| Revision as of 16:44, 5 December 2015 edit169.230.155.123 (talk) Undid revision 693886783 by Elvey (talk) Please see WP:TALK and do not revert my additions to the talk page again unless you want to finish this convo at ANI. Thanks← Previous edit | Latest revision as of 20:03, 3 August 2024 edit undoLowercase sigmabot III (talk | contribs)Bots, Template editors2,294,050 editsm Archiving 1 discussion(s) to Talk:Sacubitril/valsartan/Archive 1) (bot | ||
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| == single thing == | |||
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| The original phrase, "single molecule" was verbatim from the source cited. The intention there, as it was here, was to make it clear that LCZ696 is a single thing, not just a formulation of the two drugs together. {{u|Anypodetos}} changed that in , with edit note "LCZ696 is not a single molecule". I understand the point, but the notion should be clear. I added content in to explain that, so it now reads "LCZ696 is synthesized by co-crystallisation of ] and ], in a one-to-one ratio; it is not simply a ] of the two drugs together." Happy to discuss. ] (]) 12:24, 18 September 2014 (UTC) | |||
| :I also see your point, but I'm afraid the new phrasing is also wrong. "Synthesis" is basically the creation of new molecules. These two are synthesised seperately and then, as you wrote, co-crystallised. What about writing simply "LCZ696 is co-crystallised valsartan and sacubitril in a one-to-one ratio"? BTW, while this is interesting, it's probably of no pharmacological significance. As soon as the tablet dissolves, the two molecules float around independently in the gut, and they are also absorbed separately from each other. --] (]) 13:17, 18 September 2014 (UTC) | |||
| ::respectfully, what is your source for how LCZ696 is synthesized? The mongo source cites: | |||
| ::* Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol 2010; 50: 401–414. PMID 19934029 | |||
| ::for the statement :"The prototype of these drugs is LCZ696, a single molecule synthesized by co-crystallisation of a well-known angiotensin II antagonist, valsartan, and the neprilysin inhibitor prodrug AHU377 (1:1 molar ratio)". I looked at the Gu et al article, and it says "LCZ696 (trisodium hemipentahydrate) comprises molecular moieties of valsartan, a well-established ARB,11 and of the NEP inhibitor prodrug AHU377 ((2R, 4S)-5-biphenyl-4-yl-5-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester; Figure 1), which is metabolized to the active NEP inhibitor LBQ657 by enzymatic cleavage of its ethyl ester.12 LCZ696 is a novel single molecule in which the molecular moieties of valsartan and the molecular moieties of AHU377 are present in a 1:1 molar ratio. The details of the molecular structure of LCZ696 will be presented elsewhere (manuscript submitted)." | |||
| :: what is your source for how LCZ696 is synthesized? If your argument is semantic and not based on sources that describe how the molecule is actually made, please say so. That is an entirely different conversation. ] (]) 13:44, 18 September 2014 (UTC) | |||
| ::: shows (p.48) two structural formulae (valsartan and sacubitril) and a crystal structure that appears to be the two molecules plus sodium ions and something else built into a crystal -- but that's a bit small to decide. also shows two molecules. I can find no source showing that and how the two are built into a single molecule (which, if true, would make the term "co-crystallisation" wrong). So, in a way, this is also a semantic issue: "'''co'''-crystallisation" and "single molecule" are mutually exclusive. Also, the chemical nomenclature you quote does not seem to name a single molecule. That makes one self-contradictory source (yours) and two that say they are two molecules (but none of them really reliable). It would be nice if we had access to the submitted manuscript you quote; but if you are right about the single molecule, the title, drugbox and header of our article are awfully wrong. | |||
| ::: For your question about why I know how LCZ696 is synthesised: I don't, but it cant be ''both'' synthesised as a single molecule ''and'' co-crystallised. Sorry if I didn't make that clear. --] (]) 15:37, 18 September 2014 (UTC) | |||
