Trial of nitric oxide patch in diabetic foot ulcers

NewsBot · Sep 28, 2007

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Double blind, randomized, placebo controlled clinical trial for the treatment of diabetic foot ulcers, using a nitric oxide releasing patch: PATHON.
Silva SY, Rueda LC, Marquez G, Lopez M, Smith D, Calderon CA, Castillo JC, Matute J, Rueda-Clausen CF, Orduz A, Silva FA, Kampeerapappun P, Bhide M, Lopez-Jaramillo P.
Trials. 2007 Sep 26;8(1):26 [Epub ahead of print]

BACKGROUND: Diabetes Mellitus constitutes one of the most important public health problems due to its high prevalence and enormous social and economic consequences. Diabetic foot ulcers are one of the chronic complications of diabetes mellitus and constitute the most important cause of non-traumatic amputation of inferior limbs. It is estimated that 15% of diabetic population will develop an ulcer sometime in their life. Although novel therapies have been proposed, there is no effective treatment for this pathology. Naturally produced nitric oxide participates in the wound healing process by stimulating the synthesis of collagen, triggering the release of chemotactic cytokines, increasing blood vessels permeability, promoting angiogenic activity, stimulating the release of epidermical growth factors, and by interfering with the bacterial mitochondrial respiratory chain. Topically administered nitric oxide has demonstrated to be effective and safe for the treatment of chronic ulcers secondary to cutaneous leishmaniasis. However, due to their unstable nitric oxide release, the topical donors needed to be applied frequently, diminishing the adherence to the treatment. This difficulty has led to the development of a multilayer polymeric transdermal patch produced by electrospinning technique that guarantees a constant nitric oxide release. The main objective of this study is to evaluate the effectiveness and safety of this novel nitric oxide releasing wound dressing for the treatment of diabetic foot ulcers.

Methods and Design. A double-blind, placebo-controlled clinical trial, including 100 diabetic patients was designed. At the time of enrollment, a complete medical evaluation and laboratory tests will be performed, and those patients who meet the inclusion criteria randomly assigned to one of two groups. During 90 days group 1 will receive active patches and group 2 placebo patches. The patients will be seen by the research group at least every two weeks until the healing of the ulcer or the end of the treatment. During each visit the healing process of the ulcer, the patient's health status and the presence of adverse events will be assessed. Should the effectiveness of the patches be demonstrated an alternative treatment would then be available to patients. Trial registration: NCT00428727
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Admin2 · Sep 28, 2007

Full details of trial from CinicalTrials.gov

NewsBot · Feb 1, 2008

Here is more on the role of nitric acid:

ScienceDaily are reporting:
Diabetes Makes It Hard For Blood Vessels To Relax

ScienceDaily (Jan. 31, 2008) — One way diabetes is bad for your blood vessels is by creating too much competition for an amino acid that helps blood vessels relax, researchers say.

That amino acid, L-arginine, is broken down by the enzyme arginase to urea, which helps the body eliminate toxins resulting from the proteins we eat. Diabetics have a lot of arginase activity, which means they use a lot more L-arginine, says Dr. Maritza Romero, postdoctoral fellow at the Medical College of Georgia and lead author of the paper published in the current issue of Circulation Research.

It also means too little L-arginine is available to help nitric oxide synthase make nitric oxide, the powerful vasodilator that helps blood vessels relax, says Dr. Romero, who works in the lab of Dr. R. William Caldwell, chair of the MCG Department of Pharmacology and Toxicology and the study's corresponding author.

Researchers also found the amino acid, L-citrulline, as well as statins, compounds known to lower cholesterol, prevent elevation of arginase activity, restoring normal dilation abilities in animal models of type 1 diabetes. In fact, L-citrulline can be recycled into L-arginine.

Now they want to know specific factors and pathways involved in arginase activation and develop pharmaceutical agents to combat excessive arginase activity in diabetes. They also suggest clinical trials of L-citrulline ...
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Full story

NewsBot · Jan 16, 2010

Wound nitric oxide bioactivity: a promising diagnostic indicator for diabetic foot ulcer management.
Boykin JV Jr.
J Wound Ostomy Continence Nurs. 2010 Jan-Feb;37(1):25-32;

