Talk:Natalizumab/Archive 1

Archive 1

Archive 2

generic name

Is using the generic name for a drug as the title of the article perhaps a standard and universally followed WP convention? If so, then this article is properly titled, though I'm trying to figure out how to make the generally known name a little more prominent in the first sentence) . If it's not the universal or almost universal convention, I'm going to argue the point. I did change the cryptic section heading "PML" DGG 23:06, 4 October 2006 (UTC)

Yes, it is – see Naming of drug pages. Anyway, Tysabri redirects here, so anyone typing "Tysabri" in the search box will be brough to this article. Fvasconcellos 15:55, 5 October 2006 (UTC)

Title should be the generic name -- Samir धर्म 02:21, 6 October 2006 (UTC)

The drug is not generic, and so does not have a generic name, and will not for many years to come. Tysabri is the brand name. —Preceding unsigned comment added by Io io editor (talk • contribs) 21:48, 20 January 2008 (UTC)

All drugs have a generic name, whether or not they are currently available as generics. —Preceding unsigned comment added by 63.125.124.226 (talk) 15:18, 22 January 2008 (UTC)

Jo!

Is this notable for the Tysabri topic?

http://mugglenet.com/app/news/show/689

Subsequently, and following an outcry from MS organisations and personalities such as Ms Rowling, in both England and Scotland the Governments decided to reimburse Tysabri in cases of "highly-active" RRMS. At the start of 2008, the funding was becoming available.io-io (talk) 00:44, 21 January 2008 (UTC)

Why is there such an odd balance in this article?

Anyone have an idea why the pharmacology of this drug gets so little emphasis, while a rare brain disease and return to market get such big play in the article? Dr. Holland, Kd4ttc 15:03, 24 July 2007 (UTC)

I'm a writer, not an MD, so I can't improve it much further. Hopefully some medical/pharmaceutical editor will flesh out the pharmacology. --CliffC 01:22, 26 July 2007 (UTC)

That's because news of the successful phase III trials don't make headlines, while case reports of something horrible tend to tickle the public imagination ("Frankenstein drugs"). JFW | T@lk 18:43, 2 December 2007 (UTC)

I have added mechanism-of-action text directly from the FDA labelio-io (talk) 00:45, 21 January 2008 (UTC)

HRQOL in Crohn's

Initial improvement in health-related quality of life (measured by SF-36) is sustained when the drug is continued for a total duration of 48 weeks: doi:10.1111/j.1572-0241.2007.01508.x JFW | T@lk 18:43, 2 December 2007 (UTC)

Removal of 3 whole Sections

Someone has removed whole sections, titled "Summary of Clinical Trial Results in MS" and "Summary of Clinical Trial Results in Crohns" - presumably this is VANDALISM in order to focus on the Drug's infamous HISTORY - which is f_ing irrelveant to MS Patients ?io-io (talk) 01:25, 2 March 2008 (UTC)

Have a look at WP:SOAP - we are here to report, not condemn or praise. I did re-write several sections a couple weeks ago, the 'brief summary' sections were far from brief, and contained information better kept in other sections. Relevant, sourced information has been kept and moved around, and the lengthy quotes removed as articles are expected to be written in a summary style which does not involve extensive quotations. WLU (talk) 20:30, 2 March 2008 (UTC)

If you look closely at the discussion page, you will see that above where a year ago, a certain Dr. Holland lamented: ......... "Why is there such an odd balance in this article?"........."Anyone have an idea why the pharmacology of this drug gets so little emphasis, while a rare brain disease and return to market get such big play in the article?" This led to my revisions, and to the revisions of others.

Well I certainly had no "Praise" nor "Condemnation" quoted, nor any Soap-Box material - maybe in some section (because then as now, the History paragraphs are inappropriate), someone else had. But you also removed a quotation that I had taken from the FDA-approved MS label (a public document, not copy-righted), which directly addressed Pharmacology which the good doctor sought - if you wanted to remove that, why didn't you at least keep shorter quotations, or paraphrase it, instead of entirely removing it ?

The result is that the page is now more or less back to where it was last July when the doctor regretted the distorted content - the page is now 50% devoted to its History, and reads more like a Media story.

Also, to answer my original question, please explain why you removed the sections titled "Summary of Clinical Trial Results in MS" and "Summary of Clinical Trial Results in Crohns" - these were in no way "Praise" nor "Condemnation" nor Quotations nor Soap-Box material but FACTS. You say that this material was "far from brief, and contained information better kept in other sections" - what other sections did you have in mind ? And what could be more relevant here ? These sections should be restored.

I also think it reasonable for you to explain why, in your edit descriptions, you appeared to have attempted to cover your tracks - as these descriptions (referrring to your removal of SPAM and failing to mention the removal of at least 3 whole Sections) in no way reflect what you were really doing.io-io (talk) 23:21, 2 March 2008 (UTC)

Have you seen the indications sections on the extant page? If you think the history section is over-long, you can certainly shorten it. Unfortunately that is where much of the information was placed for lack of a better location and I'm not certain it is the best portrayal. If you have expertise and can cite reliable sources to verify claims, then feel free to trim, expand or cite information. I had brought the page to the attention of two admins, TimVickers and Jfdwolff, a biochemist and doctor respectively, and they did not see fit to alter or revert my changes. But feel free to edit the page. One thing to note would be medical manual of style section on drugs. One of my larger edits was to re-work the page to conform with the style guidelines there. Substantial revisions to pages that are relatively new or underdeveloped are pretty normal, but regards the change in headings and locations, this should be relatively fixed. Contents, of course, are still fair game. Note that WP:MEDRS are also a guideline to keep in mind - best sources are peer-reviewed journals. I don't know bow comfortable I would be adding large amounts of information on efficacy, benefits, etc. direct from the company's page, I'd stick to pubmed journals were it I. WLU (talk) 23:31, 2 March 2008 (UTC)

I have certainly seen the Indications section. These clinical trial results were most interesting as there are avalable established if inferior to at best equally effective medicines available in both indications, and in particularily in MS the results are considered astonishing. You have not answered my question as to where the "information better kept in other sections" was intended to be placed. You ask me if I have expertise and can cite reliable sources to verify claims - yet I used multiple medical citations and I dont believe I made any "claims" ? And why not use your expertise (I assume you have some, to touch the page) to at least paraphrase the FDA citation, instead of the wholesale deletion ? In doing so you simply ignore the prior Discussion on this page. Also, this was not the "company information" which you ascribe my writing to - the FDA label is a public government source, the actual medical label.io-io (talk) 00:04, 3 March 2008 (UTC)

The major problem with the old version of this article was the long quotations, which are not a good way of referring to source material. Have a look at the articles on Anabolic steroid or Paracetamol to see the kind of format this article needs to aim for. Tim Vickers (talk) 00:18, 3 March 2008 (UTC)

The "long quotations" cited by WLU is a Red Herring. The removed whole sections, titled "Summary of Clinical Trial Results in MS" and "Summary of Clinical Trial Results in Crohns" had ZERO quotations. They did have medical citations however.

The Clinical Trial Results are also what has distinguished Natalizumab, nothing else, and "formatting needs" while important, should come in second to content. Such needs do not imply that whole sections of relevant material should be deleted. I repeat, these sections should be restored.

And these deletions were without no notice to the recent author(s), no advance entry on the Discussion page, and with completely inaccurate descriptions of the Edits in the Edit History. "SPAM" indeed......io-io (talk) 00:48, 3 March 2008 (UTC)

IO, please assume good faith. I have over 18 months on the project and nearly 20K worth of edits - I'm here to help wikipedia, not to piss you off. If I have removed references, then feel free to replace them in the appropriate section in a summary style. The page needed to be significantly re-worked. Which I did. You are a new editor, with only 86 edits at this point - assume that you are not familiar with the manual of style and the myriad other policies and guidelines which determine what wikipedia will look like to readers and how editors edit. By my reading of the page, I may have removed two reference to the Elan webpage, justifying the items "Natalizumab treatment significantly increases the proportion of disease-free patients with multiple sclerosis" and "As of late December 2007, more than 21,000 MS patients were receiving natalizumab mono-therapy without a single incidence of PML occurrence". I would say these statements are quite strong ones to be justified by the company's website, they seem to push the idea that N is a safe drug (tenuous, better stated by a peer-reviewed journal) and generally don't add much good information to the page. Regards the rest of the references in those two sections, I kept them, and in one case made it much better through a citation template with a pubmed number allowing access to the abstract. As for long quotations, consider here (five sentences of quotations, easily summarized) and here (two full paragraphs). Those are long quotations I rewrote as prose.

Please discuss contributions, not contributors, and if you really think I have a specific agenda, feel free to bring it up at WP:AN/I to see what the community's administrators think. WLU (talk) 11:42, 3 March 2008 (UTC)

WLU, you say that I discuss a contributor, but where? I have a lot to say, but think have you any idea how long it took to put all my work together, with all the research needed for those citations? When I first asked you, in good faith, if you had made these deletions, your very first response (see above) was to "Have a look at WP:SOAP" and to caution me about “praise”. AND - you refer me to Wiki's “myriad other policies”. But such policies include 1) Airing concerns on Discussion pages; 2) Reading the Discussions page to see prior concerns; 3) Glancing at the Edit History before deletions to reveal who has done what, and how recently; 4) Showing respect for the Wiki contributions and the opinions of others; 5) Accurately describing edits.

When you say that you “may have removed references to the Elan webpage”, those references are news releases from not 1 but 2 companies (Biogen also) - but more importantly describe brand new Presentations to major MS conferences (e.g. read the one you listed above, it was presented on “October 13, 2007 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Prague, Czech Republic”). Such demonstrations will not be available in medical journals for perhaps a year or more, but are highly relevant TODAY because MS patients (and who else is this page for?) NOW have to ascertain the drug’s benefits amidst all the media “noise”, and it is time-critical for these patients.

