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Post by akemp3000 on Aug 17, 2017 16:02:01 GMT -5
A statement was made that current RAA's "once in the bloodstream...behave just like RHI". I understand getting faster action on the front end via inhalation but am wondering why the current RAA's, if they they truly behave the same in the bloodstream, take so much longer to EXIT the body on the back end as opposed to Afrezza.
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Post by dreamboatcruise on Aug 17, 2017 16:09:01 GMT -5
A statement was made that current RAA's "once in the bloodstream...behave just like RHI". I understand getting faster action on the front end via inhalation but am wondering why the current RAA's, if they they truly behave the same in the bloodstream, take so much longer to EXIT the body on the back end as opposed to Afrezza. I believe that is purely a function of it having a long tail to get into the blood stream... i.e. you can't get all of it out until all of it has slowly diffused in. Once it is in the bloodstream it is the active monomeric state and behaves as such.
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Post by agedhippie on Aug 17, 2017 16:14:44 GMT -5
A statement was made that current RAA's "once in the bloodstream...behave just like RHI". I understand getting faster action on the front end via inhalation but am wondering why the current RAA's, if they they truly behave the same in the bloodstream, take so much longer to EXIT the body on the back end as opposed to Afrezza. Because the insulin doesn't hit in one rush. Think of a tank with a dripping faucet - eventually the tank will empty but it takes time. Injected insulin behaves the same, the speed of absorption is based on the insulin reservoir draining through the capillaries into the blood stream and that is a slow process. In other words as the insulin is being cleared from the blood stream more insulin is arriving via the capillaries until eventually the reservoir is empty. It looks like it takes a long time to clear, but really it's arriving spread over a long period.
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Post by sayhey24 on Aug 17, 2017 18:02:13 GMT -5
Now back to One Drop and why Aged's example is important. If you look at the VDex paper www.seventhform.com/vdexdownloads/vdex-whitepaper-072817.pdf the bottom of pg 26 Scientists have long understood the need for fast-acting insulin. They have understood the need to produce an early, first phase insulin response to mimic normal physiology, and to deliver the host of benefits that flows therefrom. This is the Holy Grail of prandial insulin development. And, there has been very significant progress in this area over several decades. Today’s “rapid-acting analogs,” for example Novolog and Humalog, are much faster than their predeces -sors, and are successful products. Nevertheless, patients are still advised to inject their prandial insulin in advance of their meal in hopes of timing the presence of insulin with the presence of glucose. The RAAs achieve peak concentration in about an hour. So, while much better than the older insulins, the RAAs fail to reproduce the first-phase insulin response characteristic of normal physiology.Rapid Elimination. As important as the speed of onset with insulin is the speed at which the insulin is eliminated from the body. Since the typical person digests a meal in about three hours, ideally the insulin would be gone at that time too. Excess insulin in the blood stream simply drives blood sugar lower, risking hypoglycemia. This continues to be a significant limitation in the use of insulin today. The RAAs remain in the blood stream for hours after the meal is digested. Further, the elevated insulin levels keep gluconeogenesis arrested, thereby increasing the risk of hypos. The Magic of Afrezza. As stated elsewhere in this report, Afrezza does not suffer from the deficiencies of other insulins. In fact, the PK/PD profile seems to be almost an identical match to normal pancreatic insulin. So, what causes this? The two properties that contribute to Afrezza’s rapid “on-off” action are the molecular structure Afrezza and the route of delivery of the product. Afrezza’s Molecular Structure. Afrezza insulin is the only insulin in the world that has a monomeric molecular structure. All other insulins are hexameric. The body cannot use hexameric insulin. It needs monomeric insulin. So, the body breaks the injected hexamer molecule (6-molecule chain) into three, dimers (2-molecule chains) and then into ONE(typo in paper), monomers (single molecule chains). This process of breaking down the insulin takes time. By contrast, Afrezza is delivered as monomeric insulin (see Figure below). As soon as it reaches the bloodstream, it’s ready to do its job. Pg 27 presents a nice picture. Now, its very easy to model afrezza's absorption into the blood stream. For One Drop to do this is very straight forward with afrezza. Ondou's assumption was their modeling would require traditional hexamer absorption which varies from person to person and varies depending on a person's hydration which is constantly changing. It's really not drip drip drip as Aged mentioned. Its "drip" "slight-burst" "nothing". Its erratic. Building that Ondou model is pretty complicated. Then of course it needs to be done for each analog which is also different. The paper does not mention the molecular differences with the analogs or as I call them Frankenstein's sisters as the AspB10 was the original analog. Now I have no idea if One Drop is planning on doing dosing models. Based on what Dachis said at the ASM I assume they are. Again dosing models with afrezza are very easy because the speed of action is very constant from dose to dose. You don't have the speed variability you do with the analogs and you do not need to be precise which is huge. If its at the upper end of a small but maybe a medium dose the medium. The rule of thumb is always go big.
