First clinical evaluation of the safety and efficacy of tarumase for the debridement of venous leg ulcers.

We report the first clinical evaluation of a new enzymatic wound debridement product containing tarumase in venous leg ulcer patients. As a first-in-human study, this was a prospective, open-label, multi-centre, dose escalation study across five dose cohorts and involving a total of 43 patients treated three times weekly for up to 4 weeks (12 applications). The primary and secondary endpoints of the study were to assess the systemic safety, local tolerability, and early proof of concept both for wound debridement and healing. Results indicated that the tarumase enzyme was well tolerated when applied topically to wounds, with no indications of systemic absorption, no evidence of antibody generation, and no systemic effects on coagulation pathways. Locally, there was no evidence of pain on application, no local itching, no increases in erythema, oedema, exudate or bleeding and only a few treatment emergent adverse events were reported. As the concentration of tarumase was escalated, trends towards faster and improved effectiveness of wound debridement were observed, especially in patients with significant slough at baseline. Trends towards faster rates of healing were also noted based on observations of increased granulation tissue, increased linear healing and reduction in surface area over the 4-week treatment period.

Improvement of Chronic Venous Insufficiency Related Leg Xerosis and Dermatitis With Ceramide-Containing Cleansers and Moisturizers: An Expert-Based Consensus.

INTRODUCTION: Chronic venous insufficiency (CVI) may lead to sustained elevated pressure (aka venous hypertension) in the dermal venous microcirculation. Risk factors include advanced age, obesity, female gender, pregnancy, and prolonged standing. CVI in the lower extremities may lead to cutaneous changes such as xerosis and venous leg dermatitis (VLD). This review explores skin barrier restoration using skincare for xerosis and VLD.    Methods: Prior to the meeting, a structured literature search yielded information on fourteen draft statements. During the meeting, a multi-disciplinary group of experts adopted five statements on xerosis and VLD supported by the literature and the authors’ clinical expertise.   Results: VLD and associated xerosis is a common condition requiring more attention from healthcare providers. Compression therapy is the standard CVI and should be combined with good-quality skincare to enhance adherence to treatment. Maintaining an intact skin barrier by preventing and treating xerosis using gentle cleansers and ceramide-containing moisturizers may improve the skin sequelae of CVI. Skincare is frequently lacking or overlooked as part of the treatment of patients with CVI and VLD. This skin treatment is an unmet need that can be addressed with ceramides-containing pH balanced cleansers and moisturizers. CONCLUSION: Compression therapy is the mainstay of treatment for CVI and VLD. Quality skincare can improve treatment adherence and the efficacy of compression therapy. Using a skincare agent may reduce friction and help patients avoid skin trauma while putting on compression garments. A ceramide-containing moisturizer sustained significant improvements in skin moisturization for 24 hours and may offer synergistic benefits together with compression treatment.  J Drugs Dermatol. 2024;23(2):61-66.     doi:10.36849/JDD.7588.

Algorithm to Improve Patient Comfort and Treat Diabetes Mellitus-Related Xerosis.

BACKGROUND: Diabetes mellitus (DM)-related cutaneous disorders such as xerosis frequently occur in patients with type 1 and type 2 diabetes. Gentle cleansers and moisturizers are underused to prevent xerosis or provide effective early treatment and maintenance. METHODS: The project used a modified Delphi hybrid process comprising face-to-face discussions followed by an online review process. A panel of physicians who treat patients with diabetes with DM used information from literature searches coupled with expert opinions and their experience to develop a practical algorithm to improve outcomes for patients with DM-related xerosis. RESULTS: The algorithm for DM-related xerosis aims to inform dermatologists and other health care professionals caring for patients with DM. The first section of the algorithm addresses education and behavioral measures. Treatment adherence is a considerable challenge in people with DM, making education essential. The second section discusses the assessment of the skin condition. The third section reports on an interdisciplinary team-based approach to patients with DM-related xerosis. The algorithm describes treatment and maintenance approaches using cleansers and moisturizers for mild, moderate, and severe xerosis, distinguishing between the body, face, hands, and feet. CONCLUSION: The algorithm supports educating health care professionals and patients on xerosis prevention and treatment using ceramides-containing gentle cleansers and moisturizers to improve patient comfort and prevent complications. J Drugs Dermatol. 2023;22(4): doi:10.36849/JDD.7177 Citation: Kirsner RS, Andriessen A, Hanft JR, et al. Algorithm to improve patient comfort and treat diabetes mellitus-related xerosis. J Drugs Dermatol. 2023;22(4):356-363. doi:10.36849/JDD.7177.

