Reparagen: From Concept to Product

Introduction
Reparagen was not originally created to specifically meet the needs of the joint health sector, although the current treatment options possess significant limitations. Rather Reparagen was released to this market as a result of a decade of research & development that was focused on the mechanism of action of the constituents. This sustained devotion to understanding the science that supports medicinal plants allowed Rainforest Nutritionals (RNI) to create effective and novel approaches. The information generated by this research is essentially a portal to innovation and a unique selling position. Using this approach, where elements of traditional knowledge are combined with new scientific discoveries, novel ingredient combinations and applications can be created.

Reparagen combines two proprietary extracts of botanicals from South America, Lepidium meyenii (maca) and Uncaria guianensis (cat’s claw), from Andean and Amazonian cultures respectively. These components are not routinely mixed, in part because the cultures were distinct and also because the mechanism of action for Lepidium meyenii had remained elusive with applications linked to sexual health.

Rainforest Nutritionals, Inc. developed a concept that the health benefits of Lepium meyenii (maca) was linked to the generation of IGF-1. The preliminary data supporting this hypothesis enabled RNI to win a prestigious innovation award (SBIR) from the National Institute for Aging (NIA, NIH) for additional research and development. Subsequent research confirmed and extended the concept using human cartilage and demonstrated synergy when combined with an anti-inflammatory agent – in this case our patented cat’s claw extract (vincaria).

How Does Reparagen Work?
Reparagen operates at two opposing levels to restore balance to systems that control joint health. Importantly these actions culminate to not only limit the progress of joint destruction but to also activate a critical gene (IGF-1) responsible for cartilage repair and generation. This latter action is unique. To date activation of this repair gene (IGF-1) within cartilage, especially during inflammation when the gene is silenced, has been elusive. Reparagen has solved a major unmet therapeutic need. The approach of simultaneously blocking processes that destroy joint architecture and activating joint repair is both a conceptual as well as a therapeutic breakthrough.

Using bioassay guided fractionation various extracts were tested for the desired bioactivity. This approach commonly used for drug development, allowed RNI to generate an extract (RNI 249) that optimized the desired therapeutic activity (activation of the IGF-1 gene). Similarly, RNI had previously used bioassay guided fractionation to generate a patented extract of cat’s claw (vincariaâ) that was selected for optimal anti-inflammatory activity and limiting the content of oxindole alkaloids which are reported to be immuno-stimulatory and therefore counterproductive for this application.

Conceptualization: Vincaria (Uncaria guianensis extract)
In 1998 we reported that cat’s claw was a superior inhibitor of NF-kB [2], a critical and master transcription factor that regulates over 35 different genes in inflammation. This molecular switch activates genes that promote inflammation and cat’s claw was removed this protein switch from DNA, effectively rendering the genes dormant. Water based extracts were found to be remarkably potent inhibitors of TNFa formation, a cytokine that is a driving force behind several chronic inflammatory diseases including rheumatoid arthritis, psoriasis and colitis. Moving from cell culture studies, to animal models we were able to generate a wealth of knowledge that described cytoprotective, antioxidant and anti-inflammatory actions [3-5] and an extract that was potent and devoid of complicating alkaloids.

Appreciating the precise mechanism of action also allowed RNI to develop new applications beyond the traditional knowledge. One example is that vincaria is the only botanical that has been described to prevent the acute and chronic gastrointestinal toxicity of NSAIDs [2,4]. These complications kill 16,000 people annually and pose a great health risk for arthritis sufferers who routinely take NSAIDs. It was rewarding to demonstrate that a natural health product could limit the toxicity of commonly used pharmaceuticals.

With the appreciation that the traditional Amazonian applications included both gastrointestinal health and bone pain, we completed the circle of knowledge by performing a clinical trial in osteoarthritis [6]. In this study vincaria was effective in reducing pain and disease activity within a week of administration, despite being administered at the low dose of 100mg a day (slightly larger than a “baby aspirin”). Thus, vincaria was proven to an effective standalone product for arthritis.

Conceptualization: RNI 249 (Lepidium meyenii extract)
Most of the recent research on maca has focused on its fertility applications and especially for males. Research has failed to determine an action on various hormonal pathways (sex steroids, gonatadotrophins, prolactin or thyroid hormone) to explain these benefits. Thus the mechanism of action, the key to meaningful applications, remained elusive.

While it was evident that maca can enhance sperm counts, semen volume and libido this is an under-representation of the traditional knowledge and applications. We were aware of a number of studies performed within the Peruvian community that demonstrated that maca was able to prevent various pregnancy complications associated with high altitude – miscarriages, failure to conceive, fetal growth restriction and reduced litter size. Indeed, this knowledge were described by the conquistador Pisarro upon his conquest of the Inca Empire. These benefits reflected actions on the mother perhaps more so than males, but male orientated research continued to dominate.