As to the statement by both Elan and Biogen-Idec that 21,000+ patients are on drug without PML – how can they possibly lie ? There is a FDA-mandated registry of patients, there can be no lie. Furthermore, it is contemporary, and MS patients need to know - plus how could it possibly appear in any medical journal ? - only the first new case of PML case will ! ....As to the quoted FDA mechanism of action that you “summarized”, well you summarized so much as to eliminate the real content, and contrary to Dr. Holland’s prior lament on this page. I read Wiki policy on quotations, and it made an exception for public policy documents. If you really wanted to summarize material, then why did you create the enormous History section, over 50% of the page, and which leads off like a media piece on the PML scare ?

In the history of modern medicine, are you aware that there has only been one drug ever withdrawn and successfully returned to general availability? That drug is N. If you google for it, you will immediately see the PML shadow everywhere, a soap-opera darling of the media. An example – quotations (not placed by me) defining the FDA’s recommendations clarifying that N is actually NOT limited to 2nd-line use (following interferons, etc) – have been deleted. This was in fact highly relevant, as very few MS patients and even some doctors are not aware of it......In summary, instead of being informative to MS Patients and even to MS Doctors, this Wiki page has degenerated to something not much better than a media soap. The reader is immediately directed to the Drug’s History, due to it’s vast size, as if relevant - and all at the expense of useful contemporary information.....io-io (talk) 14:36, 4 March 2008 (UTC)

(redacted) Edit the page then, and forward future complaints to Wolff who is far better qualified to judge their merit. You do not need my approval to change the page so feel free to do so. WLU (talk) 15:18, 4 March 2008 (UTC)

WLU, please WP:CIVIL. I have explained to this editor on my talkpage that some of the content may be suitable for reinsertion but integrated with the present outline and with an emphasis on secondary sources and professional guidelines.

In the USA, it is now approvied for Crohn's - doi:10.1172/JCI35179 JFW | T@lk 15:20, 4 March 2008 (UTC)

The approval for Crohn's is on N's FDA label, previously cited.io-io (talk) 03:29, 5 March 2008 (UTC)

These were the changes I made. Tim Vickers (talk) 01:12, 5 March 2008 (UTC)

Because Dr. Holland had earlier asked for more pharmacology, I had introduced the long quotes from the FDA label, as obviously this is an unimpeachable source. I would propose to restore those quotes, and perhaps someone with specialized skills will properly summarize them. Good/Bad ?io-io (talk) 03:29, 5 March 2008 (UTC)

That depends on the quotes. If it's this set, I see no need as it's already summarized in the MS section, references 3, 4, 5 and 6. Two sentences I did remove I discuss above - in my mind they look like apologetic from the drug company, add little to the page beyond the promotion of the drug, and are better sourced to journals than a company web page. That being said, if other editors have no problem with it, I am willing to be over-ruled. If it's this section, the first reference is used again in the current pharmacokinetics section (possibly not the right place, I believe I put it there and if so, I did so because I wasn't sure where to put it). The second, much longer quotation appears to have been removed wholesale, but it could definitely be replaced (the reference is used again in history as reference 18). I see no need to replace the quotations, but the information contained does look valuable, but far above my ability to understand and summarize. Perhaps Io, Tim or Wolff could do so but I think me doing it significantly risks misrepresentation or errors. The sole remaining quotes are for reference 18 in the old page, now reference 8, and though it could be expanded with more detail, I don't see a reason to quote. Reference 23 old is now 18, and again I don't see a reason to quote as the summary covers the same information. I agree that the information should be restored, but as a summary rather than a quote. I may have a crack at it anyway, but I could miss out on significant details. WLU (talk) 18:53, 5 March 2008 (UTC)

Done. Someone (or several someones) please, please, please PLEASE review for accuracy! WLU (talk) 19:56, 5 March 2008 (UTC)

It is an improvement, and your summaries of the pharmacokinetics look very good. These are in fact the quotes I was referring to, along the lines the Dr. had asked. But I ask this philosophical question: this is "only" Wikipedia, and should we not realize that quotes taken directly from unimpeachable and authoritive sources carry more weight to those who need to know than para-phrases by mere mortals ? This is not one of the same situations which the Wiki policy on quotes was meant to address, and is particularily true here because of the media mill-stone the drug carries, and patients are looking for clarity, and fear obfuscation. For example, there is a black box label, the very existence of which which will tend to confirm the well-known fears, but when its text is actually read, it is far milder in it's content.

As to the this set, I disagree, as I explained earlier here, these are news releases that refer to posters/presentations made to the top specialized medical conferences. I do not see providing such useful information to curious patients as adding "little to the page beyond the promotion of the drug". Instead, go to the very top of the Wiki page, very first paragraph, describing how the drug has been, when used with another durg, "linked" to a rare disease - is that useful or even relevant, given that the program prevents use with any such drug? Also the words "appeared to" should not be used when it is clear that in the abstract/release that the p-values were convincing on secondary endpoints, given that primary endpoints were met. Instead "demonstrated" or similar is appropriate....I will look further at other edits later this week.....io-io (talk) 02:31, 6 March 2008 (UTC)

1) WP:SS

2) I see it as promotion and adding little of merit to the page. Ask other contributors what they think. The info in the lead about PML is definitely prominent enough to remain in my mind. The page is not a how to manual, it's meant to be an encyclopedia, so conveying notable information. Lots of reporting in peer reviewed journals means notable. WLU (talk) 12:54, 6 March 2008 (UTC)

As to WP:SS - I believe that content supercedes style, and I think that my philosphical question is a very good one, as an encylopedia should inform its likely readership. I did think your paraphrases were also very good, but I ask which is this the best approach....I would welcome independent answers to the question.

Also, by the same standard, the things you call promotion are, as I said, presentations to medical conferences on the pivotal trial secondary or tertiary endpoints. What is particularly relevant to RRMS patients is that after going on an Interferon or Copaxone they have no idea while they wait-and-see for 6 to 24 months whether their drug is helping them at all, while their QoL will quickly decline - due the very act of self-injections (up to daily), the almost ubiquitous side-effects of interferons, the inevitable steroids for flares, optical neuritus, etc. No MS therapy has succeeded in these sypmtomatic benefits the way that N has. I suggest a search on YouTube might be revealing.

I dont know about "Lots of reporting in peer reviewed journals" - if so, it was about the same tiny number of cases. You are applying Wiki standards selectively here. May I direct you to - http://wiki.riteme.site/wiki/List_of_bestselling_drugs - can you show me just ONE drug treating a serious progressive disease for which the Wiki, in its introductory words, has your standard of profiling potentially fatal AEs? Or choose from the PML page - http://wiki.riteme.site/wiki/Progressive_multifocal_leukoencephalopathy, which you yourself have editted to actually duplicate N's listing as a cause, and reveal application of the same standard? Based on this and your other edits, I really have to suggest that your thinking is conflicted as to this Wiki page, and I think achieving a balanced informative page is a long way off while this persists.io-io (talk) 00:52, 7 March 2008 (UTC)

I think I'm going to give my opinion. First of all I do think that wikipedia is an encyclopedia for any reader, and it should be writted according to it. In any encylopedia some entries would be visited more often by those interesested in it, such as people with the disease, however this page can also be visited by medical students, friends, other health workers, or simply a fourteen year old boy who has been asked to do a school project in MS, so information should be directed to the general reader as stated in WP:MOS. Secondly I do think that conferences refs are of course of less quality than peer-reviewed jounals, and the latter should be always preferred if possible, as in any peer-review jounal. However there are times where there are not yet any peer-review jounal and official conferences or workshops are the best reference possible at that time. In most peer-review articles you can find one or two refs of this kind. Finally regardig PML I agree that is important, but not as important as to center the main discussion of the lead. Its an important (even deathly) secondary effect, but an intoxication with most medical-drugs can also be if indications are not followed and its rarely given any importance. It clearly should be discussed in the article but at most it should only be mentioned in the lead when it is a clear summary of the whole article so it does not receive an excesive weight. --Garrondo (talk) 08:14, 7 March 2008 (UTC)

In reponse : 1) I would think that everyone down to the school students would be more interested in what N can do for MS itself. 2) As to the relevance of PML, the FDA's Black Box label states: "Although the cases of PML were limited to patients with recent or concomitant exposure to immunomodulators or immunosuppressants, there were too few cases to rule out the possibility that PML may occur with TYSABRI monotherapy" - hardly an indictment to merit mention in the opening words of either the History section or the Wiki Page itself. 3) As to "excessive weight" I submit that, in the Page, the words -

• "progressive multifocal leukoencephalopathy" are spelt out 3 times;
• "PML" is spelled out independently an additional 8 times

-while in terms of what N does for MS, in the entire Page, the words -

• "lesions" is mentioned Once (and only in the M-o-A section).
• "relapses" is mentioned Twice
• "disability" is mentioned Once

I ask - is this not gross imbalance? Shouldn't it be reversed???....io-io (talk) 22:46, 7 March 2008 (UTC)

Balance

Regarding the complaint that the present article overemphasizes the PML problems at the expense of reporting the clinical benefits of the drug against MS, I do have one suggestion. The paragraph at Natalizumab#Multiple_sclerosis is extremely short. It would not be out of line to explain for general readers what would be the impact of Natalizumab on MS treatment if the clinical results hold up. Even our longer account over at Multiple_sclerosis#Disease_modifying_treatments gives me the impression that Natalizumab and the similar drugs are disappointing and may not be worth the expense or trouble. Is this a reasonable conclusion?

I hope this doesn't re-ignite a general debate, I was just looking for a vague two- or three-sentence bottom line, one that is independent of the genuine uncertainties as to whether the benefits and side-effects are well-enough studied yet. All that I can tell from Natalizumab#Multiple sclerosis is that some measure is cut by 68% and some other measure is reduced by 50%. Is this significant? And I support the others above who prefer that this kind of conclusion not be drawn from drug company material. EdJohnston (talk) 23:51, 7 March 2008 (UTC)

In terms of clinical benefit, you are essentially echoing what I have been protesting here. Attempts to say more have been termed "promotional of the drug". The benefits are indeed well-studied, as the sum of clinical trials leading up to approval 2 years ago were in excess of 3,000 MS patients, easily the largest ever.