| ::::sorry but i don't agree. what the slide deck shows on slide 48, is a single molecule on the left (the same as figure 1 in the Gu et al paper) and its metabolites (the two separate drugs) on the right. It is a single molecule formed by co-crystalization - components in a cocrystal are held together by hydrogen bonds, etc and that is what the figure in Gu and in the slide deck are showing. this is not rocket science - we talk about macromolecules as single entities all the the time, even though they are made of subunits. We talk about "the" ribosome, about individual ion channels etc, even though they are made of subunits; they are stable, yet pretty easy to break apart. and as the slide deck says LCZ696 (the single thing) is "rapidly converted to NEPi and valsartan". btw I wrote to pubchem and asked them to correct the figure. they correctly provide a single molecular weight and formula for LCZ696. but the figure is wrong and shows the components of the drug in plasma after it is broken apart....] (]) 16:10, 18 September 2014 (UTC) | |||
| == Sacubitril does nothing == | |||
| ::::My impression is as follows. The complicated crystal structure with the two molecules and the sodium ions basically show this "compound" as a complex salt. It is clearly a combination of two discrete molecules that are not covalently bound to each other and which dissociate from each other upon dissolution. But depending on how much one wants to stretch the definition of chemical terms, I suppose one could call this well defined mixture a chemical substance. | |||
| ::::Two hypotheses for why they insist on calling it a single molecule. First, by establishing this one-to-one crystal form rather than mixing the two discrete powders in a pill, they help ensure that both dissolve and are absorbed at the same rate. They may be inordinately proud of this drug delivery strategy, of which I am aware of no prior examples. Alternatively, it may be some sort of patent strategy. By doing the HF trials with the co-crystal and the trials in some other indication with the two drugs as separate powders, they can price discriminate between HF and other indications, as the two forms would not be bioequivalent. | |||
| ::::If the nature of this substance is confusing, I think it is probably a deliberate effort on the part of the manufacturer. As a chemist I object less to the price discrimination or whatever other goal motivates this behavior than I do to the bastardization of chemical nomenclature. | |||
| ::::I think its less a single molecule than a novel approach to co-formulation. ] (]) 16:19, 18 September 2014 (UTC) | |||
| :::::@Jytdog: On the risk of sounding nitpicky: We talk of ion channels but we don't say an ion channel is a single molecule as far as I'm aware. Something held together by ]s isn't a molecule. Otherwise water would be a huge macromolecule. | |||
| :::::Also, solution in the GI tract isn't part of ], and so valsartan and sacubitril aren't metabolites. --] (]) 16:28, 18 September 2014 (UTC) | |||
| Why do they delete factual information (on the main page) from the LIFE clinical trial that clearly shows people lived longer and stayed out of the hospital longer using just generic valsartan? Look at secondary outcome, composite endpoints of effects. Whats wrong with posting clinical trial links?<ref>https://classic.clinicaltrials.gov/ct2/show/results/NCT02816736</ref> <!-- Template:Unsigned --><small class="autosigned">— Preceding ] comment added by ] (] • ]) 11:07, 31 July 2023 (UTC)</small> <!--Autosigned by SineBot--> | |||
| :::::::I think the best analogy here is ciprofloxacin hydrochloride, which is a hydrated HCl salt. One can call ciprofloxacin a "molecule", and could arguably even call ciprofloxacin hydrochloride a molecule, since the cipro and the HCl form a salt. But the crystal structure shows the HCl salt of ciprofloxacin with water hydrogen bonded to it. I don't think anyone would call ciprofloxacin hydrate a new molecule. ] (]) 16:36, 18 September 2014 (UTC) | |||
| Prominent physician researchers call into doubt whether sacubitril does anything at all. <ref>https://hcrenewal.blogspot.com/2015/07/entresto-blockbuster-or-just-over-hyped.html | |||
| {{od}}Thank you Formerly, i was hoping you would weigh in. what i am hearing from you, is that: a) as a chemist you are not comfortable with their calling it a "single molecule"; b) you would call it a "complex salt" (by which I am guessing you are saying this is much more than just your typical ion + counter-ion salt). I did some more digging and found this: | |||
| </ref> | |||
| * Lili Feng, L et al. LCZ696: a dual-acting sodium supramolecular complex. Tetrahedron Letters 53 (2012) 275–276 (the authors are from Novartis) | |||
| which says: | |||
