IRA

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IRA
Activation of Local IGF-1 Transcription and
Translation in Human Cartilage by a Natural
Product Combination is Chondroprotective. Mark
J.S. Miller, Salahuddin Ahmed, Paul Bobrowski,
Tariq M. Haqqi. Ctr. Cardiovascular Sci.,
Albany Medical College, Albany NY, Dept.
Medicine, Case Western Reserve University School
of Medicine, Cleveland, OH, Rainforest
Nutritionals, Inc., Raleigh, NC, USA
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Joint health market
Joint Health Market Current Therapeutic Options

• Currently this market is serviced by
• Prescription drugs
• OTC drugs (primarily NSAIDs)
• Natural products and dietary supplements
  (nutraceuticals)
• Physical Therapy Complementary Medicine

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Background to the Development of Reparagen

• Reparagen is a dietary supplement that contains
  proprietary extracts of two traditional medicine
  plants from South America
• Vincaria is extract of Uncaria guianensis (Cats
  claw subspecies) from the Amazon Rainforest,
  which we have previously described as a potent
  NF-kB inhibitor, anti-inflammatory and
  cytoprotective agent.
• RNI 249 is an extract of Lepidium meyenii (maca)
  - an Andean vegetable used for negating the
  effects of high altitude, specifically to promote
  fertility and vitality

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Amazonian Medicine - Cats Claw
Amazonian Pharmacist
Uncaria tomentosa
Uncaria guianensis
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Uncaria guianensis Background

• Effective NF-kB inhibitor and suppressor of TNF
  production
• Anti-inflammatory agent
• Negates to acute and chronic GI toxicity
  associated with NSAIDs
• Previously shown to confer symptomatic relief in
  a small trial on subjects with OA of the knee at
  the low dose of 100 mg/day

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Lepidium meyenii Background
While there is excellent evidence for the ability
of maca to promote fertility in males and
females, these actions were not associated with
changes in sex steroids, prolactin or thyroid
hormone.
Our research has revealed the mechanism of action
of both medicinal plants.
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Anabolic Actions of RNI 249 (Maca)

• When included in the diet of fingerling fish maca
  greatly accelerated growth, feed conversion ratio
  and reduced mortality
• Maca can prevent fetal growth restriction
  associated with high altitude.
• This led us to postulate that maca promoted the
  production of growth factors, specifically IGF-1

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Role of IGF-1 in Arthritis

• IGF-1 is locally produced in cartilage, bone and
  muscle and exerts reparative, anabolic actions.
• During inflammation the IGF-1 gene is silenced,
  halting production and blocking repair.
• Exogenous IGF-1, whose effects are limited by
  binding proteins, has been shown to promote new
  cartilage and bone growth quality and stimulate
  a stronger supportive musculature.
• Direct activation of IGF-1 production in joints
  has the potential to substantially improve joint
  function and architecture.

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Hypotheses

• RNI 249 stimulates the gene expression of IGF-1
  in human cartilage
• Both RNI 249 and vincaria are chondroprotective
  in IL-1 treated human cartilage explants
• The suppression of IGF-1 production in human
  cartilage treated with IL-1 would be negated by
  either vincaria or RNI 249
• Because of the contrasting of actions of vincaria
  and RNI 249 the combination of these
  phytoceutical preparations would be more
  effective than a single approach.

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Materials and Methods

• Human Chondrocyte Explants
• - Taken from surgical discard specimens and
  visibly normal
• - Placed in culture media and used to measure
  IGF-1 production or GAG release.
• Primary Cultures of Human Chondrocytes
• - derived from surgical specimens and treated to
  remove matrix, and cultured
• - used for NO production and IGF-1 gene
  expression
• GAG Release
• - Release of matrix elements, basal and IL-1
  stimulated, is primarily the result of MMP
  activity.
• Nitric Oxide Production
• - a measure of the catabolic status of the
  cartilage.
• Case Western Reserve University
• - All studies under IRB approval.

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Enhanced IGF-1 Gene Expression by RNI 249
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Enhanced IGF-1 Production by RNI 249
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Prevention of IL-1 Induced Suppression of IGF-1
Production
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Suppression of IL-1 Induced Cartilage Matrix
Degradation by RNI 249
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Summary

• RNI 249 directly activates IGF-1 gene expression
  and production in human cartilage.
• RNI 249 partially restored to baseline the
  suppressed IGF-1 production caused by IL-1.
• The combination of RNI 249 and vincaria fully
  normalized IGF-1 production by human cartilage.
• RNI 249 prevents the catabolic degradation of
  cartilage matrix caused by IL-1.
• The combination of the anti-inflammatory natural
  product Vincaria, which is a redox-active NF-kB
  inhibitor, with RNI 249 leads to additive
  chondroprotective effects.

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Conclusion
RNI 249 represents a novel, non-hormonal approach
to directly activating IGF-1 production in human
cartilage. Protection of IGF-1 production in the
presence of IL-1 by reparagen (the combination of
Vincaria and RNI 249) suggests that this approach
may promote frank joint repair. A double blind
randomized multi-center clinical trial comparing
Reparagen to glucosamine is near completion
(http//www.controlled-trials.com/ISRCTN25438351)
The enhanced benefits observed with a combination
of Vincaria and RNI 249 indicates that this dual
acting approach offers great potential for the
management of arthritis and joint dysfunction.
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RD Support and Commercialization Path
Rainforest Nutritionals, Inc received a SBIR
grant (1 R43 AG024773-01) from the National
Institute on Aging to promote the commercial
development of this innovation. The product has
being commercialized as a dietary supplement
under the brand name Reparagen by Park Labs
LLC. www.reparagen.com
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