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Post by dreamboatcruise on Aug 17, 2017 19:30:35 GMT -5
@sayhey... that's not a typo in the paper. 1 hexamer = 3 dimers = 6 monomers
Where do you get that pk profile of injected RAA's is erratic? I've not seen that in published data. Afrezza own clinical trials for pk/pd show lispro and the curve doesn't seem to be erratic. It is true that things like hydration and the particular injection spot can change the absorption rate, but I am unfamiliar with anything that would say it starts and stops in erratic fashion for a given injection as you suggest.
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Post by agedhippie on Aug 17, 2017 20:22:42 GMT -5
@sayhey... that's not a typo in the paper. 1 hexamer = 3 dimers = 6 monomers Where do you get that pk profile of injected RAA's is erratic? I've not seen that in published data. Afrezza own clinical trials for pk/pd show lispro and the curve doesn't seem to be erratic. It is true that things like hydration and the particular injection spot can change the absorption rate, but I am unfamiliar with anything that would say it starts and stops in erratic fashion for a given injection as you suggest. You are correct. He is wrong on the absorption being erratic once injected so there is no evidence for that, which is not surprising given the physiology.
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Post by sayhey24 on Aug 19, 2017 7:05:17 GMT -5
@sayhey... that's not a typo in the paper. 1 hexamer = 3 dimers = 6 monomers Where do you get that pk profile of injected RAA's is erratic? I've not seen that in published data. Afrezza own clinical trials for pk/pd show lispro and the curve doesn't seem to be erratic. It is true that things like hydration and the particular injection spot can change the absorption rate, but I am unfamiliar with anything that would say it starts and stops in erratic fashion for a given injection as you suggest. You are correct, yes 1 hexamer results in 6 monomers - I misread their meaning - thanks. OK - erratic, where to start. Insulin absorption is effected by so many things which makes it really difficult to build predictive models; hydration; temperature; exercise; where its injects; and the type of device used to inject to name a few. Afrezza has none of these issues. Its absorption is highly predictable and then its dosing requires no precision. This is the opposite of old school RAAs. Here is one example talking about injection sites and scar tissue. I think Lutz also uses the would erratic in his paper. www.ncbi.nlm.nih.gov/pmc/articles/PMC2901055/The point being for One Drop to develop models using afrezza versus an Ondou trying to develop for old school RAAs is night and day.
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Post by peppy on Aug 19, 2017 8:03:39 GMT -5
A statement was made that current RAA's "once in the bloodstream...behave just like RHI". I understand getting faster action on the front end via inhalation but am wondering why the current RAA's, if they they truly behave the same in the bloodstream, take so much longer to EXIT the body on the back end as opposed to Afrezza. When injected subq, it takes time for the insulin to get into the blood stream. Afrezza, enters the body through the alveoli. The alveolar bed is covered with a vascular bed, the same vascular bed that does the exchange of oxygen and carbon dioxide.
Absorption; Intravascular (IV) the fastest, followed by intramuscular (IM), subcutaneous (SubQ) the slowed route of absorption. pretty much as simple as that.