Nitric oxide (NO) is a critical molecular signal and mediator for normal wound healing. Nitric oxide deficiency has been established as an important mechanism responsible for poor healing in diabetic foot ulcer (DFU) patients. Preliminary clinical wound healing studies using wound fluid nitrate determinations, as measures of wound NO bioactivity, suggest that threshold wound fluid nitrate values may function as an effective diagnostic indicator of successful wound healing for the DFU patient. In this case, wound fluid nitrate measurements could predict the suitability of a wound for specialized wound therapies such as topical growth factors or bioengineered skin substitutes. Wound fluid nitrate determination would also identify DFU patients with wound NO deficiency-related impaired healing that may promote wound complications possibly leading to lower-extremity amputation. With clinical validation, wound fluid nitrate may qualify as a wound healing biomarker and surrogate endpoint for DFU treatment. Additionally, combined diagnostic determinations of wound NO bioactivity, bacterial load, and matrix metalloproteinase production will enhance DFU management by providing quantitative parameters for clinical wound treatment. The impact of wound fluid nitrate determination and the combined platform of wound diagnostic indicators for wound healing prediction and clinical treatment, respectively, is anticipated to provide substantial costs savings and improved outcomes for the DFU patient.
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NewsBot · Jul 21, 2010

Association of the G894T Polymorphism of the Endothelial Nitric Oxide Synthase Gene with Diabetic Foot Syndrome Foot Ulcer, Diabetic Complications, and Comorbid Vascular Diseases: A Turkish Case-Control Study.
Corapcioglu D, Sahin M, Emral R, Celebi ZK, Sener O, Gedik VT.
Genet Test Mol Biomarkers. 2010 Jul 19. [Epub ahead of print]

Context: There are controversial results and insufficient knowledge in the literature about the genetics of diabetes mellitus complications in the Turkish population and endothelial nitric oxide synthase (eNOS) gene polymorphisms may act as a potential modifier of diabetic vascular complications.

Objective: The objective of this study was to determine the association between eNOS G894T polymorphisms and diabetes-related diseases.

Design: A Turkish case-control study was designed. Setting: The study was carried out in the Ankara University Hospital.

Patients or Other Participants: Totally, 97 Turkish patients with diabetic foot ulcers and 102 controls were enrolled. Patients who had not received antimicrobial treatment in the preceding 6 months were included. Diabetic patients with hand and/or foot ulcers resulting from major trauma, such as road traffic accidents, were excluded.

Main Outcome Measure: The effect of eNOS gene polymorphisms on diabetic complications and comorbid diseases was measured. Results: Regarding eNOS G894T gene polymorphisms, 47.4% of the patients had GG (n = 46), 47.4% (n = 46) had GT, and 5.2% (n = 5) had TT alleles in the diabetes mellitus group, and 47.0% (n = 48), 41.2% (n = 42), and 11.8% (n = 12) had GG, GT, and TT alleles in the control group, respectively. There was no significant difference between the groups regarding the eNOS G894T gene allele ratios. Between groups with and without diabetic complications, a significant difference has only been found in the distribution of alleles in patients with comorbid atherosclerotic heart disease, whose GT-TT alleles were significantly higher than the GG alleles (p = 0.004).

Conclusion: G894T polymorphism of eNOS gene was not associated with foot ulcer and diabetic complications, except in the presence of atherosclerotic heart disease
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NewsBot · Jun 6, 2013

Preliminary investigation of topical nitroglycerin formulations containing natural wound healing agent in diabetes-induced foot ulcer.
Hotkar MS, Avachat AM, Bhosale SS, Oswal YM.
Int Wound J. 2013 Jun 3.

Nitroglycerin (NTG) is an organic nitrate rapidly denitrated by enzymes to release free radical nitric oxide and shows improved wound healing and tissue protection from oxidative damage. The purpose of this study was to evaluate whether topical application of NTG in the form of gel/ointment along with a natural wound healing agent, aloe vera, would bring about wound healing by using diabetes-induced foot ulcer model and rat excision wound model. All these formulations were evaluated for pH, viscosity, drug content and ex vivo diffusion studies using rat skin. Based on ex vivo permeation studies, the formulation consisting of carbopol 974p as a gelling agent and aloe vera was found to be suitable. The in vivo study used streptozotocin-induced diabetic foot ulcer and rat excision wound models to analyse wound healing activity. The wound size in animals of all treated groups was significantly reduced compared with that of the diabetic control and marketed treated animals. This study showed that the gel formed with carbopol 974p (1%) and aloe vera promotes significant wound healing and closure in diabetic rats compared with the commercial product and provides a promising product to be used in diabetes-induced foot ulcer.
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NewsBot · Jan 18, 2014

Involvement of nitric oxide production in the impairment of skin blood flow response to local cooling in diabetic db/db mice.
Sahara Y, Saito SY, Ishikawa T.
Eur J Pharmacol. 2013 Nov 15;720(1-3):174-9.