The reference to "drug company material" is actually a couple of news releases that report on posters and/or oral presentations at medical conferences of the pivotal trials' secondary and tertiary endpoints, and if you scroll up, you will see why these achievements are unique to N and relevant to MS patients.

Finally, to get back to clinical benefit, here are two opportunities - on the Talk page - http://wiki.riteme.site/wiki/Talk:Treatment_of_multiple_sclerosis#Relative_effectiveness - there is collaboration ongoing for a DMD relative efficacy table in MS; ....while in the Treatement of Crohn's page - http://wiki.riteme.site/wiki/Treatment_of_Crohn%27s_disease - Natalizumab is erroneously only mentioned under the "Medications in Research" section, and where its future seems in doubt due to the PML cloud (in fact it is now approved it for Crohns).....io-io (talk) 00:36, 8 March 2008 (UTC)

Isn't there some medical review article that might give perspective? Even if it were just an editorial in a medical journal, written by a practitioner, it might help. I took a look at the proposed table you mentioned, but didn't find it terribly convincing. The current summary paragraph over at Treatment of multiple sclerosis may be the best we can reasonably do:

All six medications are modestly effective at decreasing the number of attacks and slowing progression to disability, although they differ in their efficacy rate and studies of their long-term effects are still lacking.[19][20][21][22] The percentage of non-responsive patients to each medication also varies; being around 30% with interferons.[23] Comparisons between immunomodulators (all but mitoxantrone) show that the most effective is natalizumab.[24] Mitoxantrone is probably the most effective of them all in the short term;[25] however, its use is limited by severe cardiotoxicity[26], and it is not considered as a long-term therapy. This is the reason why it is mainly used to treat patients who have advanced relapsing-remitting or secondary progressive multiple sclerosis.

Unless we can find a medical review that has a nice two- to five-sentence summary of the clinical benefit, perhaps we need to stick with what we have now. EdJohnston (talk) 04:38, 9 March 2008 (UTC)

It is a complex area. It is complicated by the fact that within RRMS many patients have near-benign disease, whereas others progress very quickly. The older drugs did pass their trials, and do have milder benefits (relative to N - but even this is not definitively proven, as the PML issue abruptly terminated head-to-head trials), but in the summation of all RRMS trials, neither the Interferons ( http://www.ncbi.nlm.nih.gov/pubmed/12598138?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1 ) nor Copaxone ( http://www.ncbi.nlm.nih.gov/pubmed/14974077?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1 ) - look much good. Still, it is easier to look backwards at older drugs, as more is known about both efficacy and safety. For N, in terms of safety, probably for some doctors the jury is still out until 12 months from now. So that summary of benefits (and risk-reward) is not written yet. Doctors and patients simply need to know the real (as opposed to the celebrated) Risks and the real Rewards as best the data can tell. One indicator is that the FDA and EMEA still allow placebo-controlled trials in MS (unlike other very serious diseases, it is not considered unethical to give patients no DMD at all for 2 full years). That proposed table you mentioned is improving with the contributions of others, and I have found more data for insertion soon. Perhaps you can comment over there on what else could be done, before its insertion....io-io (talk) 05:15, 9 March 2008 (UTC)

Liver toxicity

In the tysabri pamphlet, the issue of liver toxicity is raised on page 7, section 5.5. It includes the words "In some patients, liver injury recurred upon rechallenge, providing evidence that TYSABRI caused the injury." Given that, I think the statement about liver injury occurring with placebo patients is not the best way to deal with liver toxicity. I also don't like the line "Furthermore, the rates of liver issues are higher in the interferon drugs, such as Avonex and Rebif, and have led to liver failure and transplantation.[1]" as it looks to me like it is saying 'natalizumab isn't as bad and should be used because the alternatives are worse.' The Tysabri pamphlet doesn't mention Avonex in combination with liver issues, or Rebif at all, making this WP:SYNTHy to me. The Primetherapeutics page doesn't discuss natalizumab at all, and in my opinion it is original research to make any judgment or comparison, explicitly or implicitly, between the three drugs without a reference. I've edited accordingly. WLU (talk) 00:22, 10 March 2008 (UTC)

I think your statement that "The removal, then reinstatement of natalizumab resulted in the disappearance, then reappearance of liver injury...." is one that will nver be understood. As to your references to WP:SYNTH and/or "comparison, explicitly or implicitly, between the three drugs without a reference", etc - well then -

(1) The The Primetherapeutics page - of course it doesn't discuss natalizumab at all because it specifically addresses very serious Liver damage requiring transplantions in both Avonex & Rebif, something that has never happend to natalizumab, even now, 3 years later

(2) Here is such a reference - on the top of page 8 of http://www.fda.gov/cder/foi/label/2003/ifnbser050203LB.pdf - you can read that in just 48 weeks hepatic function disorders occurred in 18% Rebif and 10% of Avonex patients. On the other hand, I had referred to the natalizumab label describing 5% vs 4% for the same issue - and occurring over a much longer period of 120 weeks.

(3) It is also well-known in the MS community that failure to interferons due to Liver toxicity is epidemic. I am not bothered to find a source....io-io (talk) 01:26, 10 March 2008 (UTC)

I've reworded to avoid a direct quote, but I believe the reword captures the original intent. WLU (talk) 12:00, 11 March 2008 (UTC)

I note that you are quite willing to use a direct quote when it aligns with your "original intent". The fact is that your treatement of this issue leaves a whole section whose size is out of all proportion to it's medical relevance, as I have explained above - the entire issue could be dropped to a foot-note....io-io (talk) 00:39, 12 March 2008 (UTC)

addendum - here is Wiki precedent, as it has been proven to you above it is far more common in interferons, and you can see in http://wiki.riteme.site/wiki/Interferon_beta-1a how it is handled....io-io (talk) 00:47, 12 March 2008 (UTC)

Refs 5 and 6

References 5 and 6 on the current page ([5] New Data on Natalizumab Demonstrate Significant Improvement in Cognitive Function in Patients With Multiple Sclerosis. Doctor's Guide and [6] New Pharmacoeconomic Data On TYSABRI® Demonstrate Significant Reduction In Steroid Use And Hospitalizations In Patients With Multiple Sclerosis) are sourced to news services. I've looked a bit on pubmed but found nothing published in medically reliable sources that says the same thing, does anyone have citations for these statements? They justify the statements "maintained cognitive function,[5] reduced the use of steroids and hospitalization[6]"; the other statements in the paragraph I tracked down pubmed journals for, but these ones I'm either not looking in the right spot or haven't been reported yet. WLU (talk) 01:01, 10 March 2008 (UTC)

I note you are asking these questions, but also you seem to have already shortened the section, summarily removing the Oct'07 Report to ECTRIMS that N "significantly increases the proportion of disease-free patients with MS". However, this Discussion has received input from others, including Garrondo who has contributed hugely to the Treatment of multiple sclerosis page, recently honored as a Wiki feature, and he has described the fact that sometimes you cannot find a better source. We will have to see if can find better citations for you, so that these secondary clinical trial results in MS symptoms can reach a wider audience, but you have to repect the Discussion. And please don't label a news release as "drug company material" when it clearly describes a poster or presentation at a leading Neurology conference....io-io (talk) 01:59, 10 March 2008 (UTC)

I have found and inserted an additional 4 abstract citations from the AAN (American Association of Neorolgy) annual meeting. On this basis I have restored at least 1 of the proven benfits that you had unilaterally deleted. Also, as no-one has contradicted my previous position stated above that this Wiki Page needs to have some balance restored, I have added bold-face paragraph headings in order to direct the reader to these proven claims of what N definitively prevents and achieves...io-io (talk) 02:53, 10 March 2008 (UTC)

Bold claims are addressed below - balance should be found by expanding sections, not SHOUTING at the reader. WP:MOSBOLD has more information. The lead could also be expanded to place more emphasis on benefits - I have done so, but only for a limited number of improvements (basically the ones I remember, but probably the most significant; though the lead should not enumerate every single benefit the most significant should be there). IO, please note that I am trying to do what I think is best for wikipedia, based on my experience on the project. I am not trying to smear or worsen the name of natalizumab. Please assume good faith that I am doing the best I can. I understand parity of sources; lacking a pubmed journal a conference presentation or publication from the drug's producer is adequate. But if such a journal is available, it is a superior source that I would prefer to cite, per WP:MEDRS. WLU (talk) 11:58, 11 March 2008 (UTC)

OK, I will assume good faith. I would point you to the WP:PILLARS and where it says that "Perfection is not required". Also WP:LOP states: "Every policy, guideline or any other rule may be ignored if it hinders improving Wikipedia." Take for example Bupropion, note how it's page departs rigid formatting into various conditions (perceived/symptomatic, and not diseases per se), some for which it is not approved. Also, the issue of how to present these trial results has been "Talked" for a week now, and two other informal WP:3O have come down on the side of more information about what N does, than what was presented hereto.....(separate issue: I believe now that, out of the 7 or 8 medical presentations, only 1 is uniquely sourced from a company news release)....io-io (talk) 00:20, 12 March 2008 (UTC)

addendum - earlier, I had proposed bullet-points below...would do later...io-io (talk) 00:23, 12 March 2008 (UTC)

Manual of style (further comments from WLU)

Acknowledging comments just received from WLU on my Talk page, and I believe the appropriate place for them is here as the Discussion is daily ongoing:

" Please review MOS:CAPS (in particular Wikipedia:Manual_of_Style_(capital_letters)#Section_headings) and WP:HEAD for restrictions and formatting of capital letters and section headings on wikipedia "

I will review and address later ....input welcome of course from others on all topics....io-io (talk) 23:41, 10 March 2008 (UTC)

Addressed the issue of capital letters in the sub-section headings...io-io (talk) 00:34, 11 March 2008 (UTC)