In parallel studies we determined that fetal growth restriction (small birthweight) and miscarriages was dictated by an over-active immune response and the excessive production of oxidants. Maca was subsequently evaluated for its antioxidant potential and catechin content, and while demonstrable this bioactivity were not consistent with the unique benefits [7]. Clearly we needed to look elsewhere.

What RNI turned to next was rational but yet not routine. Maca and extracts were evaluated in farmed fish, specifically for actions on growth and mortality in very young rainbow trout. Growth of juvenile fish has a number of parallels with fetal growth. We noted that some extracts of maca were remarkable accelerants of growth, reduced mortality and were anabolic, converting more feed into fish. Given that the primary regulator of fish growth is IGF-1, with a comparable action in mammalian fetal growth, we postulated that maca extracts promote the production of IGF-1. In adult humans IGF-1 is a major determinant of reproductive health, with production peaking in young adults and declining with age.

As declining production of IGF-1 is associated with joint dysfunction, we linked these observations to a potential action of maca extracts on the expression of the IGF-1 gene in human cartilage. With collaborators at Case Western Reserve University School of Medicine, we confirmed that maca extracts activated the IGF-1 gene in human chondrocytes, and with bioassay guided refinement RNI 249 was developed.

Reparagen for Joint Health
It is appreciated with the inflammation literature that mediators or inflammation (TNFa, IL-1) can switch off the IGF-1 gene, thereby disabling repair and promoting joint damage. It was apparent to RNI that a combination of vincaria with RNI 249 would be more effective than the single agents. Indeed this was a goal of the SBIR award. The benefits of this combined approach was confirmed in the recently reported studies [1].

With this knowledge base RNI elected to commercialize Reparagen. It was also necessary to conduct a safety and toxicity analysis. Using our alliance partner, Santerra Pharmaceuticals, a full safety profile including Acute and Sub-Chronic studies were performed in accord to OECD guidelines. No toxicity was observed at the highest doses tested, which represented 700x and 300x the recommended daily dose. Santerra Pharmaceuticals is now performing a large clinical study in osteoarthritis, comparing reparagen to glucosamine. The results of this trial will be available in the later summer of 2006.

Market development for Reparagen is under the direction of Park Labs, LLC and it is currently available at www.reparagen.com. It is anticipated that a family of reparagen products will be released over the next year.

Mark JS Miller, PhD, MBA
Santerra Pharmaceuticals, LLC

Dr. Miller has had a distinguished career as an academic, pharmaceutical industry researcher, consultant and entrepreneur. His research has made major contributions to numerous fields of medical research including gastroenterology, perinatology, cancer, inflammation and therapeutics. His recent interests centre on the development of therapeutic agents from South American ethnomedicines. Dr. Miller reviews grants for numerous international agencies, reviews for 37 journals and consults with the World Bank on industry development. This links his academic, entrepreneurial and business interests with his managerial expertise in the transformation of start-up companies to emerging status.

Bibliography
1) Miller MJS, Ahmed S, Bobrowski PJ, Haqqi TM. The chondroprotective actions of a natural product are associated with the activation of IGF-1 production by human chondrocytes despite the presence of IL-1b BMC Complementary and Alternative Medicine 2006, 6:13

2) Sandoval-Chacon M, Thompson JH, Liu X, Mannick EE, Sadowska-Krowicka H, Charbonnet R, Clark DA, Miller MJS. Anti-inflammatory actions of cat's claw: the role of NF-kB. Alimentary Pharmacology & Therapeutics 1998, 12: 1279-1289.

3) Sandoval M, Charbonnet RM, Okuhama NN, Roberts J, Krenova Z, Trentacosti AM, Miller MJS. Cat's claw inhibits TNF production and scavenges free radicals: role in cytoprotection. Free Radical Biol Med 2000, 29: 71-78.

4) Sandoval M, Okuhama NN, Zhang X-J, Condezo LA, Lao J, Angeles FM, Bobrowski P, Miller MJS. Anti-inflammatory and antioxidant activities of cat's claw (Uncaria tomentosa and Uncaria guianensis) are independent of their alkaloid content. Phytomedicine 2002, 9: 325-337.

5) Miller MJS, Angeles FM, Reuter BK, Bobrowski P, Sandoval M. Dietary antioxidants protect gut epithelial cells from oxidant induced apoptosis. BMC Complementary & Alternative Medicine 2001, 1:11.

6) Piscoya J, Rodriguez Z, Bustamante S, Miller MJS, Sandoval M. Efficacy and safety of freeze dried cat's claw in osteoarthritis of the knee: mechanisms of action of the specie Uncaria guianensis. Inflammation Research 2001, 50: 442-448.

7) Sandoval M, Okuhama NN, Lao J, Condezo L, Angeles FM, Miller MJS. Antioxidant properties of an aqueous extract of maca (Lepidium meyenii). Food Chemistry 2002, 79: 207-213.

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