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.
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.
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