An enhanced vasocontrictor activity of cutaneous vessels participates in the reduction of skin blood flow induced by cooling. The present study investigated changes in the local response to cooling in hyperglycemic conditions. Male diabetic db/db and control C57BL/6J mice, anaesthetized with pentobarbitone, were treated with tetrodotoxin for eliminating the sympathetic nerve tone and artificially ventilated. The plantar skin blood flow (PSBF) was measured by laser Doppler flowmetry. Cooling the air temperature around the foot reduced PSBF in a temperature-dependent manner in control and db/db mice. The PSBF reduction was significantly smaller in db/db mice than in control mice. Phentolamine, a non-selective α-antagonist, bunazosin, a selective α1-antagonist, MK-912, a selective α2C-antagonist, and Y-27632, a Rho-kinase inhibitor, significantly inhibited the PSBF reduction induced by cooling to 15 °C in both mice and the inhibitory effects were comparable between these mice. The cooling-induced PSBF reduction was also significantly inhibited by N(ω)-nitro-L-arginine, an inhibitor of nitric oxide synthase, in control mice; however, the inhibitory effect of N(ω)-nitro-L-arginine was not observed in db/db mice. The reduction of PSBF induced by the intraarterial administration of adrenaline was comparable between control and db/db mice both before and after the treatment with N(ω)-nitro-L-arginine. It is thus likely that the reduction of skin blood flow induced by local cooling might be partly mediated by a decrease in endothelium-derived nitric oxide production, and that an impairment of the nitric oxide production might be related to reduced vasocontrictor response to cooling in db/db mice.
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NewsBot · Feb 12, 2014

Involvement of nitric oxide production in the impairment of skin blood flow response to local cooling in diabetic db/db mice.
Sahara Y, Saito SY, Ishikawa T.
Eur J Pharmacol. 2013 Oct 24. pii: S0014-2999

An enhanced vasoconstrictor activity of cutaneous vessels participates in the reduction of skin blood flow induced by cooling. The present study investigated changes in the local response to cooling in hyperglycemic conditions. Male diabetic db/db and control C57BL/6J mice, anaesthetized with pentobarbitone, were treated with tetrodotoxin for eliminating the sympathetic nerve tone and artificially ventilated. The plantar skin blood flow (PSBF) was measured by laser Doppler flowmetry. Cooling the air temperature around the foot reduced PSBF in a temperature-dependent manner in control and db/db mice. The PSBF reduction was significantly smaller in db/db mice than in control mice. Phentolamine, a non-selective α-antagonist, bunazosin, a selective α1-antagonist, MK-912, a selective α2C-antagonist, and Y-27632, a Rho-kinase inhibitor, significantly inhibited the PSBF reduction induced by cooling to 15°C in both mice and the inhibitory effects were comparable between these mice. The cooling-induced PSBF reduction was also significantly inhibited by Nω-nitro-L-arginine, an inhibitor of nitric oxide synthase, in control mice; however, the inhibitory effect of Nω-nitro-L-arginine was not observed in db/db mice. The reduction of PSBF induced by the intraarterial administration of adrenaline was comparable between control and db/db mice both before and after the treatment with Nω-nitro-L-arginine. It is thus likely that the reduction of skin blood flow induced by local cooling might be partly mediated by a decrease in endothelium-derived nitric oxide production, and that an impairment of the nitric oxide production might be related to reduced vasoconstrictor response to cooling in db/db mice
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davidh · Feb 13, 2014

I know its been pointed out before, but how can any substance speed up the healing rate of a diabetic ulcer if the patient is overweight, and/or the circulation or lymphatics is compromised?

Or am I missing something?

