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Perianal Application of Glyceryl Trinitrate Ointment Versus Tocopherol Acetate Ointment in the Treatment of Chronic Anal Fissure: A Randomized Clinical Trial.
Ruiz-Tovar, J, Llavero, C
Diseases of the colon and rectum. 2022;(3):406-412
Abstract
BACKGROUND Medical treatment, including glyceryl trinitrate ointment, represents the first step for the management of chronic anal fissure. However, glyceryl trinitrate ointment is associated with headache and, consequently, a high withdrawal rate of the treatment. OBJECTIVE The aim of the present study was to evaluate the effect of the topical application of tocopherol acetate ointment on pain relief and chronic anal fissure epithelialization, comparing it with the effect of a standard treatment with glyceryl trinitrate ointment. DESIGN This is a 2-parallel-group, single-center, randomized controlled, intent-to-treat clinical trial. SETTINGS This study was conducted at the Garcilaso Clinic affiliated with Universidad Alfonso X (Madrid, Spain). PATIENTS Patients with chronic anal fissure were selected. INTERVENTIONS Patients were randomly assigned into 2 groups: patients receiving tocopherol acetate ointment and patients receiving glyceryl trinitrate ointment. MAIN OUTCOME MEASURES The primary end point was quantification of anal pain 8 weeks after beginning the treatment as measured by a Visual Analogue Scale ranging from 0 to 100 mm. The secondary end points were the healing rate (during the treatment period of 8 weeks) and the recurrence rate. RESULTS One hundred sixty consecutive patients were treated, 80 in each group. By 8 weeks after treatment, mean anal pain score declined by 56.2 mm in the glyceryl trinitrate ointment group compared with a mean anal pain score decline of 67.1 mm in the tocopherol acetate ointment group (mean difference, 10.9 mm (95% CI, 4.3-18.6); p = 0.018). Sixteen weeks after finishing the therapy, the recurrence rate was 13.2% in the glyceryl trinitrate ointment group vs 2.9 in the tocopherol acetate ointment group (p = 0.031). LIMITATIONS Limitations of the study include the absence of manometric measurements of the internal anal sphincter before and after the treatments and the use of glyceryl trinitrate ointment as an active comparator, whereas calcium channel blockers are actually the standard treatment. CONCLUSIONS Anal pain was significantly lower in the tocopherol acetate ointment group than in the glyceryl trinitrate ointment group at 8 weeks after treatment. Tocopherol acetate ointment achieved a greater healing rate and a lower recurrence rate 16 weeks after finishing the treatment. See Video Abstract at http://links.lww.com/DCR/B751. REGISTRATION URL: https://www.clinicaltrials.gov; Identifier: NCT03787030.APLICACIÓN PERIANAL DE POMADA DE TRINITRATO DE GLICERILO FRENTE A LA POMADA DE ACETATO DE TOCOFEROL EN EL TRATAMIENTO DE LA FISURA ANAL CRÓNICA: UN ENSAYO CLÍNICO ALEATORIZADOANTECEDENTESEl tratamiento médico, incluida la pomada de trinitrato de glicerilo, representa el primer paso para el tratamiento de la fisura anal crónica. Sin embargo, la pomada de trinitrato de glicerilo se asocia con cefalea y, en consecuencia, una alta tasa de cancelación del tratamiento.OBJETIVOEl objetivo del presente estudio fue evaluar el efecto de la aplicación tópica de pomada de acetato de tocoferol en el alivio del dolor y la epitelización de la fisura anal crónica, comparándolo con el efecto de un tratamiento estándar con pomada de trinitrato de glicerilo.DISEÑO:Ensayo clínico con intención de tratar controlado, aleatorizado, de un solo centro, con dos grupos paralelos.ESCENARIOClínica Garcilaso adscrita a la Universidad Alfonso X (Madrid, España).PACIENTESPacientes con fisura anal crónica.INTERVENCIONESLos pacientes fueron aleatorizados en 2 grupos: pacientes que recibieron pomada de acetato de tocoferol y pacientes que recibieron pomada de trinitrato de glicerilo.PRINCIPALES MEDIDAS DE RESULTADOEl criterio de valoración principal fue la cuantificación del dolor anal 8 semanas después de comenzar el tratamiento, medido por la escala analógica visual que varía de 0 a 100 mm. Los criterios de valoración secundarios fueron la tasa de curación (durante el período de tratamiento de 8 semanas) y la tasa de recurrencia.RESULTADOSSe trataron ciento sesenta pacientes consecutivos, 80 en cada grupo. A las ocho semanas después del tratamiento, la puntuación media de dolor anal se redujo en 56.2 mm en el grupo de pomada de trinitrato de glicerilo en comparación con una disminución de la puntuación de dolor anal medio de 67.1 mm en el grupo de pomada de acetato de tocoferol (diferencia media: 10.9 mm (intervalo de confianza del 95%; 4.3 a 18.6; p = 0.018) Dieciséis semanas después de finalizar la terapia, la tasa de recurrencia fue del 13.2% en el grupo de pomada de trinitrato de glicerilo frente a 2.9 en el grupo de pomada de acetato de tocoferol (p = 0.031).LIMITACIONESAusencia de medidas manométricas del esfínter anal interno antes y después de los tratamientos. Ungüento de trinitrato de glicerilo como comparador activo, mientras que los bloqueadores de los canales de calcio son en realidad el tratamiento estándar de oro.CONCLUSIONESEl dolor anal fue significativamente menor en el grupo de ungüento de acetato de tocoferol que en el grupo de ungüento de trinitrato de glicerilo a las 8 semanas después del tratamiento. La pomada de acetato de tocoferol logró una mayor tasa de curación y una menor tasa de recurrencia 16 semanas después de finalizar el tratamiento. Consulte Video Resumen en http://links.lww.com/DCR/B751. (Traducción-Dr. Jorge Silva Velazco).
