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PubMed2006

Accelerated healing of excisional skin wounds by PL 14736 in alloxan-hyperglycemic rats.

PL 14736 is a synthetic peptide, originally isolated from human gastric juice, that has anti-inflammatory and tissue-protective actions in experimental models of gastrointestinal inflammation. To investigate its possible benefit in poorly healing skin wounds, the effects of the topical application of PL 14736 in a gel formulation have been studied on full-thickness excisional wounds in rats, either healthy or made hyperglycemic by alloxan (175 mg/kg s.c.) 5 days previously. The effects of becaplermin gel (platelet-derived growth factor, PDGF-BB, Regranex, a standard therapy for diabetic foot ulcers, were investigated for comparison. Healing was evaluated for up to 7 days after wounding, using digital planimetry analysis, macroscopic scoring and histology. While healing was too rapid in healthy rats to observe enhancement by either treatment, in the hyperglycemic rats which exhibited delayed healing, PL 14736 (10-1,000 microg/wound) produced a dose-dependent acceleration of wound healing (determined by macroscopic scoring) equivalent at the highest doses to that observed with becaplermin. The beneficial effect on healing was associated with increased deposition of organized granulation tissue by day 7 for both PL 14736 and becaplermin, as determined histologically. PL 14736 tended to have a greater effect than becaplermin on the formation of granulation tissue containing mature collagen. Wound contraction, as measured by planimetry, was not significantly affected. In conclusion, topical PL 14736 produces a dose-dependent acceleration of deficient skin wound healing in hyperglycemic rats by facilitating granulation tissue formation, similar to the response seen with topical becaplermin, the standard therapy for diabetic skin wounds. PL 14736 may represent an alternative therapy for delayed wound healing, such as that seen with diabetic foot ulcers, without the proliferative concerns or immunogenicity associated with growth factors.

Alloxan↗
PubMed2002

Cost-effective management of recalcitrant diabetic foot ulcers.

The worldwide increase in prevalence of type 2 diabetes has resulted in a parallel increase in diabetic foot ulcers--a pervasive and significant problem associated with this disease [2]. Currently, an estimated 10.3 million people have been diagnosed with diabetes, while an additional estimated 5.4 million people with diabetes remain undiagnosed, representing a sixfold increase in the incidence of diabetes over the past four decades [9]. Approximately 15% (more than 2 million individuals, based on these estimates) of all people with diabetes will develop a lower-extremity ulcer during the course of the disease [10-12]. While most of these ulcers can be treated successfully on an outpatient basis, some will persist and become infected. Ultimately, between 14% and 20% of patients with lower-extremity diabetic ulcers will require amputation of the affected limb [13-15]. Diabetic foot ulcers can result in staggering financial burdens for both the healthcare system and the patient. For example, analysis of the 1995 Medicare claims revealed that lower-extremity ulcer care accounted for $1.45 billion in Medicare costs and contributed substantially to the high cost of care for diabetics, compared with Medicare costs for the general population [5]. Therapies that promote rapid and complete healing and reduce the need for expensive surgical procedures would impact these costs substantially. Results of this analysis suggest that becaplermin may ultimately be more cost-effective for the treatment of chronic diabetic foot ulcers than other treatment modalities, despite its higher initial dollar cost. This finding may be attributed to a combination of factors. First, expenses incurred in more prolonged treatment, such as office visits and the need for additional dressings, can be avoided when healing completes in a shorter period. Second, rapid and complete ulcer healing may reduce the incidence of significant morbidities (such as amputation or infection) and premature mortality; consequently, the financial burden associated with these complications would be reduced. Finally, the value of improved quality of life in patients with healed ulcers and the reduction in financial burden for patients who return to work cannot be ignored. These promising results warrant further investigation in larger controlled clinical studies to define more clearly the cost-effectiveness of becaplermin in this patient population.

Aged↗
PubMedDate not supplied

New treatments in ulcer healing and wound infection.

