| Use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: phase I dose-escalation experience. | |
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MedLine Citation:
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PMID: 17309918 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Critical limb ischemia, a manifestation of severe peripheral atherosclerosis and compromised lower-extremity blood flow, results in a high rate of limb loss. We hypothesized that adenoviral delivery of a constitutively active form of the transcription factor hypoxia-inducible factor-1alpha (ie, Ad2/HIF-1alpha/VP16 or HIF-1alpha) into the lower extremity of patients with critical limb ischemia would be safe and might result in a durable clinical response. METHODS AND RESULTS: This phase I dose-escalation program included 2 studies: a randomized, double-blind, placebo-controlled study and an open-label extension study. In total, 34 no-option patients with critical limb ischemia received HIF-1alpha at doses of 1x10(8) to 2x10(11) viral particles. No serious adverse events were attributable to study treatment. Five deaths occurred: 3 in HIF-1alpha and 2 in placebo patients. In the first (randomized) study, 7 of 21 HIF-1alpha patients met treatment failure criteria and had major amputations. Three of the 7 placebo patients rolled over to receive HIF-1alpha in the extension study. No amputations occurred in the 2 highest-dose groups of Ad2/HIF-1alpha/VP16 (1x10(11) and 2x10(11) viral particles). The most common adverse events included peripheral edema, disease progression, and peripheral ischemia. At 1 year, limb status observations in HIF-1alpha patients included complete rest pain resolution in 14 of 32 patients and complete ulcer healing in 5 of 18 patients. CONCLUSIONS: HIF-1alpha therapy in patients with critical limb ischemia was well tolerated, supporting further, larger, randomized efficacy trials. |
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Authors:
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Sanjay Rajagopalan; Jeffrey Olin; Steven Deitcher; Ann Pieczek; John Laird; P Michael Grossman; Corey K Goldman; Kevin McEllin; Ralph Kelly; Nicolas Chronos |
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Publication Detail:
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Type: Clinical Trial, Phase I; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't Date: 2007-02-19 |
Journal Detail:
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Title: Circulation Volume: 115 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2007 Mar |
Date Detail:
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Created Date: 2007-03-13 Completed Date: 2007-03-29 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 1234-43 Citation Subset: AIM; IM |
Affiliation:
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Section of Vascular Medicine, 473 W 12th Ave, Division of Cardiovascular Medicine, Ohio State University, Columbus, OH 43210-1252, USA. sanjay.rajagopalon@osumc.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenoviridae
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genetics Adult Aged Aged, 80 and over Amputation Dose-Response Relationship, Drug Double-Blind Method Female Gene Therapy / adverse effects, methods* Genetic Vectors / administration & dosage*, adverse effects, genetics Humans Hypoxia-Inducible Factor 1, alpha Subunit / genetics* Ischemia / complications, therapy* Male Middle Aged Pain / etiology, therapy Peripheral Vascular Diseases / complications, therapy* Placebos Transgenes Treatment Outcome Ulcer / etiology, therapy |
| Chemical | |
Reg. No./Substance:
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0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Placebos |
| Comments/Corrections | |
Comment In:
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Circulation. 2007 Mar 13;115(10):1180-3
[PMID:
17353455
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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