ISRN Endocrinology, Volume 2014, Article ID 816307, http://dx.doi.org/10.1155/2014/816307

RESVERATROL PROMOTES FOOT ULCER SIZE REDUCTION IN TYPE 2 DIABETES PATIENTS.

Bashmakov YK, Assaad-Khalil SH, Abou Seif M, Udumyan R, Megallaa M, Rohoma KH, Zeitoun M, Petyaev IM.

Lycotec Ltd,  Granta Park Campus, Cambridge, United Kingdom.

Department of Internal Medicine & Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.

Clinical Epidemiology and Biostatistics Unit, Örebro University Hospital, Örebro, Sweden.

 

ABSTRACT

Objective: The effect of a proprietary formulation of trans-resveratrol (t-RSV) on manifestations of diabetic foot syndrome (DFS) was studied in type 2 diabetic patients with newly diagnosed diabetic foot ulcers. Methods: Placebo-controlled, examiner-blinded, parallel-group randomized controlled pilot clinical trial (ACTRN Clinical Trial Registry number 12610000629033) involving 24 patients with DFS (15 males and 9 females, average age of 56.4 ± 9.1 years) divided into the placebo and RSV-treatment groups was performed. 50 mg of t-RSV or placebo capsules was given to each patient twice a day over a 60-day time period. Results: Reduction in the parameters reflecting diabetic ulcer size was more profound in the RSV group as compared to placebo. RSV-treated patients also had a marginally improved performance in the foot pressure test. A statistically significant decline in the plasma fibrinogen level, but not CRP, was also found in the RSV-treated patients. Some improvement in the plasma lipid profile and fasting glucose levels were not related to RSV-treatment, since they have been seen on both the RSV and placebo groups, revealing the effectiveness of medical supervision and education in the newly diagnosed patients with DFS. Conclusion: t-RSV supplementation promotes reduction of the foot ulcer size and reduces plasma fibrinogen level in type 2 diabetic patients.

PMID: 24701359  [PubMed] PMCID: PMC3950537

 

Supplement:

Lower limb amputation in patients with type 2 diabetes takes place every 30 seconds worldwide whereas five-year mortality in newly diagnosed patients with diabetic foot syndrome (DFS) exceeds known mortality rates for breast, colon and prostate cancers (1). Strikingly, pharmacological interventions in DFS treatment are nonexistent. Wound debridement, pressure relief and infection control remain the sole option in treatment of DFS for decades.

Resveratrol is a dietary polyphenol naturally present in wine, grapes, peanuts and mulberry.  Its trans-isoform (t-RSV, 3,5,4′-trihydroxy-trans-stilbene), is known to have impact  on many biological functions including glucose homeostasis  and  manifestations of type 2 diabetes.  Multiple in vitro and in vivo studies suggest that t-RSV improves glucose uptake, insulin sensitivity and hyperglycemia. However, the anti-diabetic effects of t-RSV have a low reproducibility in clinical settings due to susceptibility of t-RSV to oxidation, intestinal enzymes and its limited absorption rate resulting altogether in extremely low bioavailability.  From this standpoint we have hypothesized previously (2), that nutraceutical formulation of t-RSV with an enhanced bioavailability may be useful in treatment of type 2 diabetes and its complications including DFS.

Lycosome microemulsifying technology based on spray drying, ultrasound, supercritical CO2 application (3, 4) was employed to develop a highly bioavailable t-RSV.  This novel lycosome formulation designated as t-RSV-L contains lycopene, a hydrophobic compound used not only as a core-forming agent, but also as a vector for hepatocyte delivery, which are known to express abundantly a carotenoid receptor. In addition it contains amphiphilic phosphatydilcholine as a chaperone for lycopene, which also has hydrophilyzing as well as emulsifying properties and increases thereby intestinal absorption. In a water-free environment t-RSV-L is represented by a composition of nano-sized particles with the schematic structure shown in the Figure 1.

          fig1

Figure 1. STRUCTURAL ORGANIZATION OF t-RSV LYCOSOME

 