This review examines several of the recently introduced wound care products that have been put forward as treatment modalities for the diabetic foot ulcer. Discussed are the results of clinical trials with the platelet-derived growth factor, becaplermin, the tissue-engineered products Dermagraft and Apligraf, and Hyaff which is an ester of hyaluronic acid. In patients with an infected foot ulcer, encouraging results were obtained with the granulocyte-colony stimulating factor, Filgrastim.

Becaplermin↗
PubMedDate not supplied

Growth factors and chronic wound healing: past, present, and future.

Growth substances (cytokines and growth factors) are soluble signaling proteins affecting the process of normal wound healing. Cytokines govern the inflammatory phase that clears cellular and extracellular matrix debris. Wound repair is controlled by growth factors (platelet-derived growth factor [PDGF], keratinocyte growth factor, and transforming growth factor beta). Endogenous growth factors communicate across the dermal-epidermal interface. PDGF is important for most phases of wound healing. Becaplermin (PDGF-BB), the only growth factor approved by the Food and Drug Administration, requires daily application for neuropathic wound healing. Gene therapy is under development for more efficient growth factor delivery; a single application will induce constitutive growth factor expression for weeks. Based on dramatic preclinical animal studies, a phase 1 clinical trial planned on a PDGF genetic construct appears promising.

Anticoagulants↗
PubMed2000

Pharmacotherapy of lower limb diabetic ulcers.

OBJECTIVE: To discuss the pathophysiology, microbiology, and pharmacotherapy of lower extremity (LE) diabetic ulcers. DATA SOURCES: A MEDLINE search from 1966 to April 1999 was conducted. The search was limited to humans and English-language journals. Key search words included "diabetic ulcer," "fluoroquinolones," "beta-lactam," "hyperbaric oxygen," "diabetes mellitus," "diabetic foot," and "growth factor." STUDY SELECTION: Randomized and nonrandomized studies were selected for review. Results of randomized, placebo-controlled studies were emphasized more than nonrandomized results. DATA SYNTHESIS: LE ulcers are a common cause of hospitalization, and cause significant morbidity and mortality. Staphylococcus aureus is the most common pathogen in non-limb-threatening infections; Gram-negative bacteria and anaerobes are most prevalent in limb-threatening and life-threatening infections. Oral antibiotic therapy may be used in non-limb-threatening infections, if adequate response is achieved in 24-48 hours; otherwise, intravenous antibiotics should be started. Intravenous antibiotics should be the initial therapy for limb-threatening or life- threatening ulcers. Antimicrobial therapy of at least 10-14 days has been effective in treating LE ulcers in the absence of osteomyelitis. Growth factors offer another treatment alternative, although only becaplermin is currently approved for diabetic ulcers. CONCLUSION: Antibiotic therapy has been effective for the treatment of LE diabetic ulcers. However, further studies are required to identify optimal antibiotics and dosage regimens. Growth factors may have a role but additional research is needed to determine when best to initiate this therapy.

Aged↗
PubMedDate not supplied

SBD.4 stimulates regenerative processes in vitro, and wound healing in genetically diabetic mice and in human skin/severe-combined immunodeficiency mouse chimera.

In search of novel angiostimulators, we performed a high-throughput screening of medicinal plants beneficial for blood circulation. From the panel of positive hits, Angelica sinensis was selected for further investigation. Purified down to a low-molecular-weight fraction and characterized by high-performance liquid chromatography-mass spectrometry, the material, named SBD.4A, revealed a particularly strong wound healing activity in the diabetic mouse wound-healing model, and in the human/severe combined immunodeficiency mouse chimera wound-healing model. In both models, SBD.4A compared favorably with the Food and Drug Administration-approved wound-healing drug becaplermin, suggesting that this botanical product could be a valuable treatment for difficult-to-heal wounds. Further high-performance liquid chromatography fractionation of SBD.4A yielded a hydrophilic fraction, which strongly stimulated endothelial cell proliferation, tridimensional endothelial cell network formation, as well as the proliferation of human dermal fibroblasts and type I collagen secretion. Because angiogenesis and fibroblast proliferation are essential for wound healing, we propose that this liquid chromatography-mass spectrometry-defined hydrophilic fraction is at least partially responsible for the wound-healing activity of SBD.4A.