![](https://previews.123rf.com/images/krishnacreations/krishnacreations0910/krishnacreations091000883/5758274-Digital-illustration-of-alveoli-in-colour-background-Stock-Illustration.jpg)
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Post by agedhippie on Aug 19, 2017 11:37:55 GMT -5
OK - erratic, where to start. Insulin absorption is effected by so many things which makes it really difficult to build predictive models; hydration; temperature; exercise; where its injects; and the type of device used to inject to name a few. Afrezza has none of these issues. Its absorption is highly predictable and then its dosing requires no precision. This is the opposite of old school RAAs. Here is one example talking about injection sites and scar tissue. I think Lutz also uses the would erratic in his paper. www.ncbi.nlm.nih.gov/pmc/articles/PMC2901055/I see the problem. Once insulin is injected and begins to be absorbed it is absorbed at a constant pace. It is not erratic, stop start, or anything else. It may be absorbed slowly, it may be absorbed quickly, but it is always absorbed consistently since the internal structures do not change. Personally I have found this to be the case as well, the curve is predictable. What I think you may be talking about, and the paper is definitely talking about, is absorption from injection to injection. There are a lot of things that will change the speed of absorption because it largely comes down to the blood flow so exercise or heat both of which raise blood flow will result in a faster absorption. Injecting into muscle will raise absorption for the same reason. Injecting into scar tissue or lipohypertrophic tissue will reduce the absorption rate. This is why they tell you not to inject just before a hot shower, or to massage the injection site. Afrezza is uniquely suited to people who have absorption issues because it should be predictable because of the delivery route. IV would be even more predictable but not as practical. ![:)](//storage.proboards.com/forum/images/smiley/smiley.png) For most people the variation is not significant as the tail is sufficiently that it catches all the carb provided the absorption rate is not grossly out, in which case as I said earlier they should be on Afrezza.
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Post by mango on Aug 21, 2017 9:36:57 GMT -5
@sayhey... that's not a typo in the paper. 1 hexamer = 3 dimers = 6 monomers Where do you get that pk profile of injected RAA's is erratic? I've not seen that in published data. Afrezza own clinical trials for pk/pd show lispro and the curve doesn't seem to be erratic. It is true that things like hydration and the particular injection spot can change the absorption rate, but I am unfamiliar with anything that would say it starts and stops in erratic fashion for a given injection as you suggest. You are correct. He is wrong on the absorption being erratic once injected so there is no evidence for that, which is not surprising given the physiology. It is a known fact that injected insulins have erratic absorption when injected into areas of injected insulin-derived amyloid masses. It is stated in all of the literature. Localized insulin-derived amyloidosis is not rare, but for some reason you like to say it is 😉
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Post by liane on Aug 21, 2017 9:47:50 GMT -5
Can you folks please just stay on the topic???
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Post by itellthefuture777 on Aug 21, 2017 14:21:31 GMT -5
My view..layman terms...No other insulin maker could stabilize Monomeric active insulin..which is the exact same insulin the pancreas produces in the healthy individual...All the industrialized insulins zinc bond 6 monomeric molecules into a hexomeric (six pack)...then..it is stable but in an inactive form. Then you inject it...it's in the blood..near the injection site..slowly spreads out in the body..and then your blood has to eat through that zinc bonding...takes a long..long time...then it is active..Mannkind"s Afrezza is the worlds only stabilized Monomeric active insulin..you breath it into the lungs with a Ph balance of 7 the known inert Technosphere carrier melts away at the deep lungs Avila delivering through a 1 cell thick lung wall (which if you stretched out your lung it is about the size of a tennis court) into the blood stream systemically (like air..exchanges into your blood..feels good to get that air systemically) the difference between the healthy individuals pancreas and Afrezza is less then 30 seconds..and basically the same human monomeric insulin so...it mimics the healthy individual..NO other insulin can do this..and since type 2 diabetes starts at meal time (where you lose control) Afrezza is a meal time insulin..kol's say it's obvoius Afrezza halts progression..in a study where type 2 took Afrezza..but didn't eat..they had zero hypos..in all cases..when ised with a basil..there were some hypos but a 62% reduction when used with Afrezza..so..thats how I view it..you can't put a pencil mark between a healthy individuals kenetic profile and Afrezza..the goal to have a fast insulin..by Pfizer using the lungs failed..because while inhaled..they still were Hexomeric..and like the shot..still to slow to activate..Afrezza mimics the pancreas..and faster then rapid insulins..ultra rapid...and is a monopoly...and there is nothing else on the horizon..So Metformin doesn't halt progression to blindness..amputations..liver..heart..ect..Afrezza isers show many graphs in range..they love it..what other insulin users say that about their insulin?
