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Expert Opinion on Biological Therapy Feb 2002Chronic or non-healing lower extremity ulcerations in diabetics are a significant cause of morbidity and mortality, and account for a large proportion of the financial... (Review)
Review
Chronic or non-healing lower extremity ulcerations in diabetics are a significant cause of morbidity and mortality, and account for a large proportion of the financial burden related to the care of diabetics. Lower extremity ulcerations develop primarily as a consequence of neuropathy and the goal in addressing any wound is to re-establish tissue integrity as soon as possible. The healing of wounds is a complex procedure involving multiple growth factors, some of which have multiple effects on different cell types, in particular, platelet derived growth factor (PDGF) is a prominent agent, active in all stages of the healing process. Becaplermin (0.01% Regranex gel) is a homodimeric protein produced by recombinant DNA technology through the insertion of the gene for the B chain PDGF into the yeast Saccharomyces cerevisiae. The biological activity of becaplermin is similar to that of indigenous PDGF-BB, specifically, the promotion of chemotactic recruitment and the proliferation of cells involved in wound repair. Becaplermin has undergone extensive animal and human studies, demonstrating that it is highly effective as an adjunctive measure for the healing of ulcerations in the feet of diabetics when used in conjunction with standard wound healing practices. Specifically these practices include the provision of a moist environment free of debris and necrotic tissue, control of infection and optimal weight displacement from the affected area. Becaplermin is safe and easy to use, being applied once-daily and at present, becaplermin is the only growth factor licensed for use in wound healing.
Topics: Animals; Anticoagulants; Becaplermin; Diabetic Foot; Humans; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Recombinant Proteins; Wound Healing
PubMed: 11849120
DOI: 10.1517/14712598.2.2.211 -
American Journal of Surgery Aug 1998Becaplermin (recombinant human platelet-derived growth factor-BB [BB homodimer, rhPDGF-BB]) has demonstrated a favorable safety profile in a series of nonclinical... (Review)
Review
Becaplermin (recombinant human platelet-derived growth factor-BB [BB homodimer, rhPDGF-BB]) has demonstrated a favorable safety profile in a series of nonclinical studies designed to assess its systemic toxicity, sensitization, local irritation, and genotoxic potential. No significant local or systemic toxicity directly attributable to becaplermin was observed following single and multiple intravenous or subcutaneous administration at doses up to 3 mg/kg in monkeys. Administration of single large intravenous doses (up to 100 mg/kg) and repeated dosing at 1 or 3 mg/kg in mice resulted in rapidly reversible vasodilation and central nervous system depression. In a bone-toxicity study, becaplermin produced histomorphologic changes suggestive of accelerated bone remodeling, which were judged to be potentially reversible. Similar findings have not been observed in humans. Although becaplermin was not considered a dermal or ocular irritant, some skin-sensitizing effects were observed in animals; this finding was not unexpected for a recombinant human-derived protein. Becaplermin was not genotoxic in a variety of in vitro assays and in one in vivo assay.
Topics: Animals; Anticoagulants; Becaplermin; Bone Diseases; Dose-Response Relationship, Drug; Drug Hypersensitivity; Humans; Infusions, Intravenous; Injections, Subcutaneous; Mice; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Recombinant Proteins; Skin Diseases; Toxicity Tests; Wound Healing
PubMed: 9777973
DOI: 10.1016/s0002-9610(98)00176-7 -
Clinical Interventions in Aging 2008Diabetic foot ulcers remain a major cause of morbidity. Significant progress has been accomplished in ulcer healing by improved management of both ischemia and... (Review)
Review
Diabetic foot ulcers remain a major cause of morbidity. Significant progress has been accomplished in ulcer healing by improved management of both ischemia and neuropathy in the diabetic foot. Nevertheless, there is a vital need for further improvement. Becaplermin gel represents an important therapeutic advance for diabetic neuropathic foot ulcers with adequate blood supply. Randomized controlled trials have shown that it is effective in increasing healing rates. However, this efficacy has not translated to positive clinical experience, and the drug is not widely used. Moreover, becaplermin is an expensive medication. Even though it has repeatedly been estimated as cost-effective, its high cost may be prohibitive for some clinicians, especially in developing countries. Clearly, further work is needed to clarify whether use of becaplermin is justified in everyday clinical practice. Future research also needs to assess the potential room for improvement with becaplermin, for instance by combination with other growth factors or by exploring alternative modes of drug delivery.
