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Sunday, October 12, 2014

Treatment Of Chronic Ulcers In Diabetic Patients Topical Metalloproteinase Inhibitor, Doxycycline

The 5th Estate testing now on the editor (tropical leg ulcer), will report results  

MEDSCAPE
By Gloria A. Chin, MD, MS; Tera G. Thigpin, Karen J. Perrin, BSN, ARNP; Lyle L. Moldawer, PhD; Gregory S. Schultz, PhD
10/12/2014

Chronic diabetic ulcers are characterised by elevated levels of pro-inflammatory cytokines and proteases, which are thought to impair wound healing by degrading essential molecules. There is a need for an inexpensive, safe, and simple-to-use agent that promotes healing by selectively reducing levels of pro-inflammatory cytokines and proteases. Doxycycline, a member of the tetracycline family of antibiotics that inhibits metalloproteinases, was evaluated in vitro for inhibition of tumor necrosis factor-alpha (TNF) converting enzyme (TACE) and for inhibition of protease activities in human chronic wound fluid. In addition, topical doxycycline treatment was evaluated in a pilot, randomized, controlled trial of chronic, diabetic, lower-extremity foot ulcers. Incubation of lipopolysaccharide (LPS)-stimulated murine macrophages with doxycycline at 200mg/mL totally prevented the release of TNF. Doxycycline also reduced proteolytic degradation of azocoll, a substrate for matrix metalloproteinases (MMPs), by a chronic wound fluid in a dose-dependent manner, achieving 89-percent reduction at 2.3mg/mL. All four chronic ulcers of diabetic patients treated daily with topical one-percent doxycycline healed in the 20-week treatment period, whereas only one of three patients treated with vehicle healed (p=0.05). No adverse events were attributed to doxycycline treatment. These results demonstrate that doxycycline effectively inhibits TACE and MMPs and suggest that topical one-percent doxycycline treatment improves healing of chronic, diabetic, foot ulcers, presumably by reducing levels of TNF and MMPs.


Doxycycline
It was estimated in 1998 that there were over two million, and perhaps up to five million, chronic wounds annually in the US alone.[1] Diabetic foot ulcers account for five percent of these ulcers and 50 to 80 percent of all lower-extremity amputations. Optimal conventional treatments for chronic wounds are based on the concepts of wound bed preparation, which include eliminating necrotic tissue and fibrinous exudate, controlling infection, establishing moisture balance, and optimizing the epidermal margin.[2] However, despite applying the principles of wound bed preparation, some chronic wounds fail to heal in a timely fashion and are candidates for advanced interventions, including topical growth factors,[3,4] bioengineered skin substitutes,[5] or surgical intervention for closure. Although advanced technologies have been proven to be effective in controlled clinical studies, they are expensive and are not universally available to all patients. Thus, there is a need for an inexpensive, readily available, simple therapy that can be added to the concept of wound bed preparation.

Multiple studies have established that the molecular and cellular environments of chronic skin wounds differ dramatically from the acute wound environment. In general, chronic wounds typically contain increased levels of pro-inflammatory cytokines and increased levels of proteases that are able to degrade essential mitogenic factors.[6-9] These observations led to the hypothesis that correcting these molecular abnormalities would promote healing of chronic wounds.[10] Studies from Trengove and colleagues[6] support this hypothesis by demonstrating that elevated levels of pro-inflammatory cytokines and proteases decreased in chronic venous stasis ulcers as healing progressed. These results suggest that an inexpensive, simple-to-administer, topical agent that reduced inflammation and protease activities might be an effective adjunctive therapy for wound bed preparation. Doxycycline, an antibiotic of the tetracycline family of drugs, is an inhibitor of matrix metalloproteinases (MMPs),[11] and several animal studies reported that treatment with doxycycline or other tetracycline analogues improved healing parameters. For example, systemic treatment of rats with doxycycline increased tensile strength of rat intestinal anastomoses on Day 3 after surgery,[12] and systemic tetracycline reduced the incidence of ulceration in alkali-injured rabbit eyes.[13] Topical application of a chemically modified tetracycline, which lacks antibiotic activity but retains MMP inhibitor activity, increased hydroxyproline levels and decreased collagenase levels in skin wounds of streptozotocin-induced diabetic rats.[14] Thus, members of the tetracycline family of molecules, such as doxycycline, appear to reduce MMP activities in various animal wound models and improve parameters of healing.