Angelica sinensis↗
PubMed2000

[New developments in the treatment of diabetic foot ulcers].

Diabetic foot ulcers are frequent: 12,000 Dutch diabetes patients have such an ulcer. The ulcers have a multifactorial aetiology: polyneuropathy, biomechanical stress, infection, deficient footwear and to a less extent ischaemia are the major factors. The principles of ulcer treatment are relief of pressure, restoration of skin perfusion, treatment of infection, intensive wound care, metabolic control, treatment of comorbidity, and instruction of the patient. Wound healing is slow. The impaired wound healing is probably caused by deficiencies in local growth factors, changes in the extracellular matrix, diminished fibroblast function, decreased antimicrobial activity of leukocytes and disturbances in the macro- and microcirculation. In recent years several new treatment strategies have been developed to stimulate wound healing in diabetic foot ulcers. These (partly experimental) treatments include: topical growth factors, extracellular matrix products, bioengineered human skin, granulocyte colony stimulating factor and hyperbaric oxygen therapy. In particular recombinant human platelet derived growth factor (becaplermin) has proved to be clinically effective in chronic neuropathic foot ulcer and has been approved in the Netherlands.

Becaplermin↗
PubMed2004

Update on hemangiomas of infancy.

PURPOSE OF REVIEW: Recent clinical and basic science research has led to advances in the understanding of hemangiomas of infancy. RECENT FINDINGS: New developments include (1) the establishment of a relation between hemangiomas of infancy and placental tissue, (2) the discovery of unique immunohistochemical markers for hemangiomas of infancy, (3) the importance of morphology and location in determining potential risk for underlying complications, and (4) the discovery of becaplermin 1% gel as an effective therapy for refractory ulceration. SUMMARY: The morphology and location of a hemangioma of infancy are critically important factors in determining potential risk for complications. Ongoing research is bringing closer an understanding of the cause of hemangioma, which will provide opportunities for the development of interventional, and ultimately preventative, therapies.

Facial Neoplasms↗
PubMedDate not supplied

Effect of cytokine growth factors on the prevention of acute wound failure.

Cytokine growth factor treatment of chronic wounds has met with mixed results. The chronic wound presents a hostile environment to peptides such as growth factors. Cytokine growth factors have not been studied extensively in acute wounds. However, incisional hernias are a major example of acute wound failure that has not been solved by various mechanical approaches. A biological approach to acute wound failure by use of cytokine growth factors may offer a new strategy. A rodent incisional hernia model was used. Seventy-six rats underwent 3-cm midline celiotomies and were closed with fine, fast-absorbing sutures to induce intentional acute wound failure. Group 1 received no other treatment. The midline fascia in Groups 2-10 was infiltrated with 100 microl of vehicle alone or vehicle containing various test cytokine growth factors. Necropsy was performed on postoperative day 28 and the wounds were examined for herniation. Incisional hernias developed in 83 percent (13/16) of untreated incisional and 88 percent (7/8) and 83 percent (5/6) of the two vehicle-treated incisions (PBS and carboxymethylcellulose). Hernia incidences were decreased by priming of the fascial incision with transforming growth factor-beta(2) (12%, 1/8), basic fibroblast growth factor (25%, 2/8) and interleukin-1 beta (50%, 3/6) (p < 0.05). Aqueous platelet-derived growth factor, becaplermin, insulin-like growth factor, and granulocyte macrophage-colony stimulating factor did not significantly decrease the incidence of acute wound failure (p > 0.05). A biological approach to acute wound failure as measured by incisional hernia formation can be useful in reducing the incidence of this complication. Transforming growth factor-beta(2), basic fibroblast growth factor, and interleukin 1 beta all eliminated or significantly reduced the development of incisional hernias in the rat model.

Animals↗
PubMed2003

Development and validation of the Diabetic Foot Ulcer Scale-short form (DFS-SF).

