Topical Reformulation of Valsartan for Treatment of Chronic Diabetic Wounds (original) (raw)
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European Journal of Pharmacology, 2006
In diabetic patients, impairment of wound healing is a serious problem which represents a significant health burden. The effect of a highly selective beta-3 adrenoceptor agonist, SR58611A, on wound healing was assessed in animal models of type II diabetes. In db/db diabetic mice, a daily oral treatment with SR58611A (1, 3 and 10 mg/kg/day for two weeks) significantly reduced hyperglycaemia from 3 mg/kg/day onwards. The compound also normalized wound healing, starting from the lowest dose tested (1 mg/kg/day). SR58611A did not affect wound healing of control (lean) mice. An oral anti-diabetic agent, devoid of affinity for beta-3 adrenoceptors, troglitazone (130 mg/kg/day p.o.), normalized glycaemia but did not improve wound healing in db/db mice. Local application of SR58611A (200 μg/day in db/db mice) did not affect wound healing. SR58611A also normalized glucose levels in ob/ob mice, but only slightly improved wound healing in this strain. Moreover, in 17-week old db/db mice (i.e. severely insulin resistant) and in streptozotocin-induced diabetic mice, SR58611A slightly decreased hyperglycaemia and did not affect wound healing. In conclusion, SR58611A improves wound healing in animal models of non-insulin-dependent diabetes. This effect is not related to its effect on glucose levels, but probably implicates systemic effects of the compound.
Angiotensin converting enzyme (ACE) inhibitors are known to increase the level of bradykinin by preventing its breakdown and also promote prostaglandin synthesis by direct and indirect methods which in turn may promote wound healing. However there is paucity of scientific information in this regard. Therefore in the present study we have investigated the effect of ACE inhibitors like Captopril and Enalapril on different wound models in Wistar rats. Excision, resutured incision and dead space wounds were inflicted in male Wistar rats under light ether anaesthesia, taking aseptic precautions. Control animals received vehicle and other groups received Captopril (10mg/kg) and Enalapril (10mg/kg) orally for a period of 10 days in incision and dead space wound models, whereas similar treatments were continued in excision wound models till complete closure of wounds. On the 11th day, after estimating breaking strength of resutured incision wounds (under anaesthesia), granulation tissue was...
Accelerated healing of diabetic wounds by NorLeu3-angiotensin (1-7)
Expert Opinion on Investigational Drugs, 2011
Introduction-Diabetes is a disorder that is well known to delay wound repair resulting in the formation of colonized, chronic wounds. The resultant ulcers contribute to increased risk of morbidity, including osteomyelitis and amputations, and increased burden to the health care system. Area Covered-The only active product approved for the treatment of diabetic ulcers, Regranex, has been shown to reduce amputation risk, but is not widely used due to minimal proven efficacy and recent warnings added to the Instructions for Use. Here, we overview the development of NorLeu 3-angiotensin (1-7) (NorLeu 3-A(1-7)) as an active agent for the treatment of diabetic wounds. NorLeu 3-A(1-7) is an analogue of the naturally occurring peptide, angiotensin 1-7. The mechanisms of action include induction of progenitor proliferation and accelerated vascularization, collagen deposition and re-epithelialization. Expert Opinion-Research to date has shown that NorLeu 3-A(1-7) is highly effective in the closure of diabetic wounds and is superior to Regranex in animal studies. Further clinical development of this product as a topical agent for the healing of chronic wounds and investigation into the mechanisms by which this product accelerates healing are warranted.