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Post by itellthefuture777 on Aug 21, 2017 14:29:55 GMT -5
Just waiting on the FDA to approve a Superior label
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Post by dreamboatcruise on Aug 21, 2017 14:41:06 GMT -5
My view..layman terms...No other insulin maker could stabilize Monomeric active insulin..which is the exact same insulin the pancreas produces in the healthy individual...All the industrialized insulins zinc bond 6 monomeric molecules into a hexomeric (six pack)...then..it is stable but in an inactive form. Then you inject it...it's in the blood..near the injection site..slowly spreads out in the body..and then your blood has to eat through that zinc bonding...takes a long..long time...then it is active..Mannkind"s Afrezza is the worlds only stabilized Monomeric active insulin..you breath it into the lungs with a Ph balance of 7 the known inert Technosphere carrier melts away at the deep lungs Avila delivering through a 1 cell thick lung wall (which if you stretched out your lung it is about the size of a tennis court) into the blood stream systemically (like air..exchanges into your blood..feels good to get that air systemically) the difference between the healthy individuals pancreas and Afrezza is less then 30 seconds..and basically the same human monomeric insulin so...it mimics the healthy individual..NO other insulin can do this..and since type 2 diabetes starts at meal time (where you lose control) Afrezza is a meal time insulin..kol's say it's obvoius Afrezza halts progression..in a study where type 2 took Afrezza..but didn't eat..they had zero hypos..in all cases..when used with a basil..there were some hypos but a 62% reduction when used with Afrezza..so..the basil is probably where those came from..thats how I view it..you can't put a pencil mark between a healthy individuals kenetic profile and Afrezza..the goal to have a fast insulin..by Pfizer using the lungs failed..because while inhaled..they still were Hexomeric..and like the shot..still to slow to activate..Afrezza mimics the pancreas..and faster then rapid insulins..ultra rapid...and is a monopoly...and there is nothing else on the horizon..So Metformin doesn't halt progression to blindness..amputations..liver..heart..ect..Afrezza isers show many graphs in range..they love it..what other insulin users say that about their insulin? Actually what makes the RAA more rapid than RHI is that they are modified to contain larger amounts of stable monomeric insulin. If these are injected IV they have very rapid onset like Afrezza. Pancreas actually stores insulin as hexamers and it rapidly converts to dimers and monomers in blood as it quickly spreads throughout the body and the concentration levels drop (hexamers are favored at high insulin concentration such as where it is stored in pancreas). The slowness of RAAs is all about the diffusion through tissue and then into capillaries, that is faster for the monomers of RAA vs RHI but even with monomers that is slower than inhaled. I've never quite thought this focus on insulin molecule structure would really resonate as marketing with most patients. It is more complicated than most try to make it, and most ordinary patients don't care about that level of detail. Most people, however, do understand inhaling (smoking) something is a quick way of getting high er concentrations of substances into the bloodstream. Hence why technosphere has rapid pd profile for substances not involving multimeric forms.
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Post by saxcmann on Aug 21, 2017 14:46:21 GMT -5
Just waiting on the FDA to approve a Superior label lol... that's not gonna happen. At least not on or before Sept 30th, 2017.
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