Chronic Oral Defibrotide Counteracts Hypercholesterolemia Noxious Effects on Cardiovascular Function in the Rabbit

Rossoni, Giuseppe; Berti, F.; Trento, Fabio; Cattaneo, Franco; Porta, Roberto; Pescador, Rodolfo; Ferro, Laura

doi:10.1016/s0049-3848(99)00009-2

Cited by 7 publications

(3 citation statements)

References 38 publications

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“…Defibrotide has been studied as an anti-coagulation and endothelial protection agent in different rat models. In those studies, defibrotide was given by different routes of administration and at different dosages in different animals [ 22 – 24 ]. For example, Kim et al [ 25 ] examined the effect of defibrotide on liver ischemia-reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Defibrotide improved the outcome of monocrotaline induced rat hepatic sinusoidal obstruction syndrome

et al. 2022

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Background and aim Pyrrolizidine alkaloids (PA) induced hepatic sinusoidal obstruction syndrome (HSOS) occurred worldwide and the mortality rate remained high because there were no specific therapies. Defibrotide was effective for HSOS following hematopoietic stem cell transplantation. But the pathogenesis of the two types of HSOS were not equivalent. The purpose of this study was to see if defibrotide was also effective in PA induced rat HSOS. Methods First we improved rat HSOS model by using higher dose (230 mg/kg) of monocrotaline (a kind of PA) as the dose of median lethal dose. So drug effectiveness could be assessed by survival time. Next, male SD rats were divided into 5 groups. They were control group, model group, low dose low molecular weight heparin (LMWH) treatment group, high dose LMWH treatment group and defibrotide treatment group. Rats’ survival time, liver function, white blood cell count and cytokines were compared among the groups. The DeLeve score was used to assess the severity of liver pathology. Results The model group exhibited typical liver pathology of HSOS, such as hepatic sinus dilation, congestion, endothelial injury of central lobular vein, coagulative necrosis of hepatocytes and fibrin deposition in the subendothelial. The pathologic characteristics indicated that the model was built up successfully. The survival rate was significantly higher in defibrotide group (81.8%) than model group (43.7%), while the survival rates were similar in the two LMWH groups (62.5% and 75%) and model group. The survival time only be prolonged by defibrotide (P=0.028) but not LMWH (P>0.05). DeLeve score was improved most in the defibrotide group than the two LMWH groups (both P<0.01). Changes in DeLeve score, liver function, plasma level of tumor necrosis factor α and plasminogen activator inhibitor-1 exhibited the same trends. Conclusion Defibrotide could improve the outcome of monocrotaline-induced rat HSOS indicating that defibrotide might be a better choice than LMWH in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Defibrotide improved the outcome of monocrotaline induced rat hepatic sinusoidal obstruction syndrome

et al. 2022

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“…Inhibited formation of cysteinyl leukotrienes in leukocyte-perfused isolated rabbit hearts [23] Decreased NFjB transcriptional activity in multiple myeloma cells and bone marrow stromal cells [66] Antagonized vasoconstriction induced by endothelin-1 in human saphenous vein samples [65] Increased nitric oxide generation in isolated, perfused, guinea pig hearts [50] Improved acetylcholine-induced endothelial vasorelaxation in cholesterol-fed rabbits [68], including in rabbits with atherosclerosis [69] Other effects…”

Section: Effects On Vascular Integrity and Vascular Tonementioning

confidence: 99%

Defibrotide: A Review of Its Use in Severe Hepatic Veno-Occlusive Disease Following Haematopoietic Stem Cell Transplantation

Keating

2014

Clin Drug Investig

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Defibrotide (Defitelio(®)) was recently approved in the EU for the treatment of severe hepatic veno-occlusive disease (VOD), also known as sinusoidal obstructive syndrome, in haematopoietic stem cell transplantation (HSCT) therapy. It is indicated in adults, adolescents, children and infants over 1 month of age. Defibrotide is also available in the US via an expanded-access protocol. Defibrotide is thought to protect endothelial cells and restore the thrombo-fibrinolytic balance in VOD. In a multicentre, phase III trial, the complete response rate by day +100 (primary endpoint) was significantly higher, and mortality at day +100 was significantly lower, in patients with severe hepatic VOD and multiorgan failure following HSCT who received intravenous defibrotide 6.25 mg/kg every 6 h than in a group of historical controls. The efficacy of defibrotide in severe hepatic VOD following HSCT was also supported by findings from a phase II dose-finding study, compassionate-use data and information provided from an independent transplant registry. Intravenous defibrotide was generally well tolerated in patients with severe hepatic VOD following HSCT, and was not associated with an increased risk of haemorrhagic adverse events. In conclusion, defibrotide is the only agent approved (in the EU) for use in severe hepatic VOD following HSCT and represents a useful advance in the treatment of this condition.

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“…Also, different antioxidants or free-radical scavengers, such as probucol, superoxide dismutase, vitamin E, tomato carotenoids, and β-carotene, have positive effects on EDV in hypercholesterolemic animals (202,(215)(216)(217)(218)(219)(220)(221)(222)(223)(224)(225)(226)(227)(228). Commonly used antihypertensive therapies, such as angiotensin-converting enzyme inhibition, calcium and α-receptor blockade, endothelin receptor blockade, and neuroendopetidase inhibition, all have positive effects on EVD (194,211,(229)(230)(231)(232)(233)(234)(235)(236)(237); a number of other drugs, such as heparin and estrogens (see Table 3) (238)(239)(240)(241)(242)(243)(244)(245) have also exhibited this effect.…”

Section: Interventions In Animal Modelsmentioning

confidence: 99%

Lipids and endothelium‐dependent vasodilation—A review

Lind

2002

Lipids

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Studies using both in vitro and in vivo techniques have repeatedly shown that endothelium-dependent vasodilation (EDV) is impaired in different forms of experimental as well as human hypercholesterolemia. Clearly this impaired EDV can be reversed by lowering cholesterol levels by diet or medical therapy. Competitive blocking of L-arginine, changes in nitric oxide synthase activity, increased release of endothelin-1, and inactivation of nitric oxide due to superoxide ions all contribute to the impairment in EDV during dyslipidemia. The oxidation of low density lipoprotein, with its compound lysophosphatidylcholine, plays a critical role in these events. However, data on the role of triglycerides and fat-rich meals regarding EDV are not so consistent as data for cholesterol, although a view that the compositions of individual fatty acids and antioxidants are of major importance is emerging. Thus, this review shows that while impaired EDV is a general feature of hypercholesterolemia, the mechanisms involved and the therapeutic opportunities available still have to be investigated. Furthermore, discrepancies regarding the role of triglycerides and fat content in food may be explained by divergent effects of different fatty acids on the endothelium.

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Chronic Oral Defibrotide Counteracts Hypercholesterolemia Noxious Effects on Cardiovascular Function in the Rabbit

Cited by 7 publications

References 38 publications

Defibrotide improved the outcome of monocrotaline induced rat hepatic sinusoidal obstruction syndrome

Defibrotide improved the outcome of monocrotaline induced rat hepatic sinusoidal obstruction syndrome

Defibrotide: A Review of Its Use in Severe Hepatic Veno-Occlusive Disease Following Haematopoietic Stem Cell Transplantation

Lipids and endothelium‐dependent vasodilation—A review

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