Economic benefit of a novel dual-mode ambulatory compression device for treatment of chronic venous leg ulcers in a randomized clinical trial.

BACKGROUND: Limb compression is a key component of protocols used to heal venous leg ulcers (VLUs). A novel ambulatory pneumatic compression device was tested in comparison with multilayered bandage (MLB) compression systems for the treatment of VLUs in a prospective randomized clinical trial. METHODS: Patients with VLUs measuring 1.5 to 50 cm2 with duration of 1 to 24 months were randomized to treatment with a pneumatic compression device, the ACTitouch adaptive compression therapy (ACT) system (Tactile Medical, Minneapolis, Minn), or MLB. The ACT group patients were seen in the clinic at weeks 1, 2, 4, 6, 9, 12, and 16 or until wounds healed; the MLB group was seen weekly for bandage and dressing changes for 16 weeks or until wounds healed. All other aspects of VLU care were standardized between the two groups. The primary study objective was to compare the VLU percentage area reduction at 16 weeks in the ACT group compared with the MLB group. RESULTS: There were 56 patients randomized to treatment with ACT (n = 26) or MLB (n = 30). In the ACT group, five patients exited because of skin or wound problems related to the ACT device and five withdrew because of the inconvenience of using the device. Therefore, the trial was halted before full randomization so improvements to the ACT device could be made. Data collected on 42 patients who were able to tolerate treatment for the 16-week study period (per protocol group) showed that both groups experienced similar rates of wound healing. In the per protocol population, the percentage area size reduction was greater for the ACT group compared with the MLB group (83.8% vs 70.5%, respectively), whereas no significant differences were noted in the percentage of wounds that healed by 16 weeks (60.0% vs 63.0%, respectively). CONCLUSIONS: In this truncated clinical trial, a novel dual-mode ambulatory compression device, when tolerated, achieved wound healing results similar to those with MLB for chronic VLUs. The device requires modifications to improve the patient's comfort and ease of use. However, this mode of therapy appears to have promise for improving the cost-effectiveness of treatment for chronic VLUs.

Discovery and Development of Gaseous Nitric Oxide Under Increased Atmospheric Pressure as an Antimicrobial: In Vitro and In Vivo Testing of Nitric Oxide Against Multidrug-Resistant Organisms.

Gaseous nitric oxide under increased atmospheric pressure (gNOp) has shown ability to kill multidrug-resistant bacteria in an in vitro model and in a live mammalian (porcine) model. Factors impacting the kill rate of the multidrug-resistant bacteria include atmospheric pressures, concentration of gaseous NO, flow rate, and duration of application. Using successful in vitro parameters, gNOp showed multilog reduction of bacteria in a live mammalian (porcine) model. The in vitro testing system, using the EpiDerm-FT skin model (stem cell grown skin), was used to develop an infected wound model for Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and methicillin-resistant S aureus.

Diabetic Skin Changes Can Benefit from Moisturizer and Cleanser Use: A Review

INTRODUCTION: Diabetes mellitus (DM) associated skin changes, which may be the first sign of DM in undiagnosed patients. Frequently these patients present with dry skin, which may benefit from the use of gentle cleansers and moisturizers. A review paper was developed to explore DM-associated skin changes and possible benefits of cleanser and moisturizer use. METHODS: For this purpose, an expert panel of physicians involved in the care of patients with DM selected information from literature searches coupled with expert opinions and experience of the panel. RESULTS: A defective skin barrier predisposes the skin to water loss leading to dryness, hyperkeratosis and inflammation. Skin changes that may benefit from the use of gentle cleansers and moisturizers are, amongst others, diabetic foot syndrome, ichthyosiform skin changes, xerosis, and keratosis pilaris. Adherence to treatment is a considerable challenge making education essential, especially about the need to keep skin clean and what skin care to use. Specifically designed diabetic skin care that contains anti-aging ingredients, urea, and essential ceramides, has demonstrated benefits for dry/itchy skin. CONCLUSIONS: Skin disorders are common complications among either diabetic patients with patients with DM and may lead to serious adverse events. Evidence suggests that daily application of optimal skin care using gentle cleansers and moisturizers is one of the measures that may help improve skin barrier dysfunction, preventing complications by providing early-stage treatment of patients with diabetes. J Drugs Dermatol. 2019;18(12):1211-1217.

A multicentre prospective randomised controlled comparative parallel study of dehydrated human umbilical cord (EpiCord) allograft for the treatment of diabetic foot ulcers.