| <blockquote>Crystalline LCZ696, ... (CAS # 936623-90-4), is synthesized by dissolution of a NEP inhibitor (NEPi) ... and an angiotensin II (Ang II) receptor blocker (ARB) in the form of valsartan (Fig. 1). The subsequent addition of aqueous sodium hydroxide solution provides concurrently the sodium cations and water molecules necessary to induce crystallization of LCZ696. The crystal structure was determined using single-crystal X-ray diffraction. ... LCZ696 comprises six NEPi and six ARB moieties in their anionic forms, 18 penta- and hexa-coordinated sodium cations, and 15 water molecules providing a molecular formula of C288H330N36-O48Na18�15H2O (M.W. 5748.03). Such a 1:1 molecular ratio of NEPi to ARB is inherent as use of non-stoichiometric quantities of sodium hydroxide or either of the two moieties (±0.25 equiv) has no influence on the propensity to form LCZ696. </blockquote> | |||
| Delaware judge recently invalidated the combination patent. <ref>https://news.bloomberglaw.com/litigation/novartis-falls-as-judge-rules-entresto-patent-claim-invalid</ref> | |||
| <blockquote>The chemical structure of LCZ696 can be described as a sodium supramolecular complex, with the sodium ions coordinated by oxygen ligands derived from 12 carboxylate groups and 18 carbonyl groups of the NEPi and ARB moieties, in addition to 13 out | |||
| of the 15 water molecules (Fig. 2)....</blockquote> | |||
| A careless cyanide release occurred in the entresto lab, 5 people were rushed to the hospital on gurneys, novartis forced chemists to dispense their fume hood waste OUTSIDE of the fume hood without proper ventillation because they thought it was too expensive to do it safely. Complaints to OSHA resulted in them harassing me and pushing me out, destroying my career as a chemist, I was the guy who generated reg# LBQ657, it's bunk <!-- Template:Unsigned --><small class="autosigned">— Preceding ] comment added by ] (] • ]) 11:26, 31 July 2023 (UTC)</small> <!--Autosigned by SineBot--> | |||
| <blockquote>LCZ696 is a hemipentahydrate white powder, which is morphologically composed of very thin hexagonal plates melting at around 138 �C. ... In the solid state, LCZ696 is very stable with no degradation being observed after 1 week at 50 �C—both for LCZ696 alone and in the presence of excipients—either in sealed containers or under 58% relative humidity. The stability of LCZ696 in aqueous solutions, however, shows a pH dependency. After 1 week at 50 �C in the pH range of 5–7, the concentration of degradation products, as measured by | |||
| HPLC for the NEPi and ARB molecular moieties, was below 1.7%. Outside of this pH range, the solution stability quickly deteriorates, both at decreasing and increasing pH.</blockquote> | |||
| :Hi ]. The reason I reverted your edits was because they were improperly sourced or contained ] statements. Please have a look at ] and ] which say, among other things, that "Articles about health and medicine should generally not cite primary sources". Instead you should cite secondary sources which discuss the primary research. | |||
| So there you go, from the horses mouth. what shall we call it? ] (]) 18:44, 18 September 2014 (UTC) | |||
| :the more i think about it, yep this is just a fancy salt and the whole single molecule thing is scientific spin. i like the formulation " What about writing simply "LCZ696 is co-crystallised valsartan and sacubitril in a one-to-one ratio"? as originally proposed and will implement... thanks for discussing everybody. ] (]) 19:37, 18 September 2014 (UTC) | |||
| :As for the blog entry, in general per ] blog posts should not be used as sources for articles. Among other things, anyone can publish a blog, the identity of the blog editor often cannot be independently verified, and blogs are not generally subject to peer review. Any information in a blog post which is sufficiently reliable probably relies on other sources which could be tracked down and cited. Further, based on my reading, the blog does not independently support the statement that any of the researchers are prominent. | |||
| ::Thanks for the constructive discussion! The chemical information you dug up sounds really interesting; would you like to add it to the article? --] (]) 17:56, 19 September 2014 (UTC) | |||
| :::i don't much care about that but please feel free! ] (]) 18:52, 19 September 2014 (UTC) | |||
| :As to your last comment about being targeted by the company, please also consider ] and whether you are sufficiently distant from the subject to write independently. I can't quite follow your thought process so I'm not making any assumptions/pronouncements here, just suggesting you consider the possibility of COI. | |||
