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2,4 Dinitrophenol (DNP) As Medicine

Discussion in 'Scientific Studies' started by olive, May 13, 2019.

  1. olive

    olive Member

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    2,4 Dinitrophenol as Medicine

    Abstract
    In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950’s to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin® and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescription, as both a sleeping pill and “morning sickness” anti-nausea medication targeting pregnant women in the 1950’s. The “thalidomide babies” became the case-in-point for the need of strict guidelines by the U.S. Food & Drug Administration (FDA) or full multi-species teratogenicity testing before drug approval. More recently it was found that thalidomide is useful in graft versus host disease, leprosy and resistant tuberculosis treatment, and as an anti-angiogenesis agent as a breakthrough drug for multiple myeloma (except for pregnant female patients). Decades of diabetes drug discovery research has historically focused on every possible angle, except, the energy-out side of the equation, namely, raising mitochondrial energy expenditure with chemical uncouplers. The idea of “social responsibility” allowed energy-in agents to be explored and the portfolio is robust with medicines of insulin sensitizers, insulin analogues, secretagogues, SGLT2 inhibitors, etc., but not energy-out medicines. The primary reason? It appeared unorthodox, to return to exploring a drug platform used in the 1930s in over 100,000 obese patients used for weight loss. This is over 80-years ago and prior to Dr Peter Mitchell explaining the mechanism of how mitochondrial uncouplers, like 2,4-dinitrophenol (DNP) even worked by three decades later in 1961. Although there is a clear application for metabolic disease, it was not until recently that this platform was explored for its merit at very low, weight-neutral doses, for treating insidious human illnesses and completely unrelated to weight reduction. It is known that mitochondrial uncouplers specifically target the entire organelle’s physiology non-genomically. It has been known for years that many neuromuscular and neurodegenerative diseases are associated with overt production of reactive oxygen species (ROSs), a rise in isoprostanes (biomarker of mitochondrial ROSs in urine or blood) and poor calcium (Ca2+) handing. It has also been known that mitochondrial uncouplers lower ROS production and Ca2+ overload. There is evidence that elevation of isoprostanes precedes disease onset, in Alzheimer’s Disease (AD). It is also curious, why so many neurodegenerative diseases of known and unknown etiology start at mid-life or later, such as Multiple Sclerosis (MS), Huntington Disease (HD), AD, Parkinson Disease, and Amyotrophic Lateral Sclerosis (ALS). Is there a relationship to a buildup of mutations that are sequestered over time due to ROSs exceeding the rate of repair? If ROS production were managed, could disease onset due to aging be delayed or prevented? Is it possible that most, if not all neurodegenerative diseases are manifested through mitochondrial dysfunction? Although DNP, a historic mitochondrial uncoupler, was used in the 1930s at high doses for obesity in well over 100,000 humans, and so far, it has never been an FDA-approved drug. This review will focus on the application of using DNP, but now, repositioned as a potential disease-modifying drug for a legion of insidious diseases at much lower and paradoxically, weight neutral doses. DNP will be addressed as a treatment for “metabesity”, an emerging term related to the global comorbidities associated with the over-nutritional phenotype; obesity, diabetes, nonalcoholic steatohepatitis (NASH), metabolic syndrome, cardiovascular disease, but including neurodegenerative disorders and accelerated aging. Some unexpected drug findings will be discussed, such as DNP’s induction of neurotrophic growth factors involved in neuronal heath, learning and cognition. For the first time in 80’s years, the FDA has granted (to Mitochon Pharmaceutical, Inc., Blue Bell, PA, USA) an open Investigational New Drug (IND) approval to begin rigorous clinical testing of DNP for safety and tolerability, including for the first ever, pharmacokinetic profiling in humans. Successful completion of Phase I clinical trial will open the door to explore the merits of DNP as a possible treatment of people with many truly unmet medical needs, including those suffering from HD, MS, PD, AD, ALS, Duchenne Muscular Dystrophy (DMD), and Traumatic Brain Injury (TBI).
     
  2. Broken man

    Broken man Member

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    Wow!!...Good one.
     
  3. OP
    olive

    olive Member

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    The researchers seem to suggest a HED of 2-22mg. The lower the dose the more neuroprotective.

    Increases BDNF.
    Induces autophagy.
    Reduces ROS.
    Lowers NADH.
    Increases ATP pool via uncoupling.
    Prevents fat accumulation on a high fat diet.
    Lowers fasting glucose.
    Lowers triglycerides.
    Increases insulin sensitivity.

    Has a wide range of potential theraupitic use.
     

    Attached Files:

  4. Ingenol

    Ingenol Member

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    Interesting--thanks for posting! My biggest fear about DNP is developing cataracts, so hopefully the study will shed some light on that risk.
     
  5. Broken man

    Broken man Member

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    I love you @olive, the question is how to obtain it? As a bodybuilder, do you have any ways?
     
  6. OP
    olive

    olive Member

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    I’m not a bodybuilder, I just follow a few forums because I find the science/mechanics interesting. The body in my avatar was built doing pushups and sprinting a few times a week.
    Not sure where one would source it, sorry.
     
  7. Momado965

    Momado965 Member

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    Arent those the same benefits MB offers?
     
  8. Broken man

    Broken man Member

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    Ye, could be but I cant use much of MB unfortunately.
     
  9. Rafael Lao Wai

    Rafael Lao Wai Member

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    Do you get serotonin symptoms from MB?
     
  10. Jing

    Jing Member

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    Did you build that chest with just push ups? How many push ups? Did you add weight?
     
  11. OP
    olive

    olive Member

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    No added weight but often done with my feet on a couch or similar to make it harder. 150-300 a week. Variations in hand position; diamond, wide, one-handed, knuckles, etc.
     
  12. Wichway?

    Wichway? Member

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    I used to use it in the research lab I was in. It’s therapeutic window is extremely small unfortunately, which means that it goes from being helpful to harmful (toxic) with just a small increase in dosage. Makes it hard to get the dosage right. I only used it in animals. Even though I know how to handle and administer it, i wouldn’t be game to try it myself.
     
  13. ShotTrue

    ShotTrue Member

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    Very interesting! Sad to hear that @Wichway? , as indeed too much has to known to cause a lot of bodybuilder's deaths! What's posted above does make it feel worth figuring out for therapeutic use
     
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