Per WP:ITALICS and WP:MOSBOLD, I've removed the use of italics and bold where not necessary. I've also collapsed the number of subheadings in the MS section to a single sentence listing the effects of N on MS patients (per WP:UNDUE, giving each its own section places excessive emphasis on each finding when there's no real need to have a sub-section for every single effect), re-wrote to avoid quotation, re-added the information on antibodies (as it's referenced in a peer-reviewed journal and a valid inclusion on the page), added the mechanism of action and the mention of its withdrawal and re-approval to the lead per WP:LEAD. The lead should summarize the main information in the body text below proportionate to the coverage in the body, and I think I've captured the sub-headings and contents appropriately. Please note that citation templates are used extensively in the referencing; {{cite web}} should be used when it is a web-based link only, there are also {{cite journal}} when published in a peer-reviewed journal and {{cite conference}} for conferences. I am not against information that supports the effectiveness of natalizumab, but the page should be encyclopedic - all information that can be included, should be included. Give me references about N being good or bad, I'll add both. Most of these changes are to standardize the page against other wikipages and primarily against the manual of style. Given this is a publicly editable encyclopedia, the only touchstones we have for uniform formatting are the MOS, policies and guidelines and that is what I try to edit by. Please let me know if I have made any errors per these guidelines. WLU (talk) 11:48, 11 March 2008 (UTC)

Others in the Discussion have pleaded that above all else, what the drug actually does, should be clear. That has been the problem. I have no time now, but propose bullet-points....io-io (talk) 18:53, 11 March 2008 (UTC)

What do you believe is missing? I have edited the lead twice (MS and CD) to show the benefits to those diseases, given a reference or specific suggestion, I could add more. WLU (talk) 18:56, 11 March 2008 (UTC)

What is missing is the clarity - these are the results that distinguish it in MS; these are what patients (and doctors, even from a technical sense, because symptom improvement is a reasonably reliably surrogate that the drug is working clinically) need to see, above all else, on the Page - this would be a Wiki improvement as I described in talk-section above, and that is why I propose bullet-points...io-io (talk) 00:27, 12 March 2008 (UTC)

Unpresented conference

The current reference 4, [2], is to a conference poster that has not yet happened (note the date is for April 15th, 2008). Is this normal? Is this kosher? I understand that research is done months in advance of publication and I've always been confused by the {{cite conference}} template and would love some informed opinions on this. WLU (talk) 15:50, 11 March 2008 (UTC)

"Is this normal? Is this kosher? " - Its normal that abstracts get published based in advance upon the paper. The asbtract is a fact now, the presentation is a scheduled fact, and nothing else is really relevant...io-io (talk) 18:56, 11 March 2008 (UTC)

Here - http://wiki.riteme.site/w/index.php?title=Natalizumab&diff=197490362&oldid=197486843 - which your edit descritption lists as "adding a conference citation" - there are now 1 less proven N benefit with conference citation than before, because deleted is "(N has been shown to)... reduce the severity of MS, "? (found here - http://www.abstracts2view.com/aan2008chicago/index.php - if needed to verify). Would assume accidental, but if not, please provide justification....io_editor (talk) 17:11, 23 March 2008 (UTC)

How to standardize our reporting of negative effects in drug articles

WLU has again added, in the introductory words, a slice of history about N's link with "death", despite that:

• Its just a putative link (as confirmed by the FDA Black Box wording)
• The fact that N is used in treatement conditions different to the fatal circumstances
• There is a separate sections on Page dealing with Adverse Events
• There is a separate sections on Page dealing with ContraIndications
• There is a separate sections on Page dealing with History

This is what I wrote previously, unanswered: "You are applying Wiki standards selectively here. May I direct you to - http://wiki.riteme.site/wiki/List_of_bestselling_drugs - can you show me just ONE drug treating a serious progressive disease for which the Wiki, in its introductory words, has your standard of profiling potentially fatal AEs?" For example, look at http://wiki.riteme.site/wiki/Trastuzumab, it is very hard even to spot the safety concern ANYWHERE on the page. "Or choose from the PML page - http://wiki.riteme.site/wiki/Progressive_multifocal_leukoencephalopathy, which you yourself have editted to actually duplicate N's listing as a cause, and reveal application of the same standard?" For example, look at http://wiki.riteme.site/wiki/Infliximab, which has a long list of safety concerns, many deadly, and none appear in the introduction.

Several months ago a doctor here decried the "Odd Imbalance" on this page. When will it achieve balance ? ........io-io (talk) 01:04, 12 March 2008 (UTC)

If the fatalities in infliximab were responsible for the drug being withdrawn, then replaced on the market, perhaps it should be in the lead. I will look into it tomorrow.

Why was natalizumab withdrawn from the market? Was it because of the association with death? Am I mis-representing the reason for withdrawal?

Please comment on edits, not the editor. WLU (talk) 01:15, 12 March 2008 (UTC)

I made ZERO comments about the editor above.

I did not say you were "mis-representing the reason for withdrawal", but I say you are consistently descerating the page by repeating safety issues in FOUR (4) different sections (introductory words, interactions, contraindications, and history) - all without precedent on Wiki - while at the same time minimizing the perception that this is a medical advance by subordinating the proven benfits to a difficult-to-read paragraph - and despite the WP:3O's offered on this Talk page...io-io (talk) 01:53, 12 March 2008 (UTC)

Note the title: Continued objection to WLU's arbitrary and selective "standards"

And the first line: WLU has again...

Compare with: "I believe the emphasis placed on PML-related deaths on the page is excessive." Or, instead of blaming everything on me, edit the page and suggest alternatives. The information should appear in the lead. The lead summarizes all information of note in the page below. Death or fatalities are mentioned as follows: in the lead (appropriate given the use below); in contraindications as a sequelae of poor liver function; in interactions in conjunction with PML; twice in history - once to say it was linked with PML, once to say no deaths have occurred when used as monotherapy. Which do you feel is inappropriate or excessive? WLU (talk) 10:27, 12 March 2008 (UTC)

Of course the fact that is you who is doing this is relevant, because you have been writing, reading, and ignoring on this Talk page for 10 days now.

I had already editted the page, in January and last weekend, but you have essentially reverted both edits.

It takes you 5 lines on this Talk page even to LIST where your you have added the fatality tags. I gave you links for comparable drugs - these prove your focus is "inappropriate" and "excessive", and yet these are the Wiki standards/precedents that apply here.......io-io (talk) 13:54, 12 March 2008 (UTC)

I'm generally not finding the talk page particularly useful. For instance, I don't really have much to say in response to your above comments as you seem to be complaining about me, rather than the page itself. In cases where I found value in your comments, I have edited accordingly. You thought insufficient weight was placed on the benefits of natalizumab to MS and CD. I altered the lead. You thought extensive quotes were necessary for the mechanism of action. I reviewed, paraphrased, wikilinked and referenced the section. Is there anything else you think requires a change? Are there any sources you think require beter representation? Every minute I take to read and reply on the talk page is time away from this main page, and other wikipedia pages I could be working on. Accordingly, I try to respond parsimoniously. With no new references or specific suggestions, I don't edit. And I think I'm doing a pretty fucking good job of holding back my temper considering you are consistently accusing me of having an agenda and being responsible for making the page worse, when all I am doing is attempting to improve the page in keeping with wikipedia's policies and guidelines. WLU (talk) 14:07, 12 March 2008 (UTC)

OK, will everyone please relax? I was honestly surprised at how little emphasis is currently given to PML in the article, as the PML "scare" or whatever you'd like to call it was very notable, having caused quite a stir in both the medical and lay press (as did the later campaigning by folks with MS to get natalizumab back on the market). The notability of this event in the "universe" of natalizumab, if you will, is more than enough for it to warrant mention in the article and (IMHO) in the lead, regardless of how few cases there were, or how solid or tenuous the causative link is. Io io—for an encyclopedia article, WLU's summary of the drug's mechanism of action is far more appropriate than direct quotes; only very rarely is there a need to cite material verbatim in Wikipedia. Sorry, but I honestly don't see evidence of a COI on WLU's part. There is a wealth of literature on natalizumab, and I'm sure this can become a comprehensive, balanced article. If you don't mind my asking, what exactly about its current state is bothering you (both)? Fvasconcellos (t·c) 22:20, 12 March 2008 (UTC)

Given your comments, I wouldn't mind seeing more emphasis on the PML information - for the history section, popular sources could be appropriate. At minimum, it would also be nice to include all the pubmed journals that discuss the PML fatalities. Aside from that, all I know about natalizumab is what is on the page so I don't need any more suggestions. I'm not familiar with drug pages, so I'm not sure what the standard is. WLU (talk) 22:37, 12 March 2008 (UTC)

When an association (with PML, in this case) is the subject of 3 papers in the New England Journal of Medicine in rapid succession and leads to the temporary withdrawal of a drug from the US market, it's notable and needs to be covered, briefly in the lead and in a more detailed fashion later in the text. For secondary-type sources and reviews, I'd recommend the Cochrane Library be included (PMID 17253580 for Crohn's). Here's a 2006 review article: PMID 17122725 which estimates the incidence at 1 per 1,000 (I think this number is also cited in the Cochrane review). And a 2007 review article from Lancet Neurology: PMID 17434098. The article needs a "adverse effects" section, in line with other pharmaceutical articles. I'd suggest a cup of tea for everyone, a refill of patience and good faith, and a commitment to focusing on the article content rather than each others' alleged foibles. I'm happy to help work on the article. MastCell ^Talk 23:19, 12 March 2008 (UTC)

Thank you for your input, but you are missing the point. NOWHERE have I said that PML should NOT be mentioned, and you can see that from the balanced version that others and myself left behind in January. I was certainly committed to focusing on the article content rather than each others' alleged foibles and am responsible for around 50% of all citations on the page, as well as I believe essentially 100% of what N actually does in MS and CD. I do not believe that WLU has shown any interest in balanced content.

The central issue is that WLU wants to condense (it may have more to do with me than with N, but that should not mean a page gets held hostage) the benefits into a single paragraph and elsewhere litter the page with death-potential - because death-potential is what appears in FOUR (4) different sections.