NewsBot · Jun 2, 2014

Treatment with topical nitroglycerine may promote the healing process of diabetic foot ulcers.
Mikaili P, Moloudizargari M, Aghajanshakeri S.
Med Hypotheses. 2014 May 17

Diabetes mellitus is one of the main problems of the health care systems of all societies. A vast number of diabetic patients suffer from diabetic foot ulcers (DFUs) some of which may lead to the amputation of the organ(s). Nitric oxide (NO) is an indigenous gas that is produced at various sites in the body and has been shown to possess important roles in wound healing. Previous studies have shown that not only is the production of NO decreased in diabetic patients but also the sensitivity of the cells of such patients to NO is dramatically reduced. Nitroglycerine (isosorbide dinitrate) can be employed as an effective donor of NO to diabetic wounds. On such a basis, we suggest a novel hypothesis that delivery of compensatory amounts of NO to the ulcers by the administration of topical nitroglycerine enhances blood flow and biochemical activity of the ulcers and thus promotes wound healing
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NewsBot · Feb 6, 2015

This clinical trial was just registered:
APT001 Plasma/NO Generator to Treat Infected Diabetic Foot Ulcer in Adults (APT-14-002)

This is a 10-week, randomized, controlled study to evaluate the efficacy and safety of the APT001 plasma and nitric oxide treatment in subjects with a diabetic foot ulcer.
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The APT001 is a medical device that generates a plasma flow containing nitric oxide intended to be applied topically to wound sites. The nitric oxide / plasma flow will be directed at the wound site and surrounding skin at a distance of 11.5 to 15 centimeters from the skin surface. Dose will be 10 seconds / cm2 wound surface area. Administration of the therapy will include a 2 cm border around the defined edges of the wound site.
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NewsBot · Mar 14, 2017

This clincal trial was just registered:
A Feasibility Study of Advance Plasma Therapy001 Plasma/Nitric Oxide Therapy for the Treatment of Diabetic Foot Ulcers

The clinical trial will assess the delivery of Nitric Oxide topically to the diabetic foot ulcer wound and the surrounding wound area as it related to wound healing.

The objective of the study is to assess the Nitric Oxide Therapy treatment time (the number of minutes to deliver the treatment) and frequency (number of days per week to treat) to determine the most optimal treatment time and frequency to develop a rationale for safety and efficacy for the final APT001 clinical study.
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NewsBot · Jun 12, 2018

ISOSORBIDE DINITRATE SPRAY FOR THE TREATMENT OF DIABETIC FOOT ULCERS: A DOUBLE-BLIND, RANDOMIZED, CLINICAL TRIAL
L. Garcia Benavides; L. Garcia Valdes; S. Pascoe Gonzalez; M. Mendez del Villar; S. Totsuka Sutto; D. Hernandez Molina; J. Barajas Vega
Journal of Hypertension. 36():e280, JUN 2018

Objective:
to evaluate if Isosorbide Dinitrate spray topically applied for management of diabetic foot ulcers take advantage over conventional management using cleaning and metabolic control.

Design and method:
A randomized, placebo-controlled, double-blinded clinical trial was designed, 34 patients were divided into two groups: Group 1; treated with Isosorbide Dinitrate spray, Group 2; placebo. All them received conventional management with cleaning (microdacyn spray) and glycemic control.

Results:
Images showed a notable regeneration before and after treatment in all groups; (P < 0.001). The final assessment of the ulcer achieved 70 ± 27 of progress using Isosorbide Dinitrate spray and 50 ± 16 placebo. The number of patients that had achieved complete closure was 4 with Isosorbide Dinitrate spray and 1 with placebo. The progression in the healing process of the ulcer, produced marked inmunohistochemical differences of Von Willebrand Factor, desmin, vascular endothelial growth factor-A and alpha-smooth muscle actin in all groups (P < 0.001), but without notable changes between groups.

Conclusions:
The progress of the ulcerated area using ISDN was higher than placebo.
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NewsBot · Jul 22, 2018

The potential of transdermal nitric oxide treatment for diabetic peripheral neuropathy and diabetic foot ulcers
David M.Walton et al
Diabetes & Metabolic Syndrome: Clinical Research & Reviews; 17 July 2018

