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== single thing ==

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)

::::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)

:::::::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)

{{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:
* 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>

<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>

<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>

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)

::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)

::::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)


== This reads like an advertisement, but it's for a very controversial drug. == == This reads like an advertisement, but it's for a very controversial drug. ==

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This reads like an advertisement, but it's for a very controversial drug.

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.--Elvey 01:26, 5 December 2015 (UTC)

The information in the article is all based on WP:MEDRS compliant sources. In contrast, www.healthnewsreviews.org is not compliant with MEDRS, and probably fails even the lower standards of WP:RS. So thus far you have not presented a plausible argument that the article is unbalanced.

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. 2600:1010:B043:EC75:EFAD:9D0C:D710:2720 (talk) 04:12, 5 December 2015 (UTC)

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

2600:1010:B01D:46A9:1D35:CF9E:1113:134B (talk) 04:33, 5 December 2015 (UTC)

@Elvey: Since you obviously feel very strongly about this and your deletion of my comments on this Talk page seems to indicate a refusal to discuss with me, suggest we take this to the Medicine project talk page for outside input. 169.230.155.123 (talk) 16:47, 5 December 2015 (UTC)

Posted a request for outside input at the Medicine page. 169.230.155.123 (talk) 16:52, 5 December 2015 (UTC)

Good. Now log in and stop avoiding scrutiny by, e.g. using multiple accounts/IP addresses on multiple networks. --Elvey 20:42, 5 December 2015 (UTC)
Absolutely. Do you claim that all of the multiple sources of prominent critical responses, including the four mentioned at http://www.healthnewsreview.org/2014/09/barcelona-buzz-about-heart-drug-news/ violate MEDRS? If so, why? --Elvey 20:42, 5 December 2015 (UTC)

:::I'm not sure which four you are referring to. The Forbes blog is clearly non-MEDRS compliant. If I've correctly identified the other 3 sources as blogs, they are at a minimum lower quality sources than review articles published in peer-reviewed journals by cardiologists, and we generally don't use lower quality sources to rebut or "debunk" higher quality sources.

I have no objection to the addition of the ICER source, but there is no controversy, they say pretty much what the other sources say with a bit more skepticism. Their conclusion states:
"We judge there to be moderate certainty of an incremental to substantial net benefit for Entresto compared to standard of care with ACE inhibitor treatment in patients with Class II-IV CHF and reduced ejection fraction. There is moderate certainty because the PARADIGM-HF trial was a large, good quality study in which Entresto produced significant reductions in cardiovascular and all-cause mortality as well as in heart failure specific hospitalization and ED visits in comparison to an agent that itself has demonstrated clinical benefits in these domains. Some uncertainties remain, however, including the relative contribution of sacubitril versus valsartan to these results, the expected tolerability of Entresto, its clinical performance in real-world practice, and its potential for harm in certain patient subgroups.
Given the entire body of evidence, our rating of comparative clinical effectiveness using the ICER Evidence Rating framework is B+ (“Incremental or better”).
This material should be merged into the medical uses section with the other reviews and a more representative statement of the group's conclusions should be used.
73.162.132.47 (talk) 21:27, 5 December 2015 (UTC)
As for the IP addresses, I acknowledge responsibility for the 73, 169, and 2600 accounts. I am not a registered user (nor do the rules here require me to do so), so my edits will show up as whatever IP address I am at when I enter them. I have not attempted to deceive anyone or pretend to be multiple users. I apologize however, for not explicitly stating this connection before. 169.230.155.123 (talk) 21:51, 5 December 2015 (UTC)


