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Ohr Pharmaceutical, Inc. Message Board

  • billwilliams836 billwilliams836 Apr 10, 2014 3:59 PM Flag

    Dutch Belted Rabbit study - Translation to Human Efficacy?

    What examples are there of topical retinal drugs achieving therapeutic concentrations in DB rabbits, but failing in human trials?

    Had asked L10 this in the context of another thread, but perhaps there are others with the knowledge to comment?

    Sentiment: Buy

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    • If it's good enough fur Dutch Rabbits it's good enough fur me, BEV (bevacizumab) the Belieber

    • L10 said this on March 5th, 2014:

      "Let me explain. Glaxo's eye drops were lipophilic and thus did not take just a transcleral route in the animals tested; they also were absorbed straight through the cornea and into the anterior chamber, where they then entered the systemic circulation. So for mice and for rabbits, at least half the drug was absorbed into the anterior chamber; this would recirculate back to both retinas. For mice this extra drug accounted for a response to CNV, but for rabbits which are 80 times heavier, this amount was insignificant and only the transcleral portion was available to treat the affected retina. However as I've explained, pazopanib clears out of the retina in a few hours and does not build up; it is very weak in fact and oral doses have to be in the 100's of milligrams per day to treat cancer because the drug does not bind tightly at all to it's receptors. It is designed to recirculate and pop on then pop off ...etc. The steroids eye drops used for macular edema also are absorbed into the anterior chamber and is essentially wasted, but enough also is absorbed via the transcleral route so that the affected retina gets enough medication. Because steroids enter the anterior chamber, they can increase the risk of cataracts of the lens

      Squalamine will not enter the anterior chamber because it is hydrophilic, so it is not soluble in lipids. It goes to the back of the eye however where it can pass through the sclera due to it's being able to pass through the small holes in this connective tissue. From there it directly is absorbed into the endothelial cells of the choroid and suppresses angiogenesis. The concentration builds up in the choroid over 20 days......"

      • 1 Reply to biophd024
      • Also a repost from L10 dated March 5th :

        "Pazopanib is lipophilic and poorly soluble at a pH of 7, this forced Glaxo to complex it with cyclodextrin in order to dissolve into a suitable eye drop solution. Due to it's being fat soluble, pazopanib diffuses through the cornea which covers the front of the eye and enters the anterior chamber from which it then enter the systemic circulation. Note that this fraction of pazopanib does not pass through the choroid initially, and instead becomes diluted by the general circulation. Only a smaller fraction of pazopanib takes the transcleral route that squalamine exclusively uses to reach the choroid.

        When pazopanib eye drops were given to mice, the drug entered the systemic circulation via the anterior chamber, then recirculated back to the choroid where they could affect leaky capillaries. However the total dose the mice got was huge given their size, since the eye drops were just slightly smaller than the eye drops Glaxo gave humans and rabbits. The drop the mice got was a huge systemic dose and only this toxic dose was effective in decreasing wet amd in mice.

        Only about 140 mcg of squalamine per week is being absorbed by the choroid since only about 10% of the daily dose of 200 mcg can enter the scleral, the rest is washed out of the eye. This is only 0.3% of the weekly IV dose of 40mg that improved vision dramatically over the first 4 weeks by 8-10 letters and showed every sign that vision would have continued improving if the weekly dosing had continued.

        Kayla has a tki eye drop for wet amd that worked in rabbits for a week, but the dose was huge, comparable to a human dose used in chemotherapy, because it needed to diffuse into the anterior chamber via the cornea and enter the circulation. Xcovery has an oral tki for wet amd, but just as in Kayla's drug, or Glaxo's attempt to oral pazopanib for wet amd; they are all subjecting the whole body to a chemotherapy drug in order to treat the tiny choroid"

    • google search: Ocular Pharmacokinetics of Dorzolamide and Brinzolamide After Single and Multiple Topical Dosing: Implications for Effects on Ocular Blood Flow

    • like i said eyes drops might work a little but they wont get to the back of the eye

 
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