The aim of this study was to determine the safety and effectiveness of dehydrated human umbilical cord allograft (EpiCord) compared with alginate wound dressings for the treatment of chronic, non-healing diabetic foot ulcers (DFU). A multicentre, randomised, controlled, clinical trial was conducted at 11 centres in the United States. Individuals with a confirmed diagnosis of Type 1 or Type 2 diabetes presenting with a 1 to 15 cm2 ulcer located below the ankle that had been persisting for at least 30 days were eligible for the 14-day study run-in phase. After 14 days of weekly debridement, moist wound therapy, and off-loading, those with ≤30% wound area reduction post-debridement (n = 155) were randomised in a 2:1 ratio to receive a weekly application of EpiCord (n = 101) or standardised therapy with alginate wound dressing, non-adherent silicone dressing, absorbent non-adhesive hydropolymer secondary dressing, and gauze bandage roll (n = 54). All wounds continued to have appropriate off-loading during the treatment phase of the study. Study visits were conducted for 12 weeks. At each weekly visit, the DFU was cleaned and debrided as necessary, with the wound photographed pre- and post-debridement and measured before the application of treatment group-specific dressings. A follow-up visit was performed at week 16. The primary study end point was the percentage of complete closure of the study ulcer within 12 weeks, as assessed by Silhouette camera. Data for randomised subjects meeting study inclusion criteria were included in an intent-to-treat (ITT) analysis. Additional analysis was conducted on a group of subjects (n = 134) who completed the study per protocol (PP) (EpiCord, n = 86, alginate, n = 48) and for those subjects receiving adequate debridement (EpiCord, n = 67, alginate, n = 40). ITT analysis showed that DFUs treated with EpiCord were more likely to heal within 12 weeks than those receiving alginate dressings, 71 of 101 (70%) vs 26 of 54 (48%) for EpiCord and alginate dressings, respectively, P = 0.0089. Healing rates at 12 weeks for subjects treated PP were 70 of 86 (81%) for EpiCord-treated and 26 of 48 (54%) for alginate-treated DFUs, P = 0.0013. For those DFUs that received adequate debridement (n = 107, ITT population), 64 of 67 (96%) of the EpiCord-treated ulcers healed completely within 12 weeks, compared with 26 of 40 (65%) of adequately debrided alginate-treated ulcers, P < 0.0001. Seventy-five subjects experienced at least one adverse event, with a total of 160 adverse events recorded. There were no adverse events related to either EpiCord or alginate dressings. These results demonstrate the safety and efficacy of EpiCord as a treatment for non-healing DFUs.

Randomized Controlled Trial Comparing Collagen/Oxidized Regenerated Cellulose/Silver to Standard of Care in the Management of Venous Leg Ulcers.

OBJECTIVE: To assess healing outcomes in venous leg ulcers (VLUs) treated with a combination of collagen, oxidized regenerated cellulose, and silver in conjunction with standard of care (SOC; intervention group) compared with SOC alone (control group). Standard of care included ADAPTIC nonadhering dressing (Acelity, San Antonio, Texas) and compression. DESIGN AND SETTING: Randomized controlled trial that followed patients in 3 US facilities for 12 weeks or until complete healing. PATIENTS AND INTERVENTION: Forty-nine patients with VLUs were randomized to either the intervention group (n = 22) or the control group (n = 27). MAIN OUTCOME MEASURE: Wound healing over 12 weeks. MAIN RESULTS: Intent-to-treat analysis showed a mean percentage wound area reduction at 12 weeks of 85.6% (SD, 28.6%) for the intervention group and 72.5% (SD, 77.8%) for the control group. There was a higher healing rate in the intervention group compared with patients who received SOC only at both week 4 (23% vs 11%) and week 12 (64% vs 59%). There were no adverse events related to the study therapy. CONCLUSIONS: Although the results were not significant, there was a trend toward faster healing in the intervention group. The results of this study indicate that collagen/oxidized regenerated cellulose/silver is a suitable and safe adjunctive intervention for use with SOC to manage VLUs.