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2.
The signaling pathways of traditional Chinese medicine in promoting diabetic wound healing.
Zhou, X, Guo, Y, Yang, K, Liu, P, Wang, J
Journal of ethnopharmacology. 2022;:114662
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The diabetic wound is one of the common chronic complications of diabetes, which seriously affects patients' quality of life and even causes disability and death. Traditional Chinese medicine (TCM) is a unique and precious resource in China, which has a good curative effect and safety. At present, it has been found that Chinese herbal compounds and effective active ingredients can effectively promote diabetic wound healing, and its mechanism needs to be further studied. Signaling pathways are involved in the pathogenesis and progression of diabetic wounds, which is one of the main targets for the pathologic mechanism of diabetic wounds and the pharmacological research of therapeutic drugs. AIM OF THE REVIEW This study has been carried out to reveal the classical signaling pathways and potential targets by the action of TCM on diabetic wound healing and provides evidence for its clinical efficacy. MATERIALS AND METHODS "diabetic wound", "diabetic foot ulcer", "traditional Chinese medicine", "natural plant" and "medicinal plant", were selected as the main keywords, and various online search engines, such as PubMed, Web of Science, CNKI and other publication resources, were used for searching literature. RESULTS The results showed that TCM could regulate the signaling pathways to promote diabetic wound healing, such as Wnt, Nrf2/ARE, MAPK, PI3K/Akt, NF-κB, Notch, TGF-β/Smad, HIF-1α/VEGF, which maintaining inflammatory interaction balance, inhibiting oxidative stress and regulating abnormal glucose metabolism. CONCLUSION The effect of TCM on diabetic wound healing was reflected in multiple levels and multiple pathways. It is envisaged to carry out further research from precision-targeted therapy, provide ideas for screening the core target of TCM in treating diabetic wounds and create modern innovative drugs based on this target.
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3.
Histologic Outcomes With Vedolizumab Versus Adalimumab in Ulcerative Colitis: Results From An Efficacy and Safety Study of Vedolizumab Intravenous Compared to Adalimumab Subcutaneous in Participants With Ulcerative Colitis (VARSITY).
Peyrin-Biroulet, L, Loftus, EV, Colombel, JF, Danese, S, Rogers, R, Bornstein, JD, Chen, J, Schreiber, S, Sands, BE, Lirio, RA
Gastroenterology. 2021;(4):1156-1167.e3
Abstract
BACKGROUND AND AIMS VARSITY (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis) showed superior clinical remission and endoscopic improvement in ulcerative colitis with vedolizumab vs adalimumab. This analysis compared histologic outcomes. METHODS Patients in VARSITY were randomized 1:1 to maintenance with vedolizumab IV 300 mg every 8 weeks or adalimumab SC 40 mg every 2 weeks (both following standard induction). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52. RESULTS In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Mean baseline histologic disease activity was similar between vedolizumab and adalimumab groups. Vedolizumab induced greater histologic remission than adalimumab at week 14 (Geboes: 16.7% vs 7.3%, Δ9.4% [95% confidence interval {CI}, 4.9%-13.9%], P < .0001; RHI: 25.6% vs 16.1%, Δ9.5% [95% CI, 3.8%-15.2%], P = .0011) and week 52 (Geboes: 29.2% vs 8.3%, Δ20.9% [95% CI, 15.6%-26.2%], P < .0001; RHI: 37.6% vs 19.9%, Δ17.6% [95% CI, 11.3%-23.8%], P < .0001) overall and in both anti-tumor necrosis factor (TNF)-naïve and -failure subgroups. Results were similar for minimal histologic disease activity. Histologic outcomes were generally better in anti-TNF-naïve vs -failure patients. At week 52, rates of mucosal healing (composite end point of histologic plus endoscopic improvement) were also higher with vedolizumab than adalimumab (Geboes: 25.6% vs 6.7%; RHI: 30.5% vs 14.5%). CONCLUSIONS Higher rates of histologic remission, minimal histologic disease activity, and combined histologic plus endoscopic outcomes were observed with vedolizumab than with adalimumab in ulcerative colitis in both anti-TNF-naïve and -failure subgroups. REGISTRATION ClinicalTrials.gov NCT02497469; EudraCT 2015-000939-33.
