Novel Combination Therapy Boosts the Host Immune System, Destroys Free Radicals and Targets the Critical Flaw in Chronic Pancreatic Disease

Abstract

Aim: To investigate the role of combination therapy using the cytokines antagonist, pentoxifylline in combination with a novel powerful antioxidant derived from grape product in the treatment of pancreatic disease. Methods and Research Plan: We want to acknowledge that much of the groundwork has already been done demonstrating the positive effect of antioxidant therapy in pancreatic diseases including pancreatitis, chronic pancreatic disorders, fibrosis and even pancreatic cancer. It is also well accepted that pentoxifylline, originally described as a drug to aid blood circulation via actions on adenosine triphosphate, is also an effective and efficient inhibitor of platelet derived growth factor and other cytokines essential to the inflammatory and fibrotic processes. We have understood for several years that this immunopharmacological drug inhibits other key signalling molecules in the immune system, ultimately preventing the collagen synthesis and deposition which is critical in pancreatic, hepatic and intestinal fibrosis. Our aim is to combine these two forms of therapy in patients with chronic pancreatic disease while simultaneously optimizing conditions using as our basis the dramatic results that have already been reported widely in literature, by world class investigators. Results and Conclusion: Results to date are promising. Our results presented here clearly indicate that pentoxifylline will block a process in a relatively rare form of intestinal fibrosis called collagenous colitis. This was our proof of concept. In this very selective disease the critical step is collagen deposition. Collagen synthesis resulting in deposition is the key factor involved and has a direct effect on the outcome in these patients with collagenous colitis. We were able to show that pentoxifylline would effectively reduce collagen deposition in the colons of a group of relatively heterogeneous patients with their one consistent variable being biopsy proven colonic collagen deposition and an elevated FSI or fibrogenic stimulation index. Our results also clearly indicate that the reduction in colonic collagen deposition occurring with pentoxifylline therapy is accompanied by a measurable DII or drug inhibition index and that the FSI was predictive of which cohort of patients would respond to this drug. Pentoxifylline was an effective anti-fibrotic agent while having little if any side effect and working in a very effective way to reduce the signs and symptoms of the disease. Long before we were able to see the histological proof in colonic biopsies, patients who prior to treatment showed a predictive DII were already reporting beneficial effects on their symptoms and clinicians were reporting improvement in clinical signs. At time points during the treatment period, biopsies revealed that the collagen was diminishing and results also indicate that the rate of reduction of collagen deposition related to the chronicity of the disease itself. The combination of a novel antioxidant derived from grapes together with the drug pentoxifylline has the potential to be effective in treating chronic pancreatic disease and may prevent and likely will slow the course of pancreatic fibrosis and the ensuing pancreatic cancer [1-10].