And this is what I wrote, now for the 3rd time, and I ask you for an answer, just ONE example:

"You are applying Wiki standards selectively here. May I direct you to - http://wiki.riteme.site/wiki/List_of_bestselling_drugs - can you show me just ONE drug treating a serious progressive disease for which the Wiki, in its introductory words, has your standard of profiling potentially fatal AEs? (For example, look at http://wiki.riteme.site/wiki/Trastuzumab, it is very hard even to spot the safety concern ANYWHERE on the page)"

"Or choose from the PML page - http://wiki.riteme.site/wiki/Progressive_multifocal_leukoencephalopathy, which you yourself have editted to actually duplicate N's listing as a cause, and reveal application of the same standard? For example, look at http://wiki.riteme.site/wiki/Infliximab, which has a long list of safety concerns, many deadly, and none appear in the introduction."

- In short...after all my research work, I believe the page should be treated like any other Wiki pharma page.......why is that a problem?.....io-io (talk) 02:26, 13 March 2008 (UTC)

Well, "death-potential" isn't exactly littered across the page. It is mentioned in the lead because the PML cases, and their leading to the drug's withdrawal, were and are notable. It's mentioned in "Interactions" (perhaps correctly, perhaps erroneously) because PML occurred in people taking a combination of natalizumab and interferon, and it's mentioned in "History" for the same reasons as in the lead—the most notable events in the history of natalizumab are arguably its association with PML, the subsequent voluntary withdrawal from market, lobbying my MS patients and groups, and return to market after safety reassessment. How is any of the above mentions unnecessary or sensationalistic?

Answering your question seems fair, but I thought mine was were fair to ask too. It would be totally unprecendented on Wiki that it would be either:

• placed in the page introduction, or
• placed in two or more sections, much less four sections...io-io (talk) 03:49, 13 March 2008 (UTC)

Direct answer - It is both unnecessary and sensationalistic to place it in the introduction or in more than one (or maybe two) section.....io-io (talk) 03:49, 13 March 2008 (UTC)

If there aren't any other noteworthy interactions, perhaps the "Interactions" section could be scrapped, and a dedicated section such as "Progressive multifocal leukoencephalopathy" created as a subheading of "Adverse effects" (which is still lacking). Unless, of course, someone thinks that would be tantamount to creating a "criticism" section? Fvasconcellos (t·c) 02:33, 13 March 2008 (UTC)

Trastuzumab didn't have to be pulled from the market because of adverse effects. The proper comparison, if one is needed, is to other WP articles on drugs that were pulled from the market and then reinstated. I suggest that a quiet discussion doesn't need lots of italics and bold face, and doesn't need Io_io_editor to remind us of how many times he has asserted the same point already. No-one is obliged to answer your questions, but people can be persuaded by good arguments. EdJohnston (talk) 02:53, 13 March 2008 (UTC)

Trastuzumab didnt have to pulled off the market like all the other drugs because the safety signal is so huge that it was seen in the Clinical Trials, where Phase 1 is generally safety, Phase 2 is dose-ranging, and Phase 3 is efficacy (although they are of course all safety trials). In the case of N, it was ONLY when it was used in combination with Avonex did the problem arise, and the patient registry essentially prevents this. Therefore the profiling that you feel especially warranted for N is in fact especially unwarranted, given the facts. I used Bold Face to direct people's attention back to the CONTENT - it was not yelling. In the midst of all this, my questions go to the heart of the matter - why does this page have to be different from all of the other drugs with serious AEs ?....io-io (talk) 03:43, 13 March 2008 (UTC)

Please correct me if I am wrong, but it appears that one editor does not believe that PML should be mentioned in the summary, whereas the remainder think that it is acceptable. It appears, then, that the general consensus is that PML may be mentioned in the summary. Both sides have raised points in an effort to persuade, and it appears that the dissent has not been able to persuade the others. My $0.02. (Note: I'm not neutral here - I think that it's perfectly fine to mention PML in the summary - but I hope this is an accurate and neutral statement of the way things are, regardless of how one feels they should be.) Antelan ^talk 04:03, 13 March 2008 (UTC)

I think that's an accurate summary. I am strongly opposed to fear-mongering and pharmanoia in our articles, but the fact is that the article lead needs to briefly summarize all relevant aspects of the subject. The fact that natalizumab was pulled from the market in response to a small but high-profile series of events and then reinstated is demonstrably one of the most notable and relevant aspects of the subject. Any reader with any sort of knowledge of the topic would be surprised, I think, if it were not mentioned in the lead. MastCell ^Talk 05:47, 13 March 2008 (UTC)

Exactly. Fvasconcellos (t·c) 13:26, 13 March 2008 (UTC)

That is a completely inaccurate summary. Please focus on content. See my January revisions: http://wiki.riteme.site/w/index.php?title=Natalizumab&diff=186467429&oldid=186248003 - and my revisions in March - http://wiki.riteme.site/w/index.php?title=Natalizumab&diff=197370088&oldid=197269340 - nowhere did I remove all mention of PML. The issue is barely relevant today because the patient registry prevents "over-dosing" with N & Avonex combination. It is historically notable and journalistically notable, but not encyclopedically notable, or even medically notable to merit a prfoiling beyond that of other drugs that have more clearer links to PML (it is not even mentioned in infliximab despite dozens of PML cases). Approximately half of MS patients have cognitive impairment, which impairs deductive reasoning and assessment of risk-reward benefit; furthermore they are regularly dosed with a small pharmacy of drugs for pain, spasticity, depression, etc, all with side-effect "issues", and the "fear-mongering and pharmanoia" which you are opposed to is exactly what this article will propagate.....io-io (talk) 14:21, 13 March 2008 (UTC)

I agree with MastCell's assessment, though I think the above view of the current "dispute" is a tad narrow (no offense, Antelan :). Personally, I believe this issue is historically notable, journalistically notable, and encyclopedically notable. If infliximab has been associated with PML, then that should be mentioned in its article as well. Natalizumab is indeed a special case. Fvasconcellos (t·c) 15:35, 13 March 2008 (UTC)

None taken! Antelan ^talk 15:58, 13 March 2008 (UTC)

I do not claim the PML issue is not encyclopedically notable; indeed it is, and medically notable too - but just not enough to merit a profiling beyond that of other drugs on Wiki that have more clearer links to PML (why it was pulled from the market was more to do with a sudden problem of unknown dimensions coinciding with enormous perscription demand - especially as a severe MS relapse is not very distinct from PML). Indeed drugs that are causing PML today, because its worth trying in each individual patient....io-io (talk) 17:05, 13 March 2008 (UTC)

I've been dealing with this for a while and have pretty much hit my limit. Could others handle this and I could keep my involvement to a minimum? WLU (talk) 10:38, 13 March 2008 (UTC)

Given the consensus that exists, I believe we can now work on phrasing rather than debating whether or not this content belongs. WLU, would you be interested in sticking around for that? Antelan ^talk 15:58, 13 March 2008 (UTC)

Thank you for assisting, but this is enormously important. I expect far more people will come to the N page that need real information, rather than being just curious about fading history. Furthermore, local newspaper journalists across the country and world are held to low standards and are always looking for ready-to-go sources, and this is one of the places where they will come.

No-one has explained to me why this should be the first pharma page on Wiki which included mention of safety issues in the introduction...do you call that consensus?...Those other pharma pages were written by Wiki editors too, their work are de-facto Wiki opinions on how a pharma page should look like....io-io (talk) 17:05, 13 March 2008 (UTC)

Io io, Bupropion and Clindamycin (a Featured article and Good article respectively) mention notable safety concerns prominently in the lead. I'm sure dozens, if not hundreds, more pharma pages do so as well. Fvasconcellos (t·c) 17:56, 13 March 2008 (UTC)

Antelan - so long as I'm not the sole editor and discussant on the talk page, yes.

Io - please refer to policy and guidelines rather than other pages. This is a publically editable encyclopedia. Anyone with an IP address can edit. Which means policy is our touchstone, not examples from other pages (because oversight may be nonexistent, and there's no guarantee anyone writing the page has read the policies or guidelines). The exception is featured articles, but even they are suspect. Also note WP:CONSENSUS, WP:UCS and WP:MEDMOS (which incidentally, places history at the top for drugs. In addition, as has been mention before the lead should summarize the article below (see WP:LEAD). The approval, then withdrawal, then re-approval is a notable part of natalizumab's history. The deaths due to PML are notable. The coverage of both of these in the most reliable sources we have are also notable. Why would the PML link not be mentioned in the lead? WLU (talk) 17:14, 13 March 2008 (UTC)

WLU - contrary to what you continue to selectively lecture me on, the WP:5P clearly states that the written letter of all policies and guidelines are set aside when the issue is IMPROVING the page. And like it or not, this is the issue; this has always been the issue.....io-io (talk) 23:27, 13 March 2008 (UTC)

← Every drug article should include highly notable safety issues and side effects in the lead. If others don't, we should improve those instead of using them to justify a substandard lead on this one. In this case, the safety issues were the subject of 3 reports in the New England Journal of Medicine, as well as coverage in the major mainstream media ([3], which we should work into the "History" section). It was withdrawn from the market by FDA, which puts it in the company of a relative handful of other agents, though it has since been reinstated with more stringent informed-consent and monitoring guidelines and a PML registry - somewhat analagous to thalidomide or clozapine, and note that both of those articles cover the relevant safety issues in the lead. Surely between the group of us we can manage to describe what's known (and unknown) about the safety of this drug in an informative way which avoids both minimzation and scare-mongering? We're all rational people. Not sure if this is here or there, but one of the three patients who died of PML in the trials turned out to have no evidence of MS at autopsy, and was apparently misdiagnosed on clinical grounds, which is a whole other issue and probably outside the scope of this article (PMID 16517256). MastCell ^Talk 18:26, 13 March 2008 (UTC)

Only 2 patients died of PML, 1 in the MS trials, and 1 several years prior in the Crohns trials (confirmed only by autopsy, and for which infliximab is also highly suspect, as it has many PML deaths). And yes, only AFTER the doctors wrote their career case-study in the NEJM paper, letters-to-the-editor arrived remarking that their patient appeared to have never had MS at all, but had been mis-diagnosed from the outset(!!!) ...this was generally accepted by the FDA in the later Crohn's hearings (and I can find a reference if you want, it was embarassing of course)...yes in fact no MS patient ever died at all, bizarre as it may seem...io-io (talk) 23:27, 13 March 2008 (UTC)

Yes, this is a good starting point. We can improve this article, and then use it as a model for improving the other articles that lack adequate reporting of highly notable safety issues. Antelan ^talk 18:54, 13 March 2008 (UTC)

Thank you but in repeating myself I started to abbrevaite. Originally I did not say "every" pharma drug. What I wrote last weeek and this week was this, and I have to highlight the relevant words:

May I direct you to - http://wiki.riteme.site/wiki/List_of_bestselling_drugs - can you show me just ONE drug treating a serious progressive disease for which the Wiki, in its introductory words, has your standard of profiling potentially fatal AEs? Or choose from the PML page - http://wiki.riteme.site/wiki/Progressive_multifocal_leukoencephalopathy, which you yourself have editted to actually duplicate N's listing as a cause, and reveal application of the same standard?