Wound Biofilm: Current Perspectives and Strategies on Biofilm Disruption and Treatments

The presence of bio lm remains a challenging factor that contributes to the delayed healing of many chronic wounds. The major threat of chronic wound bio lms is their substantial protection from host immunities and extreme tolerance to antimicrobial agents. To help guide the development of wound treatment strategies, a panel of experts experienced in clinical and laboratory aspects of biofilm convened to discuss what is understood and not yet understood about biofilms and what is needed to better identify and treat chronic wounds in which biofilm is suspected. This article reviews evidence of the problem of biofilms in chronic wounds, summarizes literature-based and experience-based recommendations from the panel meeting, and identities future and emerging technologies needed to address the current gaps in knowledge. While currently there is insufficient evidence to provide an accurate comparison of the effectiveness of current therapies/products in reducing or removing biofilm, research has shown that in addition to debridement, appropriate topical antimicrobial application can suppress biofilm reformation. Because the majority of the resistance of bacteria in a biofilm population is expressed by its own secreted matrix of extracellular polymeric substance (EPS), panel members stressed the need for a paradigm shift toward biofilm treatment strategies that disrupt this shield. High-osmolarity surfactant solution technology is emerging as a potential multimodal treatment that has shown promise in EPS disruption and prevention of biofilm formation when used immediately post debridement. Panel members advocated incorporating an EPS-disrupting technology into an antibiofilm treatment approach for all chronic wounds. The activity of this panel is a step toward identifying technology and research needed to improve biofilm management of chronic wounds.

A prospective, randomized, double-blinded study with crossover to determine the efficacy of radio-frequency nerve ablation for the treatment of heel pain.

BACKGROUND: Previous studies have demonstrated that radio-frequency nerve ablation (RFNA) can be an effective treatment for plantar fasciosis. This study provides additional evidence in support of this treatment, with statistically significant data that demonstrate the success of this technique. METHODS: In this multicenter, randomized, prospective, double-blinded study with crossover, 17 patients were divided into two groups, with eight initially receiving RFNA treatment and nine initially receiving sham treatment. If no improvement was observed after 4 weeks, a crossover was offered. Results of the treatment were evaluated by the patient and by a blinded physician using a visual analog pain scale to rate first-step pain, average pain, and peak pain in the heel region. RESULTS: We observed a statistically significant improvement in the symptoms of plantar fasciosis in patients actively treated with RFNA and no significant improvement in the sham-treated group. More important, those treated with sham subsequently demonstrated statistically significant improvement after subsequent RFNA treatment. CONCLUSIONS: Using a prospective, randomized study with sham treatment and crossover, this study demonstrates the efficacy of RFNA for the treatment of plantar fasciosis.

Consensus recommendations on advancing the standard of care for treating neuropathic foot ulcers in patients with diabetes.

Diabetic foot ulcers (DFUs) are a common and serious complication of diabetes mellitus. The presence of an unhealed DFU increases the risk of infection, amputation and death. Low rates of DFU healing remain a challenge. Recognizing these issues, a consensus panel was recently convened to review the evidence and practicalities for the evaluation and treatment of patients with DFUs. This consensus panel seeks to provide clinicians with the clinical markers, evidence and recommendations that, used in conjunction with orderly decision-making and good clinical judgment, will advance the standard of care for the treatment of neuropathic DFUs.

Diabetic foot ulcers--effects on QOL, costs, and mortality and the role of standard wound care and advanced-care therapies.

Diabetic foot ulcers (DFUs) are a common and serious complication of diabetes mellitus. A review of the literature confirms that the presence of an unhealed DFU negatively affects several domains of patient quality of life (daily and social activities) and increases the risk of infection, amputation, and death. Patients with diabetes mellitus and DFUs also have higher healthcare utilization rates than patients without DFUs and reported healing rates vary from 24% to 82% after 12 weeks of care. Guidelines for the expeditious healing of DFUs are available and include debridement, infection control, offloading, and the use of dressings that maintain a moist wound bed. Wound measurements to determine progress toward healing must be obtained because percent reduction in wound area during the first 4 weeks of care is a predictor of treatment outcome. If a wound fails to respond to standard care, the use of advanced treatment approaches such as cytokines, negative pressure therapy, and living skin equivalents may be beneficial. Clinical studies to further elucidate the effects of topical, systemic, and supportive regimens of care on outcomes and costs are needed.

The lack of reliability of clinical examination in the diagnosis of wound infection: preliminary communication.

The diagnosis of infection in chronic wounds is challenging. Clinicians tend to rely on the classic signs and the symptoms. Quantitative tissue biopsy, the most accurate method, is rarely used because it is expensive, invasive, and difficult to perform. A recently completed clinical trial evaluating collagen/oxidized regenerated cellulose/antimicrobial matrix versus standard of care in venous leg ulcerations was reviewed. Patients with infected venous leg ulcers by clinical examination were excluded. In fact, none of the subjects in the 2 arms of the study had target ulcers that appeared to be infected at any time during the study. Quantitative biopsies of the ulcers were obtained and compared with investigator evaluation. In all, 14 of 49 subjects (28%) had bacterial counts greater than 10(5) or beta-hemolytic streptococcus despite the lack of clinical signs of infection. This analysis suggests that clinical examination is unreliable in the diagnosis of wound infection in venous leg ulcerations.