Another major difference in the molecular environments between acute, healing wounds and chronic wounds is elevated levels of pro-inflammatory TH1 cytokines, including TNF, and interleukin-1 (IL-1). There are several important relationships between proteases and pro-inflammatory cytokines that appear to influence wound healing. For example, TNF induced synthesis of IL-1 in human dermal fibroblasts,[15] and both TNF and IL-1 stimulated synthesis of collagenase (MMP-1) by dermal fibroblasts.[16] Furthermore, TNF inhibited synthesis of collagen mRNA and protein in cultured human fibroblasts.[17] Thus, chronically elevated levels of TNF in wounds would be expected to impair healing by reducing synthesis of collagen and increasing synthesis of MMPs.

Previous experiments showed that TNF is synthesized as a 26kDa transmembrane precursor protein that is processed to a 17kDa soluble protein and secreted from cells after proteolytic cleavage by a metalloproteinase enzyme, named TNF converting enzyme (TACE).[18-20] The proteolytic activity of TACE was inhibited in vitro by various synthetic MMP inhibitors.[18,21-23] In addition, systemic treatment of mice with these inhibitors, including doxycycline, prevented endotoxin-induced lethality by preventing secretion of TNF into serum.[18,21-24]

To better understand the possible effects of doxycycline on the environment of chronic wounds, we investigated the in-vitro effects of doxycycline on inhibiting the release of TNF from cultured macrophages and on inhibiting protease activities in a sample of human chronic wound fluid. In addition, we performed a pilot, randomized, controlled trial to evaluate the safety and efficacy of topical one-percent doxycycline treatment on healing of chronic ulcers in diabetic patients.



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ANDREW KREIG: EXPERTS REJECT FIRE AS CAUSE FOR 9/11 WTC COLLAPSES

The real truth on 9/11 slowly continues to bleed out

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Technical experts are mounting major challenges to official U.S. government accounts of how three World Trade Center skyscrapers collapsed in near-freefall after the 9/11 attacks 15 years ago.

Many researchers are focusing especially on the little-known collapse of

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The Geopolitics Of The United States, Part 1: The Inevitable Empire

The Empire and the inevitable fall of the Obama criminal regime

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STRATFOR Editor’s Note: This installment on the United States, presented in two parts, is the 16th in a series of STRATFOR monographs on the geopolitics of countries influential in world affairs.

Like nearly all of the peoples of North and South America, most Americans are not originally from the territory that became the United States.

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Geopolitics Of The United States Part 2: American Identity And The Threats of Tomorrow

A look back at 2011 predictions for the future in order to put events of today into perspective

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We have already discussed in the first part of this analysis how the American geography dooms whoever controls the territory to being a global power, but there are a number of other outcomes that shape what that power will be like. The first and most critical is the impact of that geography on the American mindset.

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By Robert S. Finnegan

This e-mail outlines and confirms the acts of espionage against Indonesia and Indonesians by Akiko Makino and the others involved both in Kobe University and in AI Lab at University of Airlangga, Surabaya; Bahasa Indonesia original follows English translation...

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UPDATED 01/07/2015 : New Analysis Challenges Tamiflu Efficacy; Hong Kong Corona Virus Outbreak

UPDATED 01/07/2015 : FOX NEWS CORPORATE PHARMA SHILL MEGAN KELLY AND FOX NEWS QUACK DOCTOR NOW PUSHING TAMIFLU FOR PREGNANT WOMEN AND CHILDREN;

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THE 5TH ESTATE UNEQUIVOCALLY WARNS THE PUBLIC NOT TO TAKE OR GIVE THIS PROVEN DANGEROUS, INEFFECTIVE DRUG TO ANYONE

Obama criminals now resulting to biowarfare in quest to destroy Chinese and ASEAN economy; "novel virus substrain" points directly to a Kawaoka / Fouchier / Ernala-Ginting Kobe lab virus weaponized and genetically altered to specifically target and infect the Asian population: Ribavirin...

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The 5th Estate has just purchased a library on H5N1 "Novel" virus pandemics, there are dozens of PDF and Exel documents we feel will assist you in saving lives following intentional releases of the H5N1 and now MERS viruses; we will begin by printing those that appear to be extremely relevant here: H5N1 Kobe-Kawaoka-Ernala series continues soon with more "Smoking Gun" e-mails from Teridah Ernala to The 5th Estate . . .

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By Robert S. Finnegan

On October 12, 2002 the Indonesian island of Bali experienced a terrorist attack that rocked the world. It was unquestionably well-coordinated and executed, the largest in the country's history.

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