Its all about risk-reward - and for drugs used in "conditions" or "symptom relief" or even a serious disease for which there is a better or even equal-but-safer treatment, then the safety issue greatly defines the drug. And so Bupropion or thalidomide are just not comparable. However, it is well-known that all the chemo-therapies kill thousands every year, and yet to flag these with their death-potential would be absurd, as the risk-reward ratio is very favorable. As to where MS belongs, well I would point you to the last paragraph of the NYT article you just added. As to MS therapies, here is the generally-acknowledged "safest" drug, but it has many AEs - http://www.drugs.com/pro/copaxone.html - now look at it's Wiki and you will see the barest mention at all of these putative links. Comparisons only with MS, Crohns, or any serious progressive disabling disease, are appropriate...I did look in the Wiki 200 list (linked above), and I do not see any comparable treated like N is, not one....io-io (talk) 23:27, 13 March 2008 (UTC)

Headers must be neutral, per Wikipedia:TALK#New_topics_and_headings_on_talk_pages. I changed the header of this thread to: 'How to standardize our reporting of negative effects in drug articles.' replacing 'Continued objection to arbitrary and selective "standards"'. Please comment if you have a better idea. EdJohnston (talk) 19:17, 13 March 2008 (UTC)

Given the interest now being paid to the page, my potential for sparking conflict, and me brutally impacting the limits of my abilities, I think I'm going to unwatch natalizumab. If people feel the need to contact me, then there's my talk page. If for some reason my opinion is required, it will almost certainly be an absurdly rigid interpretation of the relevant policy or guideline. WLU (talk) 19:45, 13 March 2008 (UTC)

Noticeboard discussion

Note discussion on AN/I: Wikipedia:Administrators'_noticeboard/Incidents#Natalizumab. WLU (talk) 20:18, 12 March 2008 (UTC)

New link

I created a new page, challenge-dechallenge-rechallenge, 'cause there is no page on it, and I believe it is the appropriate medical testing protocol referred to in the contraindications section. Could any doctors confirm (and expand?) WLU (talk) 23:10, 12 March 2008 (UTC)

Physical and chemical properties

The above section in the article doesn't actually contain any physical or chemical properties. Its content should be merged into the rest of the article, and what's already adequately covered removed altogether. Fvasconcellos (t·c) 02:39, 13 March 2008 (UTC)

I believe I did so adequately, I moved it into mechanism of action and invisibled the properties heading. WLU (talk) 13:23, 13 March 2008 (UTC)

History move

I re-ordered the page per Wikipedia:Manual_of_Style_(medicine-related_articles)#Drugs - history should actually be first, unlike disease pages. I believe User:Jfdwolff had re-ordered the history to the former section (the end, just before see also) and I thought it was because I had mis-read the MOS article. However, given the discussion above and re-examining MEDMOS, I think it is warranted that the history section go at the top. Wolff - if I missed out on the reason for the move, please let me know so we can discuss. WLU (talk) 17:21, 13 March 2008 (UTC)

What User:Jfdwolff actually wrote when he moved the History section to the end was something entirely different - that he considered it minimally relvant today......regardless of what MEDMOS says, few drug pages have the history first, if indeed they even have a history section...but dont take my word for it, instead that can be seen here - http://wiki.riteme.site/w/index.php?title=Natalizumab&diff=191920442&oldid=191684328 .....io-io (talk) 22:42, 13 March 2008 (UTC)

"History", in this case, usually refers to the drug discovery and development process, and to events preceding modern pharmacological use in humans. The events occurring after approval of natalizumab are probably better covered under the WP:MEDMOS heading "Legal status", since they deal with regulatory events rather than "history" per se. In which case they would appear later in the article. That's my 2 cents. MastCell ^Talk 22:53, 13 March 2008 (UTC)

History=drug development, Legal status is licensing/withdrawal/relicensing/restricted issuing issues - moved as per WP:MEDMOS#Drugs. David Ruben ^Talk 01:22, 17 March 2008 (UTC)

Neutrality Doubted - call for Expert (Medical) review

• Contrary to these WP:NPOV criteria: "article structure", "undue weight", "balance" and "fairness of tone" this Wiki today presents bias towards a sensational history of death and marketing withdrawal.
• New qualified eyes are badly needed, preferably with experience in advising patients of risk-reward paradigms.

The fifth WP:5P goal requires, above all else, that edits improve the page. Yet this Wiki now has a fear-mongering bias towards life-threatening danger, such that the words:

• "progressive multifocal leukoencephalopathy" are spelt out 4 times;
• "PML" appears independently an additional 3 times;
• "Death" and "Fatal" appear a combined 5 times.

But for what N is actually proven to do in MS disease, that has been subordinated to a single paragraph, where the key benefits in "lesions", "relapses" and "disability" are all mentioned just once.

PML/deaths are described in the introductory words to the Wiki page, without precedent on Wiki for any other drug treating a serious progressive disease, or even in drugs more clearly linked with PML (note: the introductory words also may be interpreted to characterize N as a symptomatic-only treatment).

The page then repeats the PML/death association in a further three sections (History, Adverse Effects, Interactions). Yet by 2008 the PML tag is spurious at best, as per this Talk page:

• no correctly clinically-diagnosed MS patient has yet to die from N-linked PML;
• no patient on N-alone therapy (as now perscribed) has ever contracted PML.

This is a travesty as it conveys an inescapable, one-sided impresssion of "russian-roulette" to reading patients, their families - especially when on the cusp of a treatment decision - and to MS nurses and practicioners....(talk) 18:58, 15 March 2008 (UTC)

Oh dear. Fvasconcellos (t·c) 19:11, 15 March 2008 (UTC)

Some of the people you've already heard from have experience in advising patients on risk-benefit ratios. The article is based on material from the New England Journal of Medicine and the New York Times, among other such quality sources, so "sensationalism" is a bit of a stretch; it's not like we're providing Joseph Mercola's take on the situation or something. The page does have room for improvement; discussion of the PML issue can be streamlined and centralized in one section, though a mention will need to remain in the lead. Descriptions of the proven benefits of natalizumab can certainly be expanded and detailed. However, let me suggest from long experience that such improvements are much more likely to take place if you can restrain the tendency you're showing to assume the worst of other editors and personalize disputes. If you can briefly suggest concrete changes to the article without the rhetoric, we'll be much more likely to make progress. MastCell ^Talk 21:41, 15 March 2008 (UTC)

I think MastCell more than adequately addressed the conduct issues, so let me give you my $0.02 on the content itself, specifically the issue of PML. The drug label has a black box warning regarding PML. Indeed, the drug can only be prescribed through a specific program whose purpose is to avoid the occurrence of PML in these people. This is atypical and remarkable in its own right, and far from a historical footnote that is best swept under the rug. Antelan ^talk 00:07, 16 March 2008 (UTC)

"After a review of safety information and no further deaths, the drug has returned to the US market under a special prescription program; it has also obtained approval in the European Union." This sentence, which closes the lead, clearly prevents any impression of natalizumab treatment as a "Russian roulette". Fvasconcellos* (t·c) 02:23, 17 March 2008 (UTC)

Io io, please return MastCell's and Antelan's replies to your concerns to their proper location (i.e. here). I've offered my opinions and am more than willing to help with further improvement of this page as necessary, but I won't be unwillingly dragged into an unnecessary dispute. From now on, I will hold myself to WP:1RR on Natalizumab and this Talk page (including edits made with this alternate account). As you seem quite resolute in your view of how this article should be written, I'd like you to be a bit more clear on that matter. Why don't you describe how you'd like to see this article structured and we (myself and the other editors who have repeatedly given their opinions on the matter) will discuss how that would conform to policies and guidelines and what we can do about it. Fvasconcellos* (t·c) 02:21, 17 March 2008 (UTC)

• I will not return them. It is not their proper location. Your group finished here on Thursday and left my requests for comparables unanswered, and no-one posted here for 2 days. Wiki clearly describes the POV-check - see NPOV - as a process whereby doubt can be expressed as to nuetrality and FRESH opinions sought. I am entitled to state that doubt because essentially zero of my contribution is left on the page, just a few citations. On the other hand, the Page as it stands today is essentially the product of your group. Them is the Wiki rules, sorry.....
• Finally, seeing as you claim you will further improve the page. All my ideas are on the Talk page above, and I dont have much time, so you are welcome to review and re-consider. You ask me to "describe how you'd like to see this article structured" - well I would answer again, just like the Wiki pages on drugs in the comparable medical-need class. Also, simply to reverse all of the issues of imbalance that I list at the top of this section.
• OK, I will say a little more, then please move the conversation upwards out of the POV-check, such that input will not be obstructed. I was talking to another contributor today, and I am invoking an Occam's razor principle to the N page - if no correctly clinically-diagnosed MS patient died of PML in the 2,500 patient trials (see prior Talk above), and here are 25,000+ patients (21,000 at Xmas) now using it without a single re-occurrence, would not Occam's razor - which IS used in medicine - http://wiki.riteme.site/wiki/Occam%27s_razor#Medicine - demote PML to something less than the primary message of the page ? Please consider this as new information, new input, please factor it in.
• Also I recall that you or someone invoked the NYT as "proof" that PML was a huge issue. Well here is the 2nd page of this month's NYT article on MS and treatment - http://query.nytimes.com/gst/fullpage.html?res=9C03E0DC123BF937A35750C0A96E9C8B63&sec=&spon=&pagewanted=2 ....note the absence of N=Tysabri from the list of the 5 approved drugs ...it actually doesnt mention PML but it is apparently now "back in clinical trials"....that would be bad enough, but note also carefully the structure, the ordering of the descriptions of the 5 approved drugs, and then "A sixth drug, Tysabri"....and then look at the same structure (FDA, drug list, etc) and wording here ...... http://wiki.riteme.site/wiki/Multiple_sclerosis#Disease_modifying_treatments ......"the sixth is natalizumab (marketed as Tysabri)".....eerie, no ? So just who is referencing who ? As I said before, all the small-town jounalists - and some of the big ones too - will read these pages when they to write on MS .....I believe this highlights the need for responsible NPOV especially WP:Undue weight compliance, and balanced content focus at the expense of all else - it is just way, way too important....io-io (talk) 03:28, 17 March 2008 (UTC)