Topics: Angiogenesis Inducing Agents; Becaplermin; Diabetic Foot; Gels; Humans; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Randomized Controlled Trials as Topic; Treatment Outcome; Wound Healing
PubMed: 18686746
DOI: 10.2147/cia.s1106 -
Annales de Dermatologie Et de... Apr 2004Becaplermine gel (Regranex) is an hydrogel which contains 100 microg of Platelet Derived Growth Factor-BB (rhPDGF-BB) per gram. Regranex is presented in 15-gram... (Review)
Review
Becaplermine gel (Regranex) is an hydrogel which contains 100 microg of Platelet Derived Growth Factor-BB (rhPDGF-BB) per gram. Regranex is presented in 15-gram multidose tubes. It has been approved as adjuvant treatment for neuropathic diabetic ulcerations of less than 5 cm2, extending into the subcutaneous tIssue, in the absence of ischemia, in conjunction with a standardised program of appropriate wound care, (control of infection, sharp debridement, provision of a moist environment and avoidance of pressure on the wound). PDGF-BB promotes cutaneous wound healing by increasing proliferation and migration of dermal fibroblasts and extracellular matrix deposition. PDGF also promotes chemotaxis of neutrophils, monocytes and smooth muscle cells in wounds. Topical application of rhPDGF-BB speeds wound healing and promotes granulation tIssue formation, synthesis of extracellular matrix and the inflammatory phase of the wound healing process in healthy and healing-impaired animal models. In clinical trials in humans, accelarated healing has been demonstrated in patients with lower extremity diabetic neuropathic ulcers and decubitus sores by increasing granulation tIssue formation and epithelialization. Local toxicity studies in humans were negative (repeated becaplermin gel application under occlusion to intact or abraded skin, dermal sensitization tests). Pharmacokinetic studies in humans have shown that systemic absorption after topical applications was minimal. In trials, systemic and local tolerance were excellent. Reported adverse effects were similar in incidence and in nature in all groups. The 0.01% Regranex gel is safe and easy to use, with single daily application. It is currently the only commercially available topical growth factor for use in cutaneous wound healing.
Topics: Becaplermin; Clinical Trials as Topic; Diabetes Complications; Gels; Humans; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Skin Ulcer
PubMed: 15258509
DOI: 10.1016/s0151-9638(04)93614-9 -
Journal of the American Podiatric... Jul 2016A comparison of the cost-effectiveness of becaplermin plus good wound care (BGWC) versus good wound care (GWC) alone in treating patients with diabetic foot ulcers... (Comparative Study)
Comparative Study Review
BACKGROUND
A comparison of the cost-effectiveness of becaplermin plus good wound care (BGWC) versus good wound care (GWC) alone in treating patients with diabetic foot ulcers (DFUs) may enable physicians and health-care decision makers in the United States to make better-informed choices about treating DFUs, which currently contribute to a substantial portion of the economic burden of diabetes.
METHODS
Data from three phase III trials were used to predict expected 1-year costs and outcomes, including the average percentage reduction from baseline in wound surface area (WSA), the direct costs of DFU therapy, and the cost per cm(2) of WSA reduction.
RESULTS
At 20 weeks, the BGWC group had a statistically greater probability of complete wound closure than the GWC group (50% versus 35%; P = .015). Based on reported WSA reduction rates, DFUs in the BGWC group were predicted to close by 100% at 27 weeks, and those in the GWC group were predicted to close by 88% at 52 weeks. The GWC group had higher total estimated 1-year direct cost of DFU care ($6,809 versus $4,414) and higher cost per cm(2) of wound closure ($3,501 versus $2,006).
CONCLUSIONS
Becaplermin plus good wound care demonstrated economic dominance compared with GWC by providing better clinical outcomes via faster reduction in WSA and higher rates of closure at a lower direct cost.
