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    August 23, 2017: by Bill Sardi

    FDA Approves Pro-Oxidant Dose Of Resveratrol Encapsulated To Reduce Gastrointestinal Side Effects To Treat Orphan Disease (Friedreich’s Ataxia)

    Capitalizing on relaxed requirements to gain FDA approval for orphan diseases (defined as a condition that affects fewer than 200,000 people nationwide), a Jupiter Florida drug company has been awarded FDA clearance to market a specially encapsulated form of resveratrol to treat a debilitating disease known as Friedreich’s ataxia.  Ataxia is a disease where full loss of control of body movements occurs.

    The resveratrol drug (JOT101) utilizes special encapsulation technology and excipients to allay gastrointestinal side effects produced by the pro-oxidant (5000 milligram) dose of resveratrol.  Improvements in measures of speech and hearing were noted in humans subjects given 5000 mg but not 1000 mg dose of resveratrol.

    Friedreich’s ataxia is an orphan disease that affects ~1 in 50,000 people in the US and is caused by a recessive gene defect where someone inherits two defective copies of the FXN gene.  This progressive disease usually emanates in the third or fourth decade of life and most patients are wheelchair bound 15 years following diagnosis.

    Caused by gene mutation

    Friedreich’s ataxia is caused by mutations in a gene for the protein frataxin that binds to iron inside the tiny cellular energy factories within cells called mitochondria.  There are hundreds of mitochondria in living cells.  Frataxin releases iron on an as needed basis.  A shortage of iron in mitochondria can result in an enzyme deficiency that impairs energy production.  Resveratrol had already been identified as a natural molecule that alters the expression of the frataxin gene.

    In the human study involving Jupiter Orphan Therapeutics resveratrol drug, frataxin levels were not altered.

    Pro-oxidant dose

    Low-dose resveratrol is an antioxidant.  Apparently the 5000 mg mega-dose of resveratrol induces oxidation that causes affected cells to become senescent, that is they cease dividing into new cells.  This “cell-cycle arrest” was demonstrated in an earlier study that utilized mega-dose resveratrol to induce cell senescence in a lab dish model of ataxia.  This approach would also be a pathway to stymie the growth of cancer cells.

    Led by Harvard professor

    Harvard professor David Sinclair, who pioneered resveratrol as a molecular mimic of calorie restriction for Sirtris Pharmaceuticals (now owned by Glaxo Smith Kline but not operational) is co-chair of Jupiter’s scientific advisory board.

    Orphan drugs flood FDA

    Orphan drug development is said to offer a new avenue for pharmaceutical companies to bring products to market.  In June of 2017 the FDA said it would attempt to pare down a backlog of 586 new drug approval requests for orphan drugs which have now flooded the FDA.

    Since the Orphan Drug Act was approved over 30 years ago the FDA is reported to have granted approval for 450 so-called orphan drugs.

    Orphan drug abomination

    Even though the Orphan Drug Act reduces the cost and time to bring a drug to market, it has resulted in monopolies that have resulted in drugs with “astronomical price tags” says a report by NPR.

    An investigation by Kaiser Health News found “a system that was created with good intent has been hijacked.”  Once FDA has granted approval, it will not approve another version to treat a rare disease for seven years even if its patent has expired.   Not subject to competition, it can charge what it wants for the drug.

    According to the Kaiser Health Foundation, seven of the best ten selling drugs in 2015 were initially approved as orphan drugs.  Once approved these orphan drugs are “repurposed” and can be prescribed for many off label uses.

    While Jupiter’s JOT101 resveratrol-based drug is not likely to be utilized to produce anti-aging effects that mimic a life-prolonging calorie restricted diet that resveratrol is well known for, its use may be expanded to address cancer.

    Modest versus mega dose resveratrol

    Modest doses of resveratrol have been shown to activate a gene transcription factor known as Nrf2 that induces internal antioxidant enzyme activity (glutathione, catalase, superoxide dismutase).  This is the well-known hormesis effect defined as a modest-dose biological stressor like heat, radiation or food deprivation (calorie restriction) that alerts internal antioxidant activity.

    Lack of bioavailability is a misnomer

    The JOT101 drug is claimed to improve resveratrol bioavailability but this is a misnomer.  It is true that resveratrol is not very soluble in water, but over 70-75% is orally absorbed.  It is then transported to the liver where it is perceived as a toxin and bound to detoxification molecules glucuronate and sulfate.

    The encapsulation process would have no effect upon glucuronidation or sulfation unless various other ingredients like quercetin or piperine (black pepper extract) are added which allows more passes through the liver before resveratrol is bound to these detoxification molecules, thus allowing more immediate bioavailability.  Eventually all circulating resveratrol is bound to glucuronate and sulfate.

    Resveratrol with or without piperine enhances cerebral blood flow in humans regardless of bioavailability.  More soluble forms of resveratrol have been shown to dramatically increase blood levels and this can be facilitated by a well-known solubilizing agent beta cyclodextrin, which has now been pioneered in a commercially available resveratrol pill (Longevinex®).  Apparently inflammation impairs resveratrol’s absorption in the digestive tract.  Other anti-inflammatory agents like IP6 rice bran extract provided with resveratrol may be beneficial in this regard.

    Lack of bioavailability: straw man argument

    It is a straw man argument that resveratrol is not bioavailable, a false allegation made by pharmaceutical interests to justify making a patentable resveratrol-like analog drugs.

    The assertion resveratrol is not bioavailable is not true because: (a) resveratrol exerts biological action via alteration of gut bacteria and does not need to be absorbed or pass by the liver detoxification system; (b) because the attachment of glucuronate and sulfate to resveratrol in the liver becomes a biologically active metabolite in itself and (c) resveratrol is unlinked from glucuronate by the enzyme glucuronidase that is 17-20 fold higher at sites of inflammation, infection or malignancy and becomes free unbound resveratrol.

    Resveratrol liver metabolites (res-glucuronate and sulfate) are found in remote organs throughout the body.  So the assertion resveratrol is not biologically active is a falsehood.

    Mega-dose resveratrol, being perceived as a toxin, is rapidly excreted (~75%) in feces and urine.  Resveratrol and its metabolites as provided in a commercially available form of resveratrol (Longevinex®), have been shown to pass through the blood-ocular barrier in humans.

    If resveratrol is not conjugated (bound to) glucuronate and sulfate it has a short half-life of ~14 minutes and is rapidly excreted whereas if it is attached to liver detox molecules it has a half-life of ~9 hours.  (Half-life is the amount of time it takes before half of the active elements are either eliminated or broken down by the body.)  Improving bioavailability is a misdirection.

    A study of patients with multiple myeloma using 5000 mg of resveratrol ended up causing kidney failure and the study had to be abandoned.  The excess resveratrol is shuttled to the kidneys where it releases copper and induces oxidation and kidney failure.

    Whether JOT1o1 becomes a blockbuster drug like other drugs that gained FDA approval via the Orphan Drug Act is to be seen.  Except for its encapsulation and excipients (inactive ingredients that facilitate absorption or bioavailability and allay gastrointestinal side effects) it is nothing more than plain resveratrol available as a dietary supplement.  Utilizing the Orphan Drug Act, pharmacology may have finally found a way to over-price resveratrol as it has other molecules.  ©2017 Bill Sardi,

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