Your removal of MastCell's and my responses to this topic is confusing, because our replies are now out of context. Before fighting to keep that change, I recommend that you consider if that ultimately benefits you. With that said, I'll move on to a couple of your points:

• The NYTimes is a fair indicator of what's big news; if your drug hits the pages of the NYT due to an adverse event, you can be assured that the adverse event was notable for some reason.
• You mentioned a concern that journalists will see the PML issues raised in this article when they write about MS. I must say that I don't see this as a bad thing; we should be presenting material here in a neutral way so that anyone can get what they need from the article. I don't think this article is scaremongering at all - it addresses something that happened and makes it clear that the drug was reintroduced with controls to reduce the chance of this happening again.

Also, you have raised your concerns with others at different venues now, including the place where medically-oriented people tend to congregate (WP:MED). I have seen responses from other people who have evaluated this article but don't see the faults that you see. My question for you is this: if you aren't ultimately able to change the consensus regarding your concerns with this article, are there other improvements that you can suggest to this or other articles that I and/or others can help with? Antelan ^talk 04:11, 17 March 2008 (UTC)

See above for NYT last week. Those "other people" on {WP:MED} -http://wiki.riteme.site/wiki/Wikipedia_talk:WikiProject_Medicine#natalizumab - - would that be the ONE responder there, who admits he doesnt edit pages likes this? Of course, any Expert looking at this page would see it is a waste of time trying to contribute....io-io (talk) 15:44, 17 March 2008 (UTC)

More on the NYT - in terms of "Liver Injury" see this - http://query.nytimes.com/gst/fullpage.html?res=9C03E0DC123BF937A35750C0A96E9C8B63&sec=&spon=&pagewanted=2 - then look at this, added the very same day (March 4) - http://wiki.riteme.site/w/index.php?title=Natalizumab&diff=195907829&oldid=195906061 --- Now, notice the consensus between the two... - this is a major issue, verified .... right ?

No, wrong, take a look at this, and read the references - http://wiki.riteme.site/wiki/Talk:Natalizumab#Liver_toxicity - again, relative to the comparables, where is the truth, where is the balance ? Isnt this really WP:Undue weight ?? It really should not be on the page at all, or at most be mentioned in a list of usual-suspects...anyway, so much for the NYT, please drop it....io-io (talk) 17:42, 17 March 2008 (UTC)

One Precedent

As PML and death/fatalities are extensively described in the Wiki, in 4 sections including the introductory words to the page itself, and with total references vastly out-numbering the purpose (medical benefit) of the drug, I am seeking just one precedent on Wiki for similar balance in any other disease-modyfing drug treating a serious progressive disease, or in any drug linked with PML....thanks for any help....io-io (talk) 20:00, 17 March 2008 (UTC)

Io io editor has been very dissatisfied with the above examples of drug articles that mention serious or fatal side effects in the lead. I am here attempting to rectify that situation. I'd like to point out, however, that what's truly unusual is not the mere possibility of a fatal side effect, but that this drug was formally withdrawn from market. A formal withdrawal is not simply a medical issue; it has enormous legal, regulatory, financial, and employment consequences. I fully support including in the lead the fact that this drug was temporarily withdrawn from market. Therefore, to be fair, I have limited my search to drugs that were also formally withdrawn from market. Here is a alphabetized list of ten other drugs that were also withdrawn from market, with short explanations of how this important fact was handled in those articles:

• Alosetron: Withdrawal from market mentioned in first paragraph. One-third of short article is about withdrawal and serious side effects.
• Cerivastatin: Second sentence. Entire third and fourth paragraphs (amounting to more than two-thirds of entire article).
• Cisapride: Withdrawal and warnings featured "above the scroll" (seventh and eighth sentences).
• Fen-phen: Every single sentence in the entire article, except the first one, is about side effects and withdrawal from market.
• Rapacuronium: Third of three sentences: one-third of stub about withdrawal.
• Rofecoxib: Entire third paragraph. Enormous section on side effects, plus sections on withdrawal from market and lawsuits.
• Tegaserod: First (and only) section after the lead is entirely about withdrawal from market.
• Thalidomide: Entire lead, except first sentence. In fact, the overwhelming majority of the article is about its withdrawal from market.
• Troglitazone: Second sentence in lead about side effects. Third (out of only seven sentences) is withdrawal from market.
• Zimelidine: Second paragraph entirely about withdrawal from market.

I think this list reasonably well establishes proof of a de facto editorial consensus that a formal withdrawal from market is widely considered an important, even critical, point of information to feature in drug articles. Natalizumab's inclusion of this information in the lead, as well as elsewhere in the article, is by no means unusual treatment on Wikipedia. WhatamIdoing (talk) 20:11, 17 March 2008 (UTC)

Even more unusual are (1) the fact natalizumab was voluntarily withdrawn, (2) the fact patients and advocacy groups actively lobbied for its return, and (3) the fact it was indeed returned to market after safety review. As recently added to the article, natalizumab was the second drug ever to return to the U.S. market after withdrawal for safety concerns. Fvasconcellos (t·c) 20:21, 17 March 2008 (UTC)

Yes, exactly. Alosetron was the first (assuming, of course, that you don't count thalidomide, which wasn't ever approved in the US before it was banned elsewhere). WhatamIdoing (talk) 20:40, 17 March 2008 (UTC)

Hmmmm.....thnkx W, and thnkx FV, but do you remember what I asked (you can read that above)? Not any drug; natalizumab is a disease-modyfing (not prophylactic, not symptomatic) drug in a serious progressive disease (not a condition or lesser disease). None of these are comparable, I opened every single link. You mention Alosetron but that is a drug that is now available and hardly ever used, and for irritable bowels. The closest (in a serious disease) is Cerivastatin; it killed 52 people, and of course it is not available today, because the risk defined it...that is not WP:UNDUE the way it is written. In natalizumab the reward greatly out-weighhs the risk, that is clear from the data and why it is quite a success today despite the big-bang type echo that reverbates in the media - and on Wiki, unfortunately...io-io (talk) 22:06, 17 March 2008 (UTC)

You have asked for the natalizumab article to be treated as every Wiki pharma page, and several editors repeatedly noted that natalizumab's is an unique case. WhatamIdoing has provided ten examples showing that the article is indeed broadly following common WP practice on pages of withdrawn drugs; now, you're asking that this article be treated differently as none of the above drugs are comparable to natalizumab. Sorry, I'm a bit lost—are we still discussing improvement of the article, or is this now an exercise in argument? Should I pull out my copy of The Art of Being Right? :) Fvasconcellos (t·c) 22:19, 17 March 2008 (UTC)

I never said "withdrawn", I said "treating a serious progressive disease" - and I said it several times on this page, for example here: http://wiki.riteme.site/wiki/Talk:Natalizumab#How_to_standardize_our_reporting_of_negative_effects_in_drug_articles - and here: http://wiki.riteme.site/wiki/Talk:Natalizumab#Neutrality_Doubted_-_call_for_Expert_.28Medical.29_review - and then here, top paragraph: http://wiki.riteme.site/wiki/Talk:Natalizumab#One_Precedent ..................as for the reference to your book, can I suggest a movie instead, remember Haley Joel Osmond in The Sixth Sense when he said "I see Dead People - they're everywhere, they just see what they want to see"........io-io (talk) 22:35, 17 March 2008 (UTC)

(Undent) You mean, can I read the changes you made to your original request while I was typing my response? And how is it that multiple myeloma is not a serious progressive disease or thalidomide not a disease-modifying treatment for it? You don't seem to be grasping every other editors' point: We are not promoting the side effect. We are not telling any patient to do anything about this drug. We are presenting information about the remarkably unusual and very important bit of regulatory paperwork that this drug's manufacturer chose to do. I'm sorry if you can't make the distinction between the cause of the paperwork and the paperwork itself, but I assure you that the paperwork is really, really important here. WhatamIdoing (talk) 06:57, 18 March 2008 (UTC)

I said "treating a serious progressive disease" from the outset - that's not part of the revision you point out - and obviously mean a DMD - what else could be "comparable"?. What made thalidomide infamous was NOT it's use in multiple myeloma of course - it was originally never used in a serious disease at all. As for the rest, WP:UNDUE is the issue, because the number of mentions of PML, deaths and fatalaties - despite being a speculative link - are both prominent and vastly outnumber what the drug is proven (without speculation) to do.....io-io (talk) 13:40, 18 March 2008 (UTC)

So what if thalidomide was infamous for one problem, but is useful in another? If Natalizumab is used in multiple diseases, and we do not remove a temporary unfavorable concern about MS just because it didn't come up with Crohn's. Thalidomide is currently used for treating a serious (deadly) progressive disease. Thalidomide modifies the course of the disease. I've met all your conditions. WhatamIdoing (talk) 18:37, 18 March 2008 (UTC)

No, because Thalidomide is not coming back as an antiemetic for morning sickness, that's the area is was withdrawn in, where the scandal was - in that area, the risk vastly outweighs the tiny reward....just not the same, is it?....io-io (talk) 19:06, 18 March 2008 (UTC)

Thank you for sharing your opinion again.