Topics: Administration, Topical; Aged; Becaplermin; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Diabetic Foot; Female; Gels; Humans; Male; Middle Aged; Proto-Oncogene Proteins c-sis; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Skin Care; Treatment Outcome; Wound Healing
PubMed: 27049838
DOI: 10.7547/15-004 -
American Journal of Surgery Aug 1998Advances in molecular biology have made possible the production of highly purified recombinant human proteins, and recombinant human growth factors have emerged as... (Review)
Review
Advances in molecular biology have made possible the production of highly purified recombinant human proteins, and recombinant human growth factors have emerged as potential therapeutic wound healing agents. Becaplermin (recombinant human platelet-derived growth factor-BB [rhPDGF-BB]) quickly emerged as one of the leading candidates for clinical trials. Before the expected therapeutic potential of rhPDGF-BB and other growth factors could be realized, a number of concerns had to be addressed (eg, would growth factors show effects in normal animals, what parameters of wound healing would be affected, and would quality of healed wounds be normal?). In animal models, rhPDGF-BB demonstrated wound healing activity, predominantly by enhancing the formation of granulation tissue, but it was not known whether this effect on granulation tissue would translate into enhanced healing of chronic skin ulcers in humans. The objective of this article is to review how the study of rhPDGF-BB in animal wound healing models has assisted in addressing the potential clinical utility of rhPDGF-BB. Results of animal studies are summarized, and the advantages and limitations of the animal models are discussed.
Topics: Animals; Anticoagulants; Becaplermin; Disease Models, Animal; Guinea Pigs; Humans; Mice; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Rats; Recombinant Proteins; Skin Ulcer; Swine; Wound Healing
PubMed: 9777972
DOI: 10.1016/s0002-9610(98)00177-9 -
Nature Biotechnology May 2002The advent of in vitro DNA amplification has enabled rapid acquisition of genomic information. We present here an analogous technique for protein detection, in which the...
The advent of in vitro DNA amplification has enabled rapid acquisition of genomic information. We present here an analogous technique for protein detection, in which the coordinated and proximal binding of a target protein by two DNA aptamers promotes ligation of oligonucleotides linked to each aptamer affinity probe. The ligation of two such proximity probes gives rise to an amplifiable DNA sequence that reflects the identity and amount of the target protein. This proximity ligation assay detects zeptomole (40 x 10(-21) mol) amounts of the cytokine platelet-derived growth factor (PDGF) without washes or separations, and the mechanism can be generalized to other forms of protein analysis.
Topics: Animals; Base Sequence; Becaplermin; Chemistry, Clinical; DNA; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Humans; Molecular Sequence Data; Oligonucleotides; Platelet-Derived Growth Factor; Proteins; Proto-Oncogene Proteins c-sis; Sensitivity and Specificity; Thrombin; Time Factors
PubMed: 11981560
DOI: 10.1038/nbt0502-473 -
The Journal of Clinical Investigation Dec 2023Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel...
Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue is well studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed to cerebrovascular calcification in male mice. Aged male mice had higher serum PDGF-BB levels and a higher incidence of brain calcification compared with young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevated serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA-Seq (scRNA-Seq) revealed that PDGF-BB upregulated multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRβ (p-PDGFRβ) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of osteoblast differentiation genes in PCs and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induced brain vascular calcification by activating the p-PDGFRβ/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.
Topics: Animals; Male; Mice; Becaplermin; Brain; Core Binding Factor Alpha 1 Subunit; Osteogenesis; Proto-Oncogene Proteins c-sis; Receptor, Platelet-Derived Growth Factor beta; Vascular Calcification
PubMed: 37815871
DOI: 10.1172/JCI168447 -
Prescrire International Aug 2010
Topics: Angiogenesis Inducing Agents; Becaplermin; Diabetic Neuropathies; Humans; Infections; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis
PubMed: 20941855
DOI: No ID Found -
Dermatologic Therapy 2016Large difficult to heal ulcers of various etiologies carry a high morbidity and mortality rate. Becaplermin is a recombinant platelet-derived growth factor approved for...
Large difficult to heal ulcers of various etiologies carry a high morbidity and mortality rate. Becaplermin is a recombinant platelet-derived growth factor approved for treatment of diabetic ulcers. In this two-case series, we report the use of becaplermin in the treatment of ulcers due to (i) calciphylaxis, an often fatal condition resulting from systemic calcification and thrombosis of vessels and (ii) pyoderma gangrenosum (PG), a neutrophilic dermatosis. We also report that topical collagenase worsened PG ulcers, consistent with pathergy. Becaplermin can be used to help treat ulcers resulting from calciphylaxis and PG. These encouraging results lend support for the utilization of becaplermin in the treatment of nondiabetic chronic ulcers of various etiologies.
Topics: Adult; Aged; Angiogenesis Inducing Agents; Becaplermin; Calciphylaxis; Humans; Male; Proto-Oncogene Proteins c-sis; Pyoderma Gangrenosum; Skin Ulcer; Treatment Outcome
PubMed: 26556220
DOI: 10.1111/dth.12318