You claim you are not a registered user but that is not true; your account is blocked. Actually, 169.230.155.123 (talk • contribs) is a sock puppet of Renamed_user_51g7z61hz5af2azs6k6 (talk • contribs). Comments struck, accordingly, and if I see any further activity, I will ask that all your many, many IPs be blocked. --Elvey 01:22, 27 December 2015 (UTC)
User:Elvey which of the accounts you mentioned is blocked? And while this user is using IPs it is not clear they are a sock puppet or pretending these IPs are different people. Or have is missed that? Thanks Doc James (talk · contribs · email) 08:32, 28 December 2015 (UTC)
What are you getting at? Are you disputing anything I've said? That he's using many, many IPs - which is what the closes of WP:SPI I opened indicate? That it's avoiding scrutiny to not use the main account (Formerly 98) that he has opened, and rather edit from a veritable shit ton of IPs? That such scrutiny avoidance is by definition, sock puppetry? Do you know this user? You're in the same city, IIRC. --Elvey 03:35, 31 December 2015 (UTC)
You mentioned an account was blocked. I am simply asking you to list what account is blocked.
The user is not pretending that this IPs are different people. That is required for sock puppetry to be present. Can you link to the case?
Yes they have an abandoned account but it does not appear they are using that account.
I have never meet this person. And no we are not in the same city. Best Doc James (talk · contribs · email) 05:46, 31 December 2015 (UTC)
I disagree; avoiding scrutiny means sock puppetry is present. You asked for a link to the case; the case says in part, "Two sock IPs blocked." So, can you accept or are you still disputing that he was using many, many IPs - which is what the closes of WP:SPI I opened indicate? It sounds like you either dispute that it's avoiding scrutiny to not use the main account that he has opened, and rather edit from a veritable shit ton of IPs, or you dispute that such scrutiny avoidance is by definition, sock puppetry. Which do you dispute? Do you dispute that the user cannot edit with the vanished account? Sorry about the city mix-up. --Elvey 17:59, 31 December 2015 (UTC)
We all agree that this user is using a number of IP accounts. The question asked here and which is not answered is is this "abusive socking"?
What I am saying is that this user was 1) being harassed 2) therefore vanished 3) decided they still wanted to edit Misplaced Pages so came back as IPs
I am not sure if they still are able to edit from that Vanished user account. It has not been used since May 2015 If the IPs and the vanished user account were being used at the same time I agree their would be a big issue. Best Doc James (talk · contribs · email) 07:05, 1 January 2016 (UTC)

I'm not aware of any evidence of your 1 or 2, but even assuming 1 & 2, the sock puppetry inherent in 3 is not justified, even if it is somewhat understandable.

Has anyone else noticed that user reportedly claims to have no CoI, but edits from machines with hostnames including:

  1. DIR-601-169230155132.ucsf.edu.
  2. udp071243uds.ucsf.edu.
  3. null-c42c03300974.ucsf.edu.

FYI,Doors22@? (Apropos https://en.wikipedia.org/Wikipedia:Administrators'_noticeboard/IncidentArchive877#COI_and_edits_by_Formerly_98  !)

It sounds like you either dispute that it's avoiding scrutiny to not use the main account that he has opened, and rather edit from IPs, or you dispute that such scrutiny avoidance is by definition, sock puppetry. Which do you dispute? --Elvey 03:26, 3 January 2016 (UTC)

Please use the Talk page to discuss the article. If you have issues with other editors please discuss them elsewhere. Thanks. Jytdog (talk) 04:39, 3 January 2016 (UTC)
Please stop defending your $%@$#%^!#!. Thanks. I was asked reasonable questions about the accounts here, and replied, as I am required to do, here, yet you direct your demand at me. It has been found that you Formerly 98 have been using one or more accounts or IPs abusively. I've struck the user's socks' comments on this page. So there's probably no more I feel the need to discuss. --Elvey 22:36, 4 January 2016 (UTC)
James is entitled to defend his friend and ally, however his minimizing of his friend's sockpuppetry is, IMO, far from exemplary. --Elvey 22:22, 6 January 2016 (UTC)
For any follow-up on this editor or their various socks, etc., folks should join the conversation "elsewhere" at Wikipedia_talk:Sockpuppet_investigations/Renamed_user_51g7z61hz5af2azs6k6.
--Elvey 22:22, 6 January 2016 (UTC)

HealthNewsReview.org

HealthNewsReview.org is peer-reviewed. http://www.healthnewsreview.org/about-us/reviewers/ I don't see any reason why it isn't a WP:MEDRS. --Nbauman (talk) 01:52, 16 January 2016 (UTC)

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