Histological evaluation of the effects of angiotensin peptides on wound repair in diabetic mice
Experimental Dermatology, 2003
Recent studies have shown that angiotensin peptides accelerate dermal repair. Histological observation of samples taken at the termination of studies showed that the wounds treated with peptides were more mature and organized by day 25 after full thickness excision in diabetic mice. However, the mechanism by which this acceleration occurs has not been determined. In the experiments described here, the effect of angiotensin peptides [AII, A(1-7) and NorLeu 3-A(1-7)] on the quality of the healing wound was evaluated histologically. Administration of the peptides accelerated collagen deposition, re-epithelialization and new blood vessel formation. By day 4, the percentage of the wound with collagen increased two-to six-fold depending upon the peptide. The increase by angiotensin peptides continued throughout the experimental period. On days 4 and 7 (only) after injury, exposure to angiotensin peptides increased the number of blood vessels at the wound site two-to threefold. Finally, the percentage of the wound site covered with new epithelium increased after administration of angiotensin peptides. Re-epithelialization was observed as early as day 4 in wounds treated with angiotensin peptides. The increase was greater at later time points [up to 8-fold at day 14 with NorLeu 3-A(1-7)]. Fibroblast infiltration and proliferation occurred earlier in wounds treated with angiotensin peptides. Wounds treated with A(1-7) and NorLeu 3-A(1-7) had an increase in neutrophils and macrophages on day 4 after wounding. Overall, administration of these peptides resulted in a healing site that was more mature, including reorganization of the collagen into a basket-weave appearance. Further, these studies confirm the superiority of NorLeu 3-A(1-7) to AII and A(1-7) in wound healing evaluated at a microscopic level.
Development of angiotensin (1-7) as an agent to accelerate dermal repair
Wound Repair and Regeneration, 2001
Angiotensin II has been shown to be a potent agent in the acceleration of wound repair. Angiotensin (1-7), a fragment of angiotensin II that is not hypertensive, was found to be comparable to angiotensin II in accelerating dermal healing. This activity was evaluated in four models: rat and diabetic mouse full-thickness excisional wounds; rat random flap; and guinea pig partial thickness thermal injury. In all models, angiotensin (1-7) was comparable to angiotensin II. Angiotensin (1-7) accelerated the closure of wounds in diabetic mice and rats. In diabetic mice the resultant tissue at day 25 after injury was more comparable to normal tissue than the fibrotic scar observed in placebo-treated wounds. In the random flap model, angiotensin (1-7) was comparable to angiotensin II in maintaining flap viability (approximately 82%) and flap survival (40%). Finally, angiotensin (1-7) increased proliferation in the hair follicles at the edge of the wound and site of thermal injury, and the number of patent blood vessels on day 7 after partial thickness thermal injury. These data may be partially explained by the effect of angiotensin II and angiotensin (1-7) on keratinocyte proliferation. While platelet-derived growth factor had no effect on keratinocyte proliferation, angiotensin II and angiotensin (1-7) significantly increased keratinocyte proliferation. These data show that angiotensin(1-7) is comparable to angiotensin II in accelerating skin repair. Furthermore, the hypertensive and wound healing effects can be separated within the family of angiotensin peptides. (WOUND REP REG 2001;9:238-247) Recent studies have shown that the vasoactive product AII Angiotensin II of the renin-angiotensin system, angiotensin II (AII), ac-CMC Carboxymethyl collulose celerates the closure of thermal injuries and full-thick-ECM Extracellular matrix EGF Epidermal growth factor ness dermal lesions as well as increases the survival of KBM Keratinocyte basal medium From the University of Southern California, Keck School of indicated that some of the effects of AII on cell function Medicine,
NorLeu 3 -Angiotensin (1-7) [DSC127] as a Therapy for the Healing of Diabetic Foot Ulcers
Advances in Wound Care, 2015
Significance: Diabetes is a disorder that is well known to delay wound repair resulting in the formation of colonized chronic wounds. Over their lifetime, diabetic patients have a 25% incidence of foot ulcers (DFUs), which contribute to increased risk of morbidity, including osteomyelitis and amputations, and increased burden to the healthcare system. Recent Advances: The only active product approved for the treatment of diabetic ulcers, Regranex Ò , is not widely used due to minimal proven efficacy and recent warnings added to the Instructions for Use. A novel topical agent that accelerates healing and increases the proportion of fully healed DFUs, DSC127 [aclerastide; active ingredient, NorLeu 3-angiotensin (1-7) (NorLeu 3-A(1-7))], is recruiting patients in Phase III clinical trials (NCT01830348 and NCT01849965). NorLeu 3-A(1-7) is an analog of the naturally occurring peptide, angiotensin 1-7. The mechanisms of action include induction of progenitor proliferation, accelerated vascularization, collagen deposition, and re-epithelialization. Critical Issues: Current modalities for the treatment of DFUs include strict offloading, bandaging, debridement and, on a limited basis, application of Regranex. Novel potent therapies are needed to combat this significant burden to the diabetic patient and the healthcare system. Future Direction: Preclinical and clinical research shows that DSC127 is highly effective in the closure of diabetic wounds and is superior to Regranex in animal studies. Clinical development of DSC127 as a topical agent for the healing of DFU is underway. Further investigation into the mechanisms by which this product accelerates healing is warranted.
