Dalteparin, a low molecular weight heparin, attenuates inflammatory responses and reduces ischemia-reperfusion–induced liver injury in rats*

Harada, Naoaki; Okajima, Kenji; Uchiba, Mitsuhiro

doi:10.1097/01.ccm.0000220764.10155.03

Cited by 44 publications

(25 citation statements)

References 40 publications

(45 reference statements)

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“…Besides its anticoagulant properties, heparin exerts a broad range of cytoprotective actions, including suppression of inflammation (Tyrell et al, 1995;Harada et al, 2006), prevention of apoptosis (Yagmurdur et al, 2005) and modulation of vascular adherence (Freischlag et al, 1992). Our previous study indicated that unfractionated heparin (UFH) ameliorates LPS-induced inflammatory response through inhibition of p38 mitogen-activated protein kinase (MAPK)/nuclear factor-B (NF-B) pathway in HPMECs (Li et al, 2012).…”

Section: Introductionmentioning

confidence: 98%

Unfractionated heparin attenuates LPS-induced IL-8 secretion via PI3K/Akt/NF-κB signaling pathway in human endothelial cells

Liu

Wang

et al. 2015

Immunobiology

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Section: Introductionmentioning

confidence: 98%

Unfractionated heparin attenuates LPS-induced IL-8 secretion via PI3K/Akt/NF-κB signaling pathway in human endothelial cells

Liu

Wang

et al. 2015

Immunobiology

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“…This was considered in view of action of effects of certain drugs on inflammatory mediators by a mechanism that differs from their known mechanism of action (Ji et al, 2006, Harada et al, 2006, Park et al, 2006, Kast RE 2006. In conclusion, TNF-and IL-8 and may be involve in stroke pathogeneses and that antiplatelet agents may have an important role in inhibition of stroke mediates cytokines.…”

Section: Discussionmentioning

confidence: 96%

TNF-α and IL-8 in Acute Stroke and the Modulation of these Cytokines by Antiplatelet Agents

Al-Bahrani¹,

Taha²,

Shaath³

et al. 2007

CNR

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Stroke is associated with elevation of several proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-8 that are correlated with central nervous system (CNS) injury. Anti-platelet therapies are important agents in stroke management. The role of antiplatelets as anti-inflammatory agents is not known in acute stroke patients. Furthermore, their effect on induction of potential cytokines as TNF-alpha and IL-8 in those patients is still not clear. Thus, we herein examined the induction of TNF-alpha and IL-8 in acute stroke patients and examined the effects of the antiplatelets drugs aspirin, clopidogrel and dipyridamole, and piracetam in their induction. Cytokines were detected intracellularly in leukocytes from patients who had first acute ischemic stroke and from matched controls by immunocytochemistry. The results showed significant increase of spontaneously produced TNF-alpha and IL-8 in patients compared to control. This induction was significantly inhibited differently by each drug and dual drug agents. The data of this work suggest that antiplatelets agents may have a role in inhibition of stroke mediated proinflammatory cytokine effects, which may initiate a new aspect of the role of antiplatelets in the treatment of acute ischemic stroke.

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“…None of the pre-clinical toxicology reports, however, suggested that the liver was a target for LMWH in either rodents or dogs [28]. In fact, research in animals has demonstrated that heparins can mitigate against liver injury in some rat models [28].…”

Section: Literature Review Of Enoxaparin and Other Anticoagulantsmentioning

confidence: 99%

Enoxaparin-Induced Liver Injury: Case Report and Review of the Literature and FDA Adverse Event Reporting System (FAERS)

Hahn

Morales

Lewis

2015

Drug Saf - Case Rep

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Anticoagulants are a well known cause of drug-induced liver injury (DILI). We recently encountered a 45-year-old male who developed DILI during treatment with enoxaparin, a low-molecular-weight heparin (LMWH), for dural venous thrombosis. The man received enoxaparin 80 mg subcutaneously, twice daily. After 4 days, the patient was asymptomatic but he developed liver aminotransferase elevations: AST 340 U/L and ALT 579 U/L. Investigation revealed an R ratio of 19.9 by day 5 and a Roussel Uclaf Causality Assessment Method score of 10, giving a high probable likelihood that enoxaparin was the cause of hepatic injury. Enoxaparin was discontinued on day 7, and 1 week later AST and ALT had decreased to 61 and 273 U/L, respectively. This case prompted a literature search and a review of the FDA Adverse Event Reporting System (FAERS) database for the range of hepatic adverse events (HAEs) associated with this class. A MEDLINE/PubMed search was conducted using DILI terms and cross-referenced with the anticoagulant classes. A Freedom of Information Act (FOIA) request was also made to identify adverse events (AEs) associated with enoxaparin in FAERS. Case type, severity of outcome, and demographic information were analyzed. Five publications have reported DILI with enoxaparin. Trial data found elevations in ALT >3 times the upper limit of normal (ULN) for unfractionated heparins (UFH) and LMWH in 8 and 4–13 % of subjects, respectively. However, liver injury in all cases was mild, self-limited, and asymptomatic. Our FOIA request yielded 8336 adverse events related to enoxaparin over a 14-year period (Jan 2000–Sept 2014). Specific HAEs were found in 4 % of reports, but all were described with other serious adverse events. The reported outcomes of hospitalization (75 %), death (17 %), and life-threatening medical events (5 %) were likely due to other related serious adverse events such as hemorrhage (28 %) and thrombocytopenia (11 %). We conclude that LMWH-related liver injury is uncommon and reversible. The mechanism of liver injury is not known, although an idiosyncratic effect is postulated. Although the FAERS database lists hepatic injury in 4 % of all enoxaparin-related AEs, it appears that serious outcomes are related to non-hepatic events.

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Dalteparin, a low molecular weight heparin, attenuates inflammatory responses and reduces ischemia-reperfusion–induced liver injury in rats*

Cited by 44 publications

References 40 publications

Unfractionated heparin attenuates LPS-induced IL-8 secretion via PI3K/Akt/NF-κB signaling pathway in human endothelial cells

Unfractionated heparin attenuates LPS-induced IL-8 secretion via PI3K/Akt/NF-κB signaling pathway in human endothelial cells

TNF-α and IL-8 in Acute Stroke and the Modulation of these Cytokines by Antiplatelet Agents

Enoxaparin-Induced Liver Injury: Case Report and Review of the Literature and FDA Adverse Event Reporting System (FAERS)

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Dalteparin, a low molecular weight heparin, attenuates inflammatory responses and reduces ischemia-reperfusion–induced liver injury in rats*

Cited by 44 publications

References 40 publications

Unfractionated heparin attenuates LPS-induced IL-8 secretion via PI3K/Akt/NF-κB signaling pathway in human endothelial cells

Unfractionated heparin attenuates LPS-induced IL-8 secretion via PI3K/Akt/NF-κB signaling pathway in human endothelial cells

TNF-&#945; and IL-8 in Acute Stroke and the Modulation of these Cytokines by Antiplatelet Agents

Enoxaparin-Induced Liver Injury: Case Report and Review of the Literature and FDA Adverse Event Reporting System (FAERS)

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Product

Resources

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TNF-α and IL-8 in Acute Stroke and the Modulation of these Cytokines by Antiplatelet Agents