-and 78-hours PI, respectively. Mild to moderate, biphasic thrombocytopenia occurred. A pronounced, transient increase in PGM occurred between 1 and 7 hours, peaking at 2 hours. Serum amyloid A began to increase after 6 hours PI and remained elevated after 72 hours PI. Serum iron was decreased between 6 and 48 hours. The clinical signs were most prominent during the first 24 hours PI and subsided within 48 hours PI. Conclusions: Neutrophilia, monocytoses, and high SAA concentrations were present in horses even after the clinical signs had subsided. Serum iron normalized before SAA. Knowledge of these findings is imperative when interpreting laboratory results in horses with possible endotoxin exposure.

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Effects of clopidogrel on horses with experimentally induced endotoxemia

Cited by 16 publications

References 50 publications

A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia

A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia

The influence of experimentally-induced endotoxaemia on clinical variables and markers of systemic inflammation in donkeys (Equus asinus)

Hematologic, prostaglandin F_2α‐metabolite, serum amyloid A, and serum iron changes in horses with experimentally induced endotoxemia

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Effects of clopidogrel on horses with experimentally induced endotoxemia

Cited by 16 publications

References 50 publications

A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia

A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia

The influence of experimentally-induced endotoxaemia on clinical variables and markers of systemic inflammation in donkeys (Equus asinus)

Hematologic, prostaglandin F2α‐metabolite, serum amyloid A, and serum iron changes in horses with experimentally induced endotoxemia

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Hematologic, prostaglandin F_2α‐metabolite, serum amyloid A, and serum iron changes in horses with experimentally induced endotoxemia