In clinical settings, t-RSV-L shows an improved pharmacokinetic profile when compared to crystalline unmodified t-RSV. First of all, there is a six-fold increment in plasma t-RSV concentration detected in one hour after ingestion of 500 mg t-RSV-L (Fig 2). This peak in plasma t-RSV level reflects a gastric phase of t-RSV absorption. However as can be seen from Figure 2, there is another ”delayed” peak in plasma t-RSV levels which takes place in nine hours following t-RSV-L ingestion. This increase did not take place when crystalline t-RSV was ingested and mirrors a “colonic “phase in the t-RSV intestinal absorption. It represents a novel and specific feature in gastrointestinal absorption pattern of t-RSV-L attributable to microencapsulation technology employed.  Such a biphasic pattern of plasma t-RSV changes may be formed due to a newly acquired resistance of the t-RSV-containing lycosome particles to the biochemical environment of duodenum and small intestine which is dreadful to pH- and enzyme-sensitive dietary polyphenols.  Overall plasma t-RSV values remained significantly higher in the volunteers ingested lycosome-formulated t-RSV throughout the follow-up period (Figure 2).

fig2

Figure 2. PLASMA t-RSV LEVELS AFTER  INGESTION OF LYCOSOME t-RSV (t-RSV-L) VERSUS CRYSTALLINE t-RSV (t-RSV-C)

 

The advantage of having t-RSV formulation with the enhanced bioavailability rate allowed us to initiate a pilot clinical trial in type 2 diabetes patients with newly diagnosed foot ulcers. Despite of relatively low number of individuals (10 patients – placebo group, 14 – treated with t-RSV-L) we found that addition of t-RSV-L to the traditional treatment algorithm applied to DFS patients (wound debridement, pressure relief, infection control) improves outcomes of 2 month observational period in statistically significant manner. There was a statistically significant reduction of ulcer size, reduction in plasma fibrinogen levels as well as an improvement in the patient’s foot pressure parameters attributable to supplementation of the patients with t-RSV-L. In contrast, patients treated with crystalline unmodified t-RSV did not show positive tendencies in DFS outcomes.

The significance of our study is at least two-fold. First of all, we showed that microencapsulated t-RSV may be used as an effective agent for treatment of complication of type 2 diabetes, in particular DFS. It may provide a long-awaited treatment option for DFS patients. Secondly, our results confirm that lycosome microencapsulation technology may be used as an effective tool to overcome bioavailability problem for nutraceutical and pharmacological agents with poor intestinal absorption and susceptibility for oxidation. These results are in a good agreement with our recent reports revealing that lycosome microencapsulation enhances therapeutic potential of statins (5) and boosts some biological effects of whey protein peptides (6).

 

References:

1.Robbins JM, Strauss G, Aron D, Long J, Kuba J, Kaplan Y. Mortality rates and diabetic foot ulcers:isit time to communicate mortality risk to patients with diabetic footulceration? J Am Podiatr Med Assoc. 2008 Nov-Dec;98(6):489-93.
2.Bashmakov YK, Assaad-Khalil S, Petyaev IM. Resveratrol may be beneficial in treatment of diabetic foot syndrome. Med Hypotheses. 2011 Sep;77(3):364-7.
3.CAROTENOID PARTICLES AND USES THEREOF. GB Patent Application No. 1101669.8, PCT/GB2012/000075, 25.01.2012.
4.Patel D, Sawant KK. Self micro-emulsifying drug delivery system: formulation development and biopharmaceutical evaluation of lipophilic drugs. Curr Drug Deliv. 2009 Aug;6(4):419-24.
5.Petyaev IM. Imrovement of hepatic bioavailability as a new step for statin future. Arch Med Sci. 2014 (accepted, in press).
6.Petyaev IM, Dovgalevsky PY, Klochkov VA, Chalyk NE, Kyle N. Whey protein lycosome formulation improves vascular functions and plasma lipids with reduction of markers of inflammation and oxidative stress in prehypertension. ScientificWorldJournal. 2012;2012:269476.

 

Contacts:   

fig3Yuriy Bashmakov MD. Principal Investigator. Senior Scientific Officer, Lycotec Ltd, Cambridge UK, yuriy.bashmakov@lycotec.com

fig4Samir Assaad-Khalil MD. Head of Diabetic Foot Center, Faculty of Medicine, Alexandria University, Egypt. assaadkhalils@gmail.com

fig5Ivan Petyaev MD.  CEO Lycotec Ltd, Cambridge, UK. petyaev@lycotec.com

 

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