Absorption Through the Peritoneum of the Macromolecular Profibrinolytic Drug Defibrotide in the Rabbit

Porta, Roberto; Calvani, Angelo Benvenuto; Pescador, Rodolfo; Mantovani, M; Prino, G

doi:10.1055/s-2007-1002644

Cited by 3 publications

(3 citation statements)

References 7 publications

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“…DFT's profibrinolytic activity was the first activity to be unraveled, thanks to the efforts of Mantovani (Pescador et al, 1983) and other authors (Porta et al, 1991;Mussoni et al, 1979;Klocking, 1992).…”

Section: The History Of Defibrotidementioning

confidence: 99%

Defibrotide: Properties and clinical use of an old/new drug

Pescador

Capuzzi

Mantovani

et al. 2013

Vascular Pharmacology

105

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The drug named defibrotide (DFT) has been studied for many years. It has been shown to possess many activities: profibrinolytic, antithrombotic-thrombolytic, antiischemic (heart, liver, kidney, skin, brain), antishock, antiatherosclerotic, antirejection and anti-angiogenic. The previously displayed activities, as antithrombotic, profibrinolytic and anti-inflammatory, suggested its use in vascular disorders, as in the treatment of peripheral obliterative arterial disease and in thrombophlebitis. Some years after, the use of DFT in hepatic veno-occlusive disease has been also proposed. Even if DFT was considered for long time a multi-target drug, now it could be considered on the whole as a drug able to protect endothelium against activation. The present work reviews the more important experimental and clinical studies performed to detect DFT effects.

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Section: The History Of Defibrotidementioning

confidence: 99%

Defibrotide: Properties and clinical use of an old/new drug

Pescador

Capuzzi

Mantovani

et al. 2013

Vascular Pharmacology

105

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“…Defibrotide is a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue. Although the mechanism of action of defibrotide is not fully elucidated, preclinical data suggest that it stabilizes endothelial cells by reducing endothelial cell activation, increasing the expression of tissue plasminogen activator and thrombomodulin, while decreasing von Willebrand factor and plasminogen activator inhibitor 1 expression, and by protecting endothelial cells from further damage, resulting in the restoration of thrombofibrinolytic balance [8][9][10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Defibrotide for Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Interim Results from a Treatment IND Study

Richardson

Smith

Triplett

et al. 2017

Biology of Blood and Marrow Transplantation

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Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (≤16 years) and adult (>16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was generally well tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MOD symptoms, the most commonly reported treatment-emergent adverse event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD.

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“…In vitro evidence suggests that defibrotide protects and stabilizes endothelial cells through antithrombotic, profibrinolytic, and anti-inflammatory actions, and restores the endothelial thrombo-fibrinolytic balance 25–30. Because of defibrotide’s demonstrated efficacy in the treatment of hepatic VOD/SOS with MOD (including renal dysfunction),15,23,31 evidence of tolerability in other conditions,32–34 and the high prevalence of renal impairment in patients with VOD/SOS, a two-part study was conducted to assess the pharmacokinetics (PK) of defibrotide in renal-impaired subjects.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic profile of defibrotide in patients with renal impairment

Tocchetti¹,

Tudone²,

Marier³

et al. 2016

DDDT

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Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage renal disease (ESRD) on defibrotide pharmacokinetics (PK). Part 1 compared defibrotide PK during single 6.25 mg/kg doses infused with and without dialysis. Part 2 assessed defibrotide plasma PK after multiple 6.25 mg/kg doses in nondialysis-dependent subjects with severe/ESRD versus healthy matching subjects. Among six subjects enrolled in Part 1, percent ratios of least-squares mean and 90% confidence intervals (CIs) on dialysis and nondialysis days were 109.71 (CI: 97.23, 123.78) for maximum observed plasma concentration (Cmax); 108.39 (CI: 97.85, 120.07) for area under the concentration–time curve to the time of the last quantifiable plasma concentration (AUC0–t); and 109.98 (CI: 99.39, 121.70) for AUC extrapolated to infinity (AUC0–∞). These ranges were within 80%–125%, indicating no significant effect of dialysis on defibrotide exposure/clearance. In Part 2, defibrotide exposure parameters in six subjects with severe/ESRD after multiple doses (AUC0–t, 113 µg·h/mL; AUC over dosing interval, 113 µg·h/mL; Cmax, 53.8 µg/mL) were within 5%–8% of parameters after the first dose (AUC0–t, 117 µg·h/mL; AUC0–∞, 118 µg·h/mL; Cmax, 54.9 µg/mL), indicating no accumulation. Defibrotide peak and extent of exposures in those with severe/ESRD were ~35%–37% and 50%–60% higher, respectively, versus controls, following single and multiple doses. One adverse event (vomiting, possibly drug-related) was reported. These findings support defibrotide prescribing guidance stating no dose adjustment is necessary for hemodialysis or severe/ESRD.

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Absorption Through the Peritoneum of the Macromolecular Profibrinolytic Drug Defibrotide in the Rabbit

Cited by 3 publications

References 7 publications

Defibrotide: Properties and clinical use of an old/new drug

Defibrotide: Properties and clinical use of an old/new drug

Defibrotide for Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Interim Results from a Treatment IND Study

Pharmacokinetic profile of defibrotide in patients with renal impairment

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