Parenteral therapy with lipo-ecraprost, a lipid-based formulation of a PGE1 analog, does not alter six-month outcomes in patients with critical leg ischemia

Brass, Eric P.; Anthony, Richard; Dormandy, J. A.; Hiatt, William R.; Jiao, Jenny; Nakanishi, Atsushi; McNamara, Tom; Nehler, Mark R.

doi:10.1016/j.jvs.2005.11.041

Cited by 114 publications

(84 citation statements)

References 17 publications

(16 reference statements)

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“…A randomized trial of patients with CLI, with or without a prostaglandin E1 analog, revealed that the 6-month death rate and the major amputation rate were 10.2% and 16.2% in the prostaglandin E1 group (nϭ179) and 5.6% and 13.0% in the placebo group (nϭ177), respectively. 26 These results suggest that HGF gene therapy provides a favorable outcome compared with natural history.…”

Section: Discussionmentioning

confidence: 92%

Phase I/IIa Clinical Trial of Therapeutic Angiogenesis Using Hepatocyte Growth Factor Gene Transfer to Treat Critical Limb Ischemia

Morishita

Makino

Aoki

et al. 2011

ATVB

112

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Objective-To evaluate the safety and feasibility of intramuscular gene transfer using naked plasmid DNA-encoding hepatocyte growth factor (HGF) and to assess its potential therapeutic benefit in patients with critical limb ischemia. Methods and Results-Gene transfer was performed in 22 patients with critical limb ischemia by intramuscular injection of HGF plasmid, either 2 or 4 mg, 2 times. Safety, ankle-brachial index, resting pain on a 10-cm visual analog scale, wound healing, and walking distance were evaluated before treatment and at 2 months after injection. No serious adverse event caused by gene transfer was detected over a follow-up of 6 months. Of particular importance, no peripheral edema, in contrast to that seen after treatment with vascular endothelial growth factor, was observed. In addition, the systemic HGF protein level did not increase during the study. At 2 months after gene transfer, the meanϮSD ankle-brachial index increased from 0.46Ϯ0.08 to 0.59Ϯ0.13 (PϽ0.001), the meanϮSD size of the largest ischemic ulcers decreased from 3.08Ϯ1.54 to 2.32Ϯ1.88 cm (Pϭ0.007), and the meanϮSD visual analog scale score decreased from 5.92Ϯ1.67 to 3.04Ϯ2.50 cm (Pϭ0.001). An increase in ankle-brachial index by Ͼ0.1, a reduction in ulcer size by Ͼ25%, and a reduction in visual analog scale score by Ͼ2 cm at 2 months after gene transfer were observed in 11 (64. Key Words: gene therapy Ⅲ growth factors Ⅲ peripheral arterial disease R ecent progress in molecular biology has led to the development of gene therapy using intramuscular transfection of genes encoding angiogenic cytokines as a potential new strategy to treat patients with peripheral arterial disease (PAD) or myocardial ischemia. Although beneficial effects of therapeutic angiogenesis using vascular endothelial growth factor (VEGF) gene transfer have been reported in clinical trials, 1-4 some recent reports [1][2][3]5 have documented disadvantages of VEGF, such as the development of leg edema. Placebo-controlled studies 6 -8 failed to show efficacy. In addition, some recent trials 9 using fibroblast growth factor 4 did not show improvement of clinical end points. Thus, it is important to examine the feasibility of other angiogenic growth factors. From this view point, we focused on hepatocyte growth factor (HGF) because it is a potent angiogenic growth factor in mouse, rat, and rabbit ischemia models, including high-risk conditions such as diabetes mellitus and high lipoprotein(a) concentrations. 10 -16 More important, the mitogenic activity of HGF might be more potent than that of VEGF, without edema formation. 11,17 Based on previous data, we designed a human clinical trial of gene therapy for PAD using the HGF gene as an open-labeled phase I/IIa study. The primary objective of this study was to evaluate the safety and feasibility of intramuscular injection of plasmid HGF in patients with critical limb ischemia. The secondary objective was to assess its potential therapeutic benefit. Methods Plasmid DNAA 3.0-kb plasmid vector (pVAX1), commercially pro...

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Section: Discussionmentioning

confidence: 92%

Phase I/IIa Clinical Trial of Therapeutic Angiogenesis Using Hepatocyte Growth Factor Gene Transfer to Treat Critical Limb Ischemia

Morishita

Makino

Aoki

et al. 2011

ATVB

112

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“…9 The Circulase trial, a randomized placebo-controlled pharmacotherapy trial for CLI patients without revascularization options, demonstrated an all-cause mortality of 10% within the first year in both placebo and treatment arms. 10 The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial randomized patients with advanced ischemia to either percutaneous or open surgical revascularization. 11,12 At 2 years, all-cause mortality was 25% independent of treatment type.…”

Section: Critical Limb Ischemiamentioning

confidence: 99%

Surgical Intervention for Peripheral Arterial Disease

Vartanian

Conte

2015

Circ Res

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The prevalence of peripheral arterial disease (PAD) is increasing worldwide, with recent global estimates exceeding 200 million people. Advanced PAD leads to a decline in ambulatory function and diminished quality of life. In its most severe form, critical limb ischemia, rest pain, and tissue necrosis are associated with high rates of limb loss, morbidity, and mortality. Revascularization of the limb plays a central role in the management of symptomatic PAD. Concomitant with advances in the pathogenesis, genetics, and medical management of PAD during the last 20 years, there has been an ongoing evolution of revascularization options. The increasing application of endovascular techniques has resulted in dramatic changes in practice patterns and has refocused the question of which patients should be offered surgical revascularization. Nonetheless, surgical therapy remains a cornerstone of management for advanced PAD, providing versatile and durable solutions to challenging patterns of disease. Although there is little high-quality comparative effectiveness data to guide patient selection, existing evidence suggests that outcomes are dependent on definable patient factors such as distribution of disease, status of the limb, comorbid conditions, and conduit availability. As it stands, surgical revascularization remains the standard against which emerging percutaneous techniques are compared. This review summarizes the principles of surgical revascularization, patient selection, and expected outcomes, while highlighting areas in need of further research and technological advancement.

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“…30 Brass et al and Nehler et al reported other randomized, multicenter, double-blind and controlled studies that showed that the intravenous administration of 60 μg of lipo-ecraprost, a PGE1 analog, 5 days per week for 8 weeks had no benefit in the reduction of major amputation or death at 180 days for patients with CLI. 31,32 Further studies are therefore needed to elucidate the efficacy of PGE1 for critical limb ischemia.…”

Section: Clinical Study Of Pge1mentioning

confidence: 99%

Local Sustained Release of Prostaglandin E1 Induces Neovascularization in Murine Hindlimb Ischemia

Esaki

Sakaguchi

Marui

et al. 2009

Circ J

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Parenteral therapy with lipo-ecraprost, a lipid-based formulation of a PGE1 analog, does not alter six-month outcomes in patients with critical leg ischemia

Abstract: Intensive treatment with lipo-ecraprost failed to modify the 6-month amputation rate in patients with CLI who were not candidates for revascularization.

Cited by 114 publications

References 17 publications

Phase I/IIa Clinical Trial of Therapeutic Angiogenesis Using Hepatocyte Growth Factor Gene Transfer to Treat Critical Limb Ischemia

Phase I/IIa Clinical Trial of Therapeutic Angiogenesis Using Hepatocyte Growth Factor Gene Transfer to Treat Critical Limb Ischemia

Surgical Intervention for Peripheral Arterial Disease

Local Sustained Release of Prostaglandin E1 Induces Neovascularization in Murine Hindlimb Ischemia

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