BACKGROUND: The Diabetic Foot Ulcer Scale (DFS) provides comprehensive measurement of the impact of diabetic foot ulcers on patients' QOL through self-administration of 64 items comprising 15 subscales. OBJECTIVE: To develop and evaluate a short form of the DFS (DFS-SF) to reduce patient burden and the number of outcome measures, and to improve sensitivity to change in clinical condition. METHODS: The DFS-SF was created through the analysis of data from a double-blind, placebo-controlled, randomised trial of the efficacy and safety of becaplermin (recombinant human platelet-derived growth factor BB) in the treatment of chronic, full-thickness, neuropathic, diabetic foot ulcers. Using these data, items demonstrating poor psychometric properties were eliminated. Exploratory factor analyses were then conducted to develop a new, more parsimonious scaling algorithm that optimised the internal consistency of the new subscales. Finally, data from two additional clinical trials were used to assess replicability of the DFS-SF subscale structure. RESULTS: The DFS-SF contains a total of 29 items comprising six subscales. The results of both confirmatory and exploratory factor analyses provided support for the scaling algorithm. The DFS-SF subscales showed good internal consistency, reliability and construct validity, and demonstrated sensitivity to ulcer healing. CONCLUSIONS: The results of this investigation indicate that the DFS-SF has good psychometric properties and replicability.

Adult↗
PubMedDate not supplied

Lower extremity management in patients with diabetes.

Foot ulcers are a major cause of disability, morbidity, and mortality in people with diabetes. The three major etiological factors for diabetic foot ulcers are peripheral neuropathy, peripheral vascular disease, and infection. Tight control of blood glucose and proper foot care are essential for prevention of foot ulcers and lower extremity amputations. Treatment of lower extremity diabetic ulcers typically includes surgical debridement of the wound and appropriate oral or intravenous antibiotics. Becaplermin gel, a prescription, recombinant wound-healing therapy, may be used to promote healing of diabetic foot ulcers in select patients. Pharmacists can make a significant contribution to the prevention of diabetic foot ulcers and lower extremity amputations.

Amputation, Surgical↗
PubMed2006

Outcomes of conventional wound treatment in a comprehensive wound center.

Conventional wound care is the elementary treatment modality for treating chronic wounds. However, early treatment with topical growth factors may be needed for a subset of chronic wounds that fail to heal with good wound care alone. A prospective nonrandomized case series from a single-community outpatient wound care clinic is presented here in an effort to identify the subset of chronic wounds that may require early adjuvant intervention. There were 378 consecutive patients with 774 chronic wounds of varying etiology. All patients received 4 weeks of conventional wound care, including weekly debridement and twice-daily dressing changes. Wounds not reduced by 50 per cent volume at 4 weeks were nonrandomly treated with human skin equivalent (Apligraf), platelet-derived wound healing factor, or platelet-derived growth factor isoform BB (becaplermin gel, Regranex). A total of 601 of 774 (78%) wounds healed regardless of treatment type. The median time to heal for all wounds was 49 days (interquartile range = 26-93). More women than men healed (85% vs 71%, respectively, P < 0.0001). Diabetic wounds were as likely to heal as nondiabetic wounds (78% vs 80%, P = 0.5675). Wounds that did not heal had larger volumes and higher grade compared with wounds that healed (P < 0.0001 for both variables). The data presented here show that the majority of chronic wounds will heal with conventional wound care, regardless of etiology. Large wounds with higher grades are less responsive to conventional wound care and will benefit from topical growth factor treatment early in the treatment course.

Aged↗
PubMed1994

A phase II study to evaluate recombinant platelet-derived growth factor-BB in the treatment of stage 3 and 4 pressure ulcers.