Highlights
•Currently available treatments can manage painful symptoms of Diabetic Peripheral Neuropathy (DPN) but do not address the underlying pathologies of DPN and diabetic wound ulcers.
•A deficiency of nitric oxide synthase in diabetic patients may lead to a lack of vascularization of the peripheral nerves, which causes DPN.
•A transdermal nitric oxide application is envisioned for the treatment of DPN and diabetic wound ulcers by increasing vasodilation.
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The Center for Disease Control (CDC) estimates that 29 million Americans have diabetes, and 70% of diabetic patients develop diabetic peripheral neuropathy [1,2]. Up to 27% of the direct medical cost of diabetes may be attributed to DPN [3]. A 2013 article from the American Diabetes Association reported a $176 billion direct medical cost of diabetes in 2012 [4]. DPN patients often suffer from shooting and burning pain in their distal limbs and a severe loss of sensation. Diabetic foot ulcers, infections, and amputations may follow. Currently available treatments: tricyclic antidepressants, anticonvulsants such as gabapentin and pregabalin, serotonin and norepinephrine reuptake inhibitor, duloxetine, topical 5% lidocaine (applied to the most painful area) can manage painful symptoms but do not address the underlying pathologies of DPN and diabetic wound ulcers. A combination of pain-reducing medications can provide relief when individual medications fail, and opioids such as tramadol and oxycodone may be administered with these medications to reduce pain [5]. Due to the prevalence of diabetes, DPN, and diabetic foot ulcers, and because of the lack of available effective treatments to directly address the pathology contributing to these conditions, novel treatments are being sought. Our hypothesis is that a deficiency of nitric oxide synthase in diabetic patients leads to a lack of vascularization of the peripheral nerves, which causes DPN; and this could be treated with vasodilators such as nitric oxide. In this paper, the mechanisms of DPN are reviewed and analyzed to elucidate the potential of a transdermal nitric oxide application for the treatment of DPN and diabetic wound ulcers by increasing vasodilation.
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NewsBot · Nov 6, 2018

Measurement of Real-Time Nitric Oxide (NO) Release from Macrophages, Fibroblasts and Keratinocytes to Direct the Development of Smart Dressings for Diabetic Foot Ulcers
Free Radical Biology and Medicine
Volume 128, Supplement 1, 20 November 2018, Page S19

Diabetic foot ulcers (DFUs) are the leading cause of lower extremity amputation in the United States, and the prognosis after an initial amputation is fairly grim. Many advanced wound healing therapies are currently available for the treatment of DFUs, including growth factor therapy, bioengineered skin substitutes, and autologous platelet solutions. Under current treatment guidelines, these advanced treatments can be used after 4 weeks of non-healing with standard wound care; however, studies have shown that DFU healing times averaged 128 days, even with the use of advanced therapies. A key player in the dysregulation of wound healing is the inappropriate production of nitric oxide (NO). This free radical gas is a potent signaling molecule in many cellular processes and has been reported to be both beneficial and pathological in the same cell populations when delivered at different doses and for different durations. We have developed a novel measurement system that allows the direct, real-time, continuous measurement of NO produced from cells under conventional culturing conditions. We are using this system to specifically elucidate the level of NO produced by macrophages, fibroblasts and keratinocytes and what quantify the temporal production of NO from these cells is under normal and high glucose conditions. Understanding how these cells interact with each other and respond to precisely delivered doses and durations of NO will allow the engineering of smart wound dressings which addresses a significant and growing global health problem. Quantitative data regarding the cellular production of NO under normal and high glucose conditions specifically elucidating real-time NO production, deposition of ECM, protein expression and migration behavior of cells involved in wound healing; will be presented. Our goal is to ultimately achieve wound closure of diabetic foot ulcers in 14-21 days.
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NewsBot · Jan 19, 2019

Nitric Oxide Therapy for Diabetic Wound Healing
Maggie J. Malone‐Povolny Sara E. Maloney Mark H. Schoenfisch
15 January 2019 https://doi.org/10.1002/adhm.201801210

Nitric oxide (NO) represents a potential wound therapeutic agent due to its ability to regulate inflammation and eradicate bacterial infections. Two broad strategies exist to utilize NO for wound healing; liberating NO from endogenous reservoirs, and supplementing NO from exogenous sources. This progress report examines the efficacy of a variety of NO‐based methods to improve wound outcomes, with particular attention given to diabetes‐associated chronic wounds.
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NewsBot · Aug 10, 2023

Two-Pronged Microbe Delivery of Nitric Oxide and Oxygen for Diabetic Wound Healing
Huan-Huan Chen et al
Nano Lett. 2023 Jun 28;23(12):5595-5602.

Chronic inflammation and hypoxia in the microenvironment of diabetic foot ulcers (DFUs) can result in sustained vascular impairment, hindering tissue regeneration. While both nitric oxide and oxygen have been shown to promote wound healing in DFUs through anti-inflammatory and neovascularization, there is currently no available therapy that delivers both. We present a novel hydrogel consisting of Weissella and Chlorella, which alternates between nitric oxide and oxygen production to reduce chronic inflammation and hypoxia. Further experiments indicate that the hydrogel accelerates wound closure, re-epithelialization, and angiogenesis in diabetic mice and improves the survival of skin grafts. This dual-gas therapy holds promise as a potential treatment option for the management of diabetic wounds.
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