Annals of Plastic Surgery, 2004
Advanced glycation end products (AGEs) accumulate in diabetic wounds as a result of the glycosylation of various proteins. Interaction of AGEs with the receptor for AGEs (RAGE) results in an exaggerated inflammatory response and compromised collagen production. These changes lead to impaired wound healing. A soluble form of RAGE (sRAGE) has been shown to bind AGEs and thereby blunt their pathogenetic effects. Using genetically diabetic C57BLks-db/db mice, the authors applied sRAGE topically to standardized full-thickness wounds to improve diabetic wound healing. They measured various parameters of wound healing such as neovascularization, reepithelialization, collagen formation, and granulation tissue area. Their results showed a statistically significant increase in granulation tissue area and microvascular density in the sRAGE group compared with untreated wounds. There was a trend toward a smaller epithelial gap in the sRAGE-treated group that did not reach statistical significance. The authors conclude that sRAGE may be a powerful treatment of accelerating diabetic wound healing.
Topical prolyl hydroxylase domain-2 silencing improves diabetic murine wound closure
Wound Repair and Regeneration, 2011
Background-Prolyl hydroxylase domain 2 (PHD2) has been implicated in several pathways of cell signaling, most notably in its regulation of hypoxia inducible factor (HIF)-1α stability. In normoxia, PHD2 hydroxylates proline residues on HIF-1α, rendering it inactive. However in hypoxia, PHD2 is inactive, HIF-1α is stabilized and downstream effectors such as VEGF and FGF-2 are produced to promote angiogenesis. In the present study we utilize RNAi to PHD2 to promote therapeutic angiogenesis in a diabetic wound model, presumably by the stabilization of HIF-1α.
Differential expression of angiotensin receptors in human cutaneous wound healing
British Journal of Dermatology, 2005
Background Angiotensin AT1 and AT2 receptors are expressed in human skin. Furthermore, AT2 receptors have been reported to be upregulated during tissue repair and remodelling in various noncutaneous human tissues. Objectives Detection of alterations in angiotensin II receptor expression during wound healing in human skin. Methods Three models were employed. (i) Primary human keratinocytes were razor scraped in culture flasks and alterations in the expression of angiotensin receptor mRNA determined by semiquantitative reverse transcription-polymerase chain reaction for 1-12 h thereafter. (ii) Early wound healing (48 h after cutting) was studied in punch biopsies from human skin ex vivo by means of immunohistochemical staining using polyclonal antibodies against the AT1 or AT2 receptor. (iii) In vivo wound healing was studied in sections of human cutaneous scars by immunohistochemistry to determine receptor expression early (2 days) and late (2 weeks)3 months) after surgery. Results In all experimental settings, an upregulation of both receptor subtypes was noticed after wounding. Immunohistochemically stained skin sections showed a stronger expression of AT2 than of AT1 receptors within the area of scarring. Enhanced receptor expression was detectable as early as 24 h after injury and lasted for up to 3 months. Conclusions From these data, we conclude that angiotensin AT1 and AT2 receptors are upregulated in human cutaneous wounds, giving further support to the concept that angiotensin II plays a role even at an early stage during cutaneous wound healing.
Effect of Pravastatin on Experimental Diabetic Wound Healing
Journal of Surgical Research, 2010
Background. Impaired wound healing in diabetes has been associated with abnormalities in wound nitric oxide (NO) and nitric oxide synthase (NOS) availability. Efforts to alter the profile of NO expression in the wound microenvironment have proven to be successful in partially restoring wound healing deficits. We investigated the effects of pravastatin, a HMG Co A reductase inhibitor on endothelial nitric oxide synthase (eNOS) expression, NO production, and wound healing in a diabetic acute wound healing model.