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The effects of curcumin intake on wound healing and metabolic status in patients with diabetic foot ulcer: A randomized, double-blind, placebo-controlled trial.
Mokhtari, M, Razzaghi, R, Momen-Heravi, M
Phytotherapy research : PTR. 2021;(4):2099-2107
Abstract
This study was conducted to determine the effects of curcumin intake on wound healing and metabolic status in patients with diabetic foot ulcer (DFU). The current randomized, double-blind, placebo-controlled trial was conducted among 60 patients with grade 3 DFU. Participants were randomly allocated into two groups (30 participants each group), received either 80 mg nanocurcumin daily for 12 weeks or placebo. Primary endpoints in this study were serum insulin levels and insulin resistance. Curcumin intake significantly decreased fasting plasma glucose (p = .02), insulin (p = .01), insulin resistance (p = .02), and significantly increased insulin sensitivity (p = .008) compared with the placebo. Moreover, curcumin intake led to a significant reduction in total- (p < .001), LDL-cholesterol (p < .001), and a significant increase in total antioxidant capacity (TAC) (p < .001) and total glutathione (GSH) (p = .01) compared with the placebo. However, there was no significant improvement in wound healing parameters. Overall, our study demonstrated that nanocurcumin intake in patients with DFU resulted in a significant improvement of glycemic control, total- and LDL-cholesterol, TAC, and GSH but did not affect the indicators of ulcer size.
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5.
Therapeutic candidates for keloid scars identified by qualitative review of scratch assay research for wound healing.
Alishahedani, ME, Yadav, M, McCann, KJ, Gough, P, Castillo, CR, Matriz, J, Myles, IA
PloS one. 2021;(6):e0253669
Abstract
The scratch assay is an in vitro technique used to analyze cell migration, proliferation, and cell-to-cell interaction. In the assay, cells are grown to confluence and then 'scratched' with a sterile instrument. For the cells in the leading edge, the resulting polarity induces migration and proliferation in attempt to 'heal' the modeled wound. Keloid scars are known to have an accelerated wound closure phenotype in the scratch assay, representing an overactivation of wound healing. We performed a qualitative review of the recent literature searching for inhibitors of scratch assay activity that were already available in topical formulations under the hypothesis that such compounds may offer therapeutic potential in keloid treatment. Although several shortcomings in the scratch assay literature were identified, caffeine and allicin successfully inhibited the scratch assay closure and inflammatory abnormalities in the commercially available keloid fibroblast cell line. Caffeine and allicin also impacted ATP production in keloid cells, most notably with inhibition of non-mitochondrial oxygen consumption. The traditional Chinese medicine, shikonin, was also successful in inhibiting scratch closure but displayed less dramatic impacts on metabolism. Together, our results partially summarize the strengths and limitations of current scratch assay literature and suggest clinical assessment of the therapeutic potential for these identified compounds against keloid scars may be warranted.
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Development of films from natural sources for infections during wound healing.