OBJECTIVE: To determine the efficacy of the daily topical application of recombinant platelet-derived growth factor-BB (rPDGF-BB), a recognized vulnerary agent, in the treatment of deep pressure ulcers. DESIGN: Prospective, randomized, double-blind trial. SETTING: Patients were treated in a nursing home or a hospital setting before transfer to a nursing home. PATIENTS: Eligibility criteria included a clean pressure ulcer that had been adequately debrided and the absence of severe cardiac, pulmonary, or renal conditions. The causes of the ulcers were not related to a venous or arterial vascular disorder. The patients were elderly (mean age, 68 to 74 years). INTERVENTIONS: After randomization, patients were given daily topical aqueous rPDGF-BB (dosage, 100 or 300 micrograms/mL) or placebo and saline gauze dressings were applied daily in addition to frequent turning. MAIN OUTCOME MEASURE: Serial volume measurements of the healing wounds were taken using alginate molds. RESULTS: The ulcers of 41 patients were analyzed. At the end of 28 days, median ulcer volumes had decreased to 83%, 29%, and 40% of the initial size in the groups receiving placebo, rPDGF-BB, 100 micrograms/dL, and rPDGF-BB, 300 micrograms/mL, respectively. When adjusted for initial volume, ulcer volume after 28 days of treatment was smaller in the rPDGF-BB-treated groups compared with the placebo group (analysis of covariance, P = .056). Ulcers in the two rPDGF-BB-treated groups were significantly smaller in volume compared with those in the placebo group, using a linear contrast procedure. CONCLUSIONS: Data from this small trial suggest that local application of rPDGF-BB may be of therapeutic benefit in accelerating the healing of chronic pressure ulcers.

Administration, Topical↗
PubMed1994

Effect of hyperbaric oxygen and growth factors on rabbit ear ischemic ulcers.

OBJECTIVE: To test the influence of hyperbaric oxygen (HBO), platelet-derived growth factor-BB (PDGF-BB), and transforming growth factor-beta 1 (TGF-beta 1) on the deficit in wound healing produced by ischemia in a noncontractive dermal ulcer standardized model in the rabbit ear. DESIGN AND INTERVENTIONS: Dermal ulcers were created in the ischemic ears of 42 anesthetized young female New Zealand white rabbits. The controls were ulcers created in nonischemic ears of eight anesthetized young female New Zealand white rabbits. Either PDGF-BB (5 micrograms), TGF-beta 1 (1 microgram), or buffer alone was applied to each wound, which was then covered. Some groups were treated with HBO on days 0 through 4. Wounds were harvested on day 7 and were evaluated histologically. MAIN OUTCOME MEASURES: The amount of epithelial regrowth and granulation tissue production were measured. The wounds were evaluated for glycosaminoglycan and collagen content. Angiogenesis was measured. RESULTS: Hyperbaric oxygen alone, in the ischemic model, increased the production of new granulation tissue by approximately 100% at 7 days without significantly affecting new epithelial growth (P = .03). In contrast, PDGF-BB and TGF-beta 1 each increased the new granulation tissue volume by greater than 200% in 7 days (P = .0001) and also had a statistically significant effect on new epithelial growth. However, the addition of growth factors to HBO treatment produced a synergistic total reversal of the wound-healing deficit produced by ischemia (P = .0001). CONCLUSIONS: Both PDGF-BB and TGF-beta 1 alone are more effective than HBO treatment by itself in accelerating the impaired wound healing produced by ischemia. However, the combination of HBO with either of the growth factors has a synergistic effect that totally reverses the deficit produced by ischemia.

Animals↗
PubMed1996

Factors influencing fetal macrophage development: II. Effects of the PDGF subfamily of protein-tyrosine kinase receptor ligands as studied in organ-cultured rat lungs.