| ::::Seems ''patently'' obvious that it's a bastardization of chemical nomenclature intended to further a patent scam. Wish we had an RS saying so; then we could add it to the article.--]<sup>(]•])</sup> 01:16, 9 July 2015 (UTC) | |||
| :I hope this helps explain, and apologies if my reasons for reverting the edits were not sufficiently explained in my original edit summary.] (]) 11:31, 31 July 2023 (UTC) | |||
| == This reads like an advertisement, but it's for a very controversial drug. == | |||
| ::I've posted references to prominent doctor/researchers debunking sacubitril. They go into explicit detail regarding the issues surrounding sales of this drug. Regardless of where they post this information, blog or youtube channel, they make clear arguments and many other doctors have become convinced. Pharmaceutical companies inundate the internet and social media with their hype and spin, it's next to impossible to find truthful information that could adversely effect sales, even worse they just threatened costly frivolous legal action against anyone who challenges them. Please review Dr Vinay prasads youtube channel video "do we have evidence for new drugs, Denmark lectures. I was the chemist who first made this sacubitril nonsense when I worked at Novartis in 2006. If I can't speak out about it then who can? Lastly, pharmaceutical companies have distorted the meaning of FDA approval. They approve so called drugs that don't do anything all the time, they admit it themselves. The FDA is a poorly funded government agency, no match for pharma crafty scientists and highly paid legal teams. There are very few people with the courage to stand up to the pharmaceutical industry, my work is important. | |||
| ::Sacubitril represents the loss of billions in healthcare dollars, even worse a Harvard professor is behind it. Please allow me to post in the talk section for sacubitril | |||
| ::Look for and read "6 things big pharma doesn't want you to know" by doctors without borders. | |||
| ::Also review "medical reversal" by Dr Prasad and Dr Cifu. | |||
| ::Again, I'm doing important work as a whistle-blower, please allow me to be heard ] (]) 15:45, 5 May 2024 (UTC) | |||
| ::: Misplaced Pages isn't a soapbox for whistle-blowing, but If you have secondary sources for the negative comments, perhaps we could have a section maybe called Controversies or Criticisms ? Would anyone object ? - ] (]) 21:56, 1 August 2024 (UTC) | |||
| All mention of any of the prominent critical responses, e.g. those mentioned at http://www.healthnewsreview.org/2014/09/barcelona-buzz-about-heart-drug-news/ is lacking from the article. Hence the tagging. Do not remove the tags 'till this is addressed in the article.--]<sup>(]•])</sup> 01:26, 5 December 2015 (UTC) | |||
| {{reflist-talk}} | |||
| :The information in the article is all based on ] compliant sources. In contrast, www.healthnewsreviews.org is not compliant with MEDRS, and probably fails even the lower standards of ]. So thus far you have not presented a plausible argument that the articl is unbalanced. | |||
| == More on generics - a new section perhaps == | |||
| I'm removing the flag for this reason, but if you find MEDRS compliant sources that express views divergent from those currently in the article, please feel free to add them. As it stands, there is no dispute about the addition of reliable medical sources expressing other POVs, so the flag is premature. ] (]) 04:12, 5 December 2015 (UTC) | |||
| Lead says there are generics, but rest of article doesn't say what they are. Presumably it should. | |||
| Heres a pubmed search on the drug. There does not seem to be any controversy about this drug in the peer reviewed literature that I can see. It extends lives, and thats a good thing. http://www.ncbi.nlm.nih.gov/pubmed/?term=Valsartan+sacubitril | |||
| Economics section says there is a generic to one component. | |||
| Now FDA has approved a generic that Novartis is contesting : - ] (]) 21:53, 1 August 2024 (UTC) | |||
| ] (]) 04:33, 5 December 2015 (UTC) | |||
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Sacubitril does nothing
Why do they delete factual information (on the main page) from the LIFE clinical trial that clearly shows people lived longer and stayed out of the hospital longer using just generic valsartan? Look at secondary outcome, composite endpoints of effects. Whats wrong with posting clinical trial links? — Preceding unsigned comment added by Steve Brackett (talk • contribs) 11:07, 31 July 2023 (UTC)
Prominent physician researchers call into doubt whether sacubitril does anything at all.