Leyva-Gómez, G, González-Torres, M, Alcalá-Alcalá, S, Bernal-Chávez, SA, Morales-Morfin, JC, González-Del Carmen, M, Sharifi-Rad, J, Figueroa-González, G, Reyes-Hernández, OD, Del Prado-Audelo, MAL, et al
Cellular and molecular biology (Noisy-le-Grand, France). 2021;(1):96-100
Abstract
The skin is the largest organ in the human body, and due to its barrier function, it is susceptible to multiple injuries. The appearance of infections during the wound healing process is a complication that represents a formidable hospital challenge. The presence of opportunistic bacteria with sophisticated resistance mechanisms is difficult to eradicate and compromises patients' lives. Therefore, the search for new efficacious treatments from natural sources that prevent and counteract infections, in addition to promoting the healing process, has increased in recent years. In this respect, films with the capability to protect wounds and release drugs are the presentation that predominates commercially in the hospital environment. Those films can offer several mechanical advantages such as physical protection to prevent opportunistic bacteria's entry, regulation of gas exchange, and capture of exudate through a swelling process. Wound dressings are generally curative materials easily adaptable to different anatomical regions, with high strength and elasticity, and some are even bioabsorbable. Additionally, the components of the films can actively participate in promoting the healing process. Even more, the film can be made up of carriers with other active participants to prevent and eradicate infections. Therefore, the extensive versatility, practicality, and usefulness of films from natural sources to address infectious processes during wound healing are relevant and recurrent themes. This work presents an analysis of the state-of-the-art of films with natural products focused on preventing and eradicating infections in wound healing.
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7.
The Modulatory Influence of Plant-Derived Compounds on Human Keratinocyte Function.
Merecz-Sadowska, A, Sitarek, P, Zajdel, K, Kucharska, E, Kowalczyk, T, Zajdel, R
International journal of molecular sciences. 2021;(22)
Abstract
The plant kingdom is a rich source of secondary metabolites with numerous properties, including the potential to modify keratinocyte biology. Keratinocytes are important epithelial cells that play a protective role against various chemical, physical and biological stimuli, and participate in reactive oxygen scavenging and inflammation and wound healing processes. The epidermal cell response may be modulated by phytochemicals via changes in signal transduction pathways. Plant extracts and single secondary compounds can possess a high antioxidant capacity and may suppress reactive oxygen species release, inhibit pro-apoptotic proteins and apoptosis and activate antioxidant enzymes in keratinocytes. Moreover, selected plant extracts and single compounds also exhibit anti-inflammatory properties and exposure may result in limited production of adhesion molecules, pro-inflammatory cytokines and chemokines in keratinocytes. In addition, plant extracts and single compounds may promote keratinocyte motility and proliferation via the regulation of growth factor production and enhance wound healing. While such plant compounds may modulate keratinocyte functions, further in vitro and in vivo studies are needed on their mechanisms of action, and more specific toxicity and clinical studies are needed to ensure their effectiveness and safety for use on human skin.
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8.
Noncoding RNAs and RNA-binding proteins in diabetic wound healing.
Li, X, Li, N, Li, B, Feng, Y, Zhou, D, Chen, G
Bioorganic & medicinal chemistry letters. 2021;:128311
Abstract
Poor wound healing is a common complication in diabetic patients. It often leads to intractable infections and lower limb amputations and is associated with cardiovascular morbidity and mortality. NcRNAs, which can regulate gene expression, have emerged as important regulators of various physiological processes. Herein, we summarize the diverse roles of ncRNAs in the key stages of diabetic wound healing, including inflammation, angiogenesis, re-epithelialization, and extracellular matrix remodeling. Meanwhile, the potential use of ncRNAs as novel therapeutic targets for wound healing in diabetic patients is also discussed. In addition, we summarize the role of RNA-binding proteins (RBPs) in the regulation of gene expression and signaling pathways during skin repair, which may provide opportunities for therapeutic intervention for this potentially devastating disease. However, so far, research on the modulated drug based on ncRNAs that lead to significantly altered gene expression in diabetic patients is scarce. We have compiled some drugs that may be able to modulate ncRNAs, which significantly regulate the gene expression in diabetic patients.
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Wound cleansing for treating venous leg ulcers.