A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers.

Nonhealing diabetic foot ulcers are a common cause of amputation. Emerging cellular therapies such as platelet-rich plasma gel provide ulcer management options to avoid loss of limb. The purpose of this prospective, randomized, controlled, blinded, multicenter clinical study was to evaluate the safety and efficacy of autologous platelet-rich plasma gel for the treatment of nonhealing diabetic foot ulcers. One hundred, twenty-nine (129) patients were screened; 72 completed a 7-day screening period and met the study inclusion criteria. Patients were randomized into two groups - the standard care with platelet-rich plasma gel or control (saline gel) dressing group - and evaluated biweekly for 12 weeks or until healing. Healing was confirmed 1 week following closure and monitored for another 11 weeks. An independent audit led to the exclusion of 32 patients from the final per-protocol analysis because of protocol violations and failure to complete treatment. In this group, 13 out of 19 (68.4%) of the platelet-rich plasma gel and nine out of 21 (42.9%) of the control wounds healed. After adjusting for wound size outliers (n = 5), significantly more platelet-rich plasma gel (13 out of 16, 81.3%) than control gel (eight out of 19, 42.1%) treated wounds healed (P = 0.036, Fisher's exact test). Kaplan-Meier time-to-healing also was significantly different between groups (log-rank, P = 0.0177). No treatment-related serious adverse events were reported and bovine thrombin used in the preparation of PRP did not cause Factor V inhibition. When used with good standards of care, the majority of nonhealing diabetic foot ulcers treated with autologous platelet-rich plasma gel can be expected to heal.

The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial.

OBJECTIVE: To determine if a human fibroblast-derived dermal substitute could promote the healing of diabetic foot ulcers. RESEARCH DESIGN AND METHODS: A randomized, controlled, multicenter study was undertaken at 35 centers throughout the U.S. and enrolled 314 patients to evaluate complete wound closure by 12 weeks. Patients were randomized to either the Dermagraft treatment group or control (conventional therapy). Except for the application of Dermagraft, treatment of study ulcers was identical for patients in both groups. All patients received pressure-reducing footwear and were allowed to be ambulatory during the study. RESULTS: The results demonstrated that patients with chronic diabetic foot ulcers of >6 weeks duration experienced a significant clinical benefit when treated with Dermagraft versus patients treated with conventional therapy alone. With regard to complete wound closure by week 12, 30.0% (39 of 130) of Dermagraft patients healed compared with 18.3% (21 of 115) of control patients (P = 0.023). The overall incidence of adverse events was similar for both the Dermagraft and control groups, but the Dermagraft group experienced significantly fewer ulcer-related adverse events. CONCLUSIONS: The data from this study show that Dermagraft is a safe and effective treatment for chronic diabetic foot ulcers.

Healing of chronic foot ulcers in diabetic patients treated with a human fibroblast-derived dermis.

A prospective, multicenter, randomized, controlled 12-week study was undertaken to evaluate the effectiveness of a human fibroblast-derived dermis for treating foot ulcers in the diabetic patient. This report summarizes the findings from one center. Following a 2-week screening period, patients were randomized to either human fibroblast-derived dermis (HFDD) (Dermagraft) plus saline-moistened gauze or to the control group (CT) of saline-moistened gauze alone. Effectiveness end points were: 1) wound closure by week 12, 2) time to wound closure, and 3) percent wound closure by week 12. Safety was assessed by review of adverse events and laboratory findings. Patients randomized to HFDD received an application at day 0 and up to seven additional treatments. All patients in each group received shoes with custom-molded inserts and were seen weekly. The study population was comprised of 28 patients (14 HFDD/14 CT) with chronic ulcers (>6 weeks' duration at time of screening). By week 12, significantly more chronic ulcers healed in the HFDD group than in the CT group (71.4% versus 14.3%, p = .003). Healed HFDD patients achieved wound closure significantly faster than CT patients (p = .004). Patients treated with HFDD showed a statistically significant higher percent of wound closure by week 12 than did CT patients (p = .002). The percent of patients who experienced an infection involving their study wound was less in the HFDD group than in the CT group. It was concluded that HFDD is a safe and effective treatment for chronic foot ulcers in diabetic patients.