Delaware judge recently invalidated the combination patent.
A careless cyanide release occurred in the entresto lab, 5 people were rushed to the hospital on gurneys, novartis forced chemists to dispense their fume hood waste OUTSIDE of the fume hood without proper ventillation because they thought it was too expensive to do it safely. Complaints to OSHA resulted in them harassing me and pushing me out, destroying my career as a chemist, I was the guy who generated reg# LBQ657, it's bunk — Preceding unsigned comment added by Steve Brackett (talk • contribs) 11:26, 31 July 2023 (UTC)
- Hi Steve Brackett. The reason I reverted your edits was because they were improperly sourced or contained WP:POV statements. Please have a look at WP:MEDREF and WP:MEDRS which say, among other things, that "Articles about health and medicine should generally not cite primary sources". Instead you should cite secondary sources which discuss the primary research.
- As for the blog entry, in general per WP:BLOG blog posts should not be used as sources for articles. Among other things, anyone can publish a blog, the identity of the blog editor often cannot be independently verified, and blogs are not generally subject to peer review. Any information in a blog post which is sufficiently reliable probably relies on other sources which could be tracked down and cited. Further, based on my reading, the blog does not independently support the statement that any of the researchers are prominent.
- As to your last comment about being targeted by the company, please also consider WP:COI and whether you are sufficiently distant from the subject to write independently. I can't quite follow your thought process so I'm not making any assumptions/pronouncements here, just suggesting you consider the possibility of COI.
- I hope this helps explain, and apologies if my reasons for reverting the edits were not sufficiently explained in my original edit summary.Oblivy (talk) 11:31, 31 July 2023 (UTC)
- I've posted references to prominent doctor/researchers debunking sacubitril. They go into explicit detail regarding the issues surrounding sales of this drug. Regardless of where they post this information, blog or youtube channel, they make clear arguments and many other doctors have become convinced. Pharmaceutical companies inundate the internet and social media with their hype and spin, it's next to impossible to find truthful information that could adversely effect sales, even worse they just threatened costly frivolous legal action against anyone who challenges them. Please review Dr Vinay prasads youtube channel video "do we have evidence for new drugs, Denmark lectures. I was the chemist who first made this sacubitril nonsense when I worked at Novartis in 2006. If I can't speak out about it then who can? Lastly, pharmaceutical companies have distorted the meaning of FDA approval. They approve so called drugs that don't do anything all the time, they admit it themselves. The FDA is a poorly funded government agency, no match for pharma crafty scientists and highly paid legal teams. There are very few people with the courage to stand up to the pharmaceutical industry, my work is important.
- Sacubitril represents the loss of billions in healthcare dollars, even worse a Harvard professor is behind it. Please allow me to post in the talk section for sacubitril
- Look for and read "6 things big pharma doesn't want you to know" by doctors without borders.
- Also review "medical reversal" by Dr Prasad and Dr Cifu.
- Again, I'm doing important work as a whistle-blower, please allow me to be heard Steve Brackett (talk) 15:45, 5 May 2024 (UTC)
- Misplaced Pages isn't a soapbox for whistle-blowing, but If you have secondary sources for the negative comments, perhaps we could have a section maybe called Controversies or Criticisms ? Would anyone object ? - Rod57 (talk) 21:56, 1 August 2024 (UTC)
References
- https://classic.clinicaltrials.gov/ct2/show/results/NCT02816736
- https://hcrenewal.blogspot.com/2015/07/entresto-blockbuster-or-just-over-hyped.html
- https://news.bloomberglaw.com/litigation/novartis-falls-as-judge-rules-entresto-patent-claim-invalid
More on generics - a new section perhaps
Lead says there are generics, but rest of article doesn't say what they are. Presumably it should. Economics section says there is a generic to one component.
Now FDA has approved a generic that Novartis is contesting : - Rod57 (talk) 21:53, 1 August 2024 (UTC)
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