McLain, NE, Moore, ZE, Avsar, P
The Cochrane database of systematic reviews. 2021;(3):CD011675
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Abstract
BACKGROUND Leg ulcers are open skin wounds that occur below the knee but above the foot. The majority of leg ulcers are venous in origin, occurring as a result of venous insufficiency, where the flow of blood through the veins is impaired; they commonly arise due to blood clots and varicose veins. Compression therapy, using bandages or stockings, is the primary treatment for venous leg ulcers. Wound cleansing can be used to remove surface contaminants, bacteria, dead tissue and excess wound fluid from the wound bed and surrounding skin, however, there is uncertainty regarding the effectiveness of cleansing and the best method or solution to use. OBJECTIVES To assess the effects of wound cleansing, wound cleansing solutions and wound cleansing techniques for treating venous leg ulcers. SEARCH METHODS In September 2019 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA We considered randomised controlled trials (RCTs) comparing wound cleansing with no wound cleansing, or RCTs comparing different wound cleansing solutions, or different wound cleansing techniques. DATA COLLECTION AND ANALYSIS We screened studies for their appropriateness for inclusion, assessed their risk of bias using the Cochrane 'Risk of bias' tool, and used GRADE methodology to determine the certainty of evidence. Two review authors undertook these tasks independently, using predetermined criteria. We contacted study authors for missing data where possible. MAIN RESULTS We included four studies with a total of 254 participants. All studies included comparisons between different types of cleansing solutions, and three of these reported our primary outcomes of complete wound healing or change in ulcer size over time, or both. Two studies reported the secondary outcome, pain. One study (27 participants), which compared polyhexamethylene biguanide (PHMB) solution with saline solution for cleansing venous leg ulcers, did not report any of the review's primary or secondary outcomes. We did not identify any studies that compared cleansing with no cleansing, or that explored comparisons between different cleansing techniques. One study (61 participants) compared aqueous oxygen peroxide with sterile water. We are uncertain whether aqueous oxygen peroxide makes any difference to the number of wounds completely healed after 12 months of follow-up (risk ratio (RR) 1.88, 95% confidence interval (CI) 1.10 to 3.20). Similarly, we are uncertain whether aqueous oxygen peroxide makes any difference to change in ulcer size after eight weeks of follow-up (mean difference (MD) -1.38 cm2, 95% CI -4.35 to 1.59 cm2). Finally, we are uncertain whether aqueous oxygen peroxide makes any difference to pain reduction, assessed after eight weeks of follow-up using a 0 to 100 pain rating, (MD 3.80, 95% CI -10.83 to 18.43). The evidence for these outcomes is of very low certainty (we downgraded for study limitations and imprecision; for the pain outcome we also downgraded for indirectness). Another study (40 participants) compared propyl betaine and polihexanide with a saline solution. The authors did not present the raw data in the study report so we were unable to conduct independent statistical analysis of the data. We are uncertain whether propyl betaine and polihexanide make any difference to the number of wounds completely healed, change in ulcer size over time, or wound pain reduction. The evidence is of very low certainty (we downgraded for study limitations and imprecision). The final study (126 participants) compared octenidine dihydrochloride/phenoxyethanol (OHP) with Ringer's solution. We are uncertain whether OHP makes any difference to the number of wounds healed (RR 0.96, 95% CI 0.53 to 1.72) or to the change in ulcer size over time (we were unable to conduct independent statistical analysis of available data). The evidence is of very low certainty (we downgraded for study limitations and imprecision). None of the studies reported patient preference, ease of use of the method of cleansing, cost or health-related quality of life. In one study comparing propyl betaine and polihexanide with saline solution the authors do not report any adverse events occurring. We are uncertain whether OHP makes any difference to the number of adverse events compared with Ringer's solution (RR 0.58, 95% CI 0.29 to 1.14). The evidence is of very low certainty (we downgraded for study limitations and imprecision). AUTHORS' CONCLUSIONS There is currently a lack of RCT evidence to guide decision making about the effectiveness of wound cleansing compared with no cleansing and the optimal approaches to cleansing of venous leg ulcers. From the four studies identified, there is insufficient evidence to demonstrate whether the use of PHMB solution compared with saline solution; aqueous oxygen peroxide compared with sterile water; propyl betaine and polihexanide compared with a saline solution; or OHP compared with Ringer's solution makes any difference in the treatment of venous leg ulcers. Evidence from three of the studies is of very low certainty, due to study limitations and imprecision. One study did not present data for the primary or secondary outcomes. Further well-designed studies that address important clinical, quality of life and economic outcomes may be important, based on the clinical and patient priority of this uncertainty.
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PRP in wound healing applications.
Oneto, P, Etulain, J
Platelets. 2021;(2):189-199
Abstract
Platelets play a crucial role in hemostasis, tissue regeneration and host defense. Based on these settings, platelet-rich plasma (PRP) and its derivatives are therapeutically used to promote wound healing in several scenarios. This review summarizes the biological mechanisms underlying the most traditional as well as innovative applications of PRP in wound healing. These mechanisms involve the combined action of platelet-derived growth factors and cytokines, together with the role of plasma-derived fibrillar, antioxidant and homeostatic factors. In addition, regenerative treatments with PRP consist of personalized and non-standardized methods. Thus, the quality of PRP varies depending on endogenous factors (e.g., age; gender; concomitant medication; disease-associated systemic factors; nutrition) and exogenous factors (anticoagulants and cellular composition). This review also analyses whether these factors affect the biological mechanisms of PRP in wound healing applications.