BACKGROUND: Macrophage precursors in pseudoglandular rat lungs rapidly differentiate into phagocytes in organ culture, although this occurs only gradually in vivo. Macrophage colony-stimulating factor is vital for the process, but the possible importance of other ligands in the platelet-derived growth factor (PDGF) subfamily is scarcely appreciated. METHODS: Macrophage development was compared in 15-day fetal rat lungs cultured on solid, serum-containing media with and without added stem cell factor (SCF) (100 ng/mL) or antibodies to PDGF-AA and -BB (10-15 micrograms/mL each). In addition, organ cultures and intact lungs were immunostained for PDGF-AA and -BB to confirm their presence in the tissues. Macrophage population growth was measured by coronal area assay. RESULTS: SCF initially stimulated macrophage production. Thereafter, results varied depending on baseline production by control cultures: where this was vigorous, SCF-exposed explants performed similarly; where this was moderate, the SCF explants outperformed them 1.5-2.6 times over (P < 0.01-0.001). Inhibition of macrophage production by pyrrolidine dithiocarbamate (100 microM) was not significantly diminished in the presence of SCF (10 ng/mL). Immunoreactivity for PDGF-AA and -BB was prevalent in cells of the airway epithelium and stroma during the period macrophage precursors were converting, and both isoforms were detected in differentiating macrophages as early as 2 days in vitro. Nonetheless, exposure of cultures to anti-PDGFs had no significant effect on macrophage population growth. CONCLUSIONS: Ligands of the PDGF subfamily differ greatly in their influence over development of fetal macrophages. Whereas the PDGFs are ineffective, SCF stimulates growth of macrophage precursors and early differentiating forms and enhances survival of older cells. It appears to act mainly in synergy with other growth factors present in fetal lungs. Furthermore, in the hierarchy of hematopoietic progenitors, the macrophage precursors may be ranked on a par with burst-forming units in the red cell lineage.

Animals↗
PubMed1999

Redundancy of autocrine loops in human osteosarcoma cells.

With the aim of identifying innovative therapeutic strategies for osteosarcoma patients who are refractory to conventional chemotherapy, we analyzed the in vitro effects of the blockage of autocrine circuits. Since the insulin-like growth factor-I receptor (IGF-IR)-mediated loop is relevant to the growth of osteosarcoma, we analyzed the activity of the IGF-IR-blocking antibody alphaIR3 in both sensitive and multidrug-resistant osteosarcoma cell lines. Only limited effects, however, were observed, suggesting the simultaneous existence of other autocrine circuits. Indeed, in a representative panel of 12 human osteosarcoma cell lines, in addition to the IGF-IR-mediated circuit, we demonstrated also a loop mediated by epidermal growth factor receptor as well as the presence of nerve growth factor, low-affinity nerve growth factor receptor as well as tyrosine receptor kinase A in the great majority of osteosarcomas. Therapies based on the inhibition of single circuits may have only limited effects in osteosarcoma, whereas the use of suramin, a drug which, besides other activities, non-selectively interferes with the binding of growth factors to their receptors, appears as a promising alternative, in both sensitive and drug-resistant osteosarcoma cells.

Antineoplastic Agents↗
PubMed1996

Depletion of intracellular calcium stores facilitates the influx of extracellular calcium in platelet derived growth factor stimulated A172 glioblastoma cells.

Calcium signaling in non-excitable cells is the consequence of calcium release from intracellular stores, at times followed by entry of extracellular calcium through the plasma membrane. To study whether entry of calcium depends upon the level of saturation of intracellular stores, we measured calcium channel opening in the plasma membrane of single confluent A172 glioblastoma cells stimulated with platelet derived growth factor (PDGF) and/or bradykinin (BK). We monitored the entry of extracellular calcium by measuring manganese quenching of Indo-1 fluorescence. PDGF raised intracellular calcium concentration ([Ca2+]i) after a dose-dependent delay (tdel) and then opened calcium channels after a dose-independent delay (tch). At higher doses (> 3 nM), BK increased [Ca2+]i after a tdel approximately 0 s, and tch decreased inversely with both dose and peak [Ca2+]i. Experiments with thapsigargin (TG), BK, and PDGF indicated that BK and PDGF share intracellular Ca2+ pools that are sensitive to TG. When these stores were depleted by treatment with BK and intracellular BAPTA, tdel did not change, but tch fell to almost 0 s in PDGF stimulated cells, indicating that depletion of calcium stores affects calcium channel opening in the plasma membrane. Our data support the capacitative model for calcium channel opening and the steady-state model describing quantal Ca2+ release from intracellular stores.

Becaplermin↗