I think we've reached a good decision, which is supported by everyone except one editor. I think further conversation on this point is wasting everyone's time and energy, and I recommend that we stop the discussion. WhatamIdoing (talk) 19:18, 18 March 2008 (UTC)

Yes, no point in further discussion...obviously both the POV-check and call-for-Expert-review never really got started - I am thinking arbitration although that's not really intended for content...maybe it just has to stay "wrong"....io-io (talk) 19:26, 18 March 2008 (UTC)

"compare the drug with others in its class" - per MEDMOS

MEDMOS / drugs - http://wiki.riteme.site/wiki/Wikipedia:MEDMOS#Drugs - guides that Drug pages be written - "For example, a long list of side effects is largely useless without some idea of which are common or serious. It can be illuminating to compare the drug with others in its class...." Accordingly:

- Multiple Sclerosis DMD class

• Avonex - mention of liver side effects confined to single sentence in the middle of "Overview" section, despite Primetherapeutics; no mention of PML, even though the 2 patients who got PML in the N trials were on Avonex; no mention of any safety issues in the lead.
• Rebif - same as above, (with the exception that PML has not been linked to it).
• Betaseron - speaks only of beneficial effects, liver issues not mentioned anywhere
• Glatiramer acetate - issues are confined to a single section; nothing in lead
• Mitoxantrone - side effects in sngle section; despite absolute limit on usage due to cumulative heart damage - no mention in lead

- Crohns Disease DMD class

• Infliximab - despite black box and multiple FDA warnings, safety issues confined to a single section, and nothing in lead. Although linked with PML, this is not even mentioned. Article is generally glowing, which it should, given the versatility.
• Adalimumab - despite black box and FDA warnings, safety issues confined to a single section, and nothing in lead.

- Drugs linked to PML

• Rituximab - despite black box and multiple FDA warnings, safety issues including PML confined to a single section. Nothing in lead. Interesting becase this is the best hope for a PPMS treatment.
• Chemotherapy - obviously countless die from it's toxocity, but no mention of safety is lead. Immunosuppression and myelosuppression titles a sub-section.
• Corticosteroids - this is class of drugs with inevitable serious side-effects - but nothing in lead, and very little mention on page - no meniton of PML anywhere.
• Tacrolimus - thousands die post-transplant from immune suppression, but no mention of safety is lead. Immunosuppresion following transplantation titles a sub-section.
• Avonex - see above.

- Conclusion - of 11 comparables, none of their Wiki pages seem close to the layout of the N page - this supports my thesis of WP:NPOV / WP:UNDUE problems.....io-io (talk) 20:01, 22 March 2008 (UTC)

Again, I think further conversation on this point is wasting everyone's time and energy, and I recommend that we stop the discussion. Perhaps we can revisit it at a much later date. WhatamIdoing (talk) 20:21, 22 March 2008 (UTC)

WhatamIdoing is accurately reporting the views of a pretty broad consensus here, and I think his suggestion to revisit at a much later date is a reasonable one. Antelan^talk 20:28, 22 March 2008 (UTC)

OK, say for the world within Wiki, it's true, better keep the status quo. But the world outside Wiki, what about that world, it doesn't matter? can it wait?.....io_editor (talk) 21:04, 22 March 2008 (UTC)

I think you've done a good job of compiling that list. Instead of posting that here, however, why not remedy the problem and add in appropriate adverse event information into the other articles? That will be a boon to the encyclopedia. Antelan^talk 21:11, 22 March 2008 (UTC)

Recall Occam's razor? From their many contributors, no-one has expressed an opinion that any of those pages have WP:NPOV / WP:undue problems....io_editor (talk) 23:38, 22 March 2008 (UTC)

Occam's razor - do not postulate plurality unnecessarily. Here, it is necessary to postulate plurality. Id est, there are several (plural) articles lacking in relevant adverse events. If there are sources to back what you've said, then those articles need to be updated. Would you like to work with me on improving them? Antelan^talk 23:47, 22 March 2008 (UTC)

because: 1) No opinion there of WP:NPOV / WP:undue problems...2) Still other serious progressive diseases affirm same WP:NPOV standard...3) I am wiki-busy/backlogged...4)Why are we here?...5)The outside Wiki world need not wait when WP:undue has grave consequences....io_editor (talk) 01:21, 23 March 2008 (UTC)

You need to stop speaking in policy code. I don't see how NPOV/UNDUE are relevant to the fact that other articles are lacking in information. I'm offering help to you - you have identified articles that are lacking in info on adverse events. I'm willing to help you add those adverse events. Now, please feel free to reply to me on my talk page or here, though this is not truly a relevant place for this discussion, on the condition that you actually want to help bring these other articles up to par. Antelan^talk 01:41, 23 March 2008 (UTC)

sticking to N subject; suggest confirm relevance to the outside-wiki world by reading: http://www.msrc.co.uk/index.cfm?fuseaction=show&pageid=2396 (hope you understand implications) - before pursuing those tactics....io_editor (talk) 02:05, 23 March 2008 (UTC)

Improving Wikipedia articles is now a "tactic"? I'm sorry you're not interested in working with me to improve other articles. Better luck in the future, Antelan^talk 03:00, 23 March 2008 (UTC)

already comitted to working on 1 of them; in others I dont see anything mis-leading; suggest if you see WP:undue issues, bring them up on their own talk pages; only issue that belongs here is N....io_editor (talk) 16:28, 23 March 2008 (UTC)

Stem cells

An interesting property of natalizumab, and possibly even a therapeutic mechanism, it is ability of mobilising haematopoietic stem cells (CD34+ mononuclear population) from the bone marrow: doi:10.1182/blood-2007-10-120329 JFW | T@lk 10:46, 25 March 2008 (UTC)

I enquired today of colleagues if this had any significance, and apparently the drug will be trialled in multiple myeloma. Nothing on the clinicaltrials.gov site however.io_editor (talk) 01:50, 27 March 2008 (UTC)

FDA did not withdraw Tysabri nor cancel it's License

Reference #1 - from NEJM - withdrawal by Biogen -http://content.nejm.org/cgi/content/full/353/4/432

Reference #2 - FDA approval history - subsequent "re-approval" was actually a "supplemental" (Biological License); original License was in place - http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist ....io_editor (talk) 01:17, 29 March 2008 (UTC)

the PML deaths

There were 3 PML cases; of which 2 died. Only in full-blown Aids is PML usually seen, and is usually fatal due to the absence of an immune system. So how did these patients die?

1. http://content.nejm.org/cgi/content/full/353/4/375?ijkey=b24b4864c7f8f2c41bcc31d8e021ff52b2f40430
2. http://content.nejm.org/cgi/content/full/353/4/369?ijkey=f3eceb18a94aa8b54237f55ba4a7286c8f4e071f
3. http://content.nejm.org/cgi/content/full/353/4/362

What all 3 had in common were 2 things:

1. con-committant drugs (avonex in 2 "MS" patients; and in the CD patient, not simultaneous but was
already chronically immuno-suppressed - had already low lymphocyte counts due to prior immuran and infliximab).
2. a bungling period 3 to 5 months of PML mis-diagnosis before death or partial recovery (in one
case of course the mis-diagnosis of a brain tumor continued for 2 years post-mortem). In this 3 to 5
months of PML mis-diagnosis, all 3 received massive amounts of powerful immuno-suppressive medications - all
for the wrong issues.

Treatment of PML in these non-Aids cases appears possible - http://archneur.ama-assn.org/cgi/content/abstract/64/2/169 - ....io_editor (talk) 01:33, 29 March 2008 (UTC)

How many "real" MS patients on N (and Avonex) got PML?

By "original diagnosis", 2 is the answer; 1 died, 1 lived. However, a few months after the NEJM simultaneously published the case histories, it published a pair of letters (presumably, among many) which, to the embarrassment of the authors, cast doubt on the MS diagnosis of both patients - http://content.nejm.org/cgi/content/full/353/16/1744 - rather than explain all that, and for those who have no NEJM access, here is a full copy, minus the references -

<<<<<" To the Editor: According to the established definition of multiple sclerosis, the condition in the patient described by Kleinschmidt-DeMasters and Tyler (July 28 issue) should not have been diagnosed as multiple sclerosis. Apart from the unusual clinical findings, no oligoclonal bands were detected in two separate examinations of the cerebrospinal fluid, and repeated magnetic resonance imaging (MRI) scans obtained over the course of several years showed new and enlarging, but never enhancing, lesions. The most convincing argument against a diagnosis of multiple sclerosis is the neuropathology: no lesions that are characteristic for multiple sclerosis were detected. The patient described by Langer-Gould et al. in another article in the same issue may also raise concern about the diagnosis of at least "typical" multiple sclerosis. One to two oligoclonal bands in the cerebrospinal fluid would have to be considered negative, and repeated MRI scans would not show enhancing lesions. Therefore, it does not seem appropriate to conclude that patients with multiple sclerosis may be at risk for progressive multifocal leukoencephalopathy (PML) owing to treatment with natalizumab and interferon beta-1a. Is it possible to misdiagnose subclinical nonfatal cases of PML as multiple sclerosis in patients who are not obviously immunosuppressed? Further investigations of JC virus infections should extend our knowledge of this scenario.

Thomas Berger, M.D., M.Sc. Florian Deisenhammer, M.D., M.Sc. Innsbruck Medical University A-6020 Innsbruck, Austria

Dr. Berger reports having received unrestricted research-grant support, lecture fees, and consulting fees from Berlex, Biogen-Idec, Sanofi-Aventis, Schering, and Serono; and Dr. Deisenhammer, unrestricted research-grant support, lecture fees, and consulting fees from Biogen-Idec, Schering, and Serono.">>>>> (Io-Editors's note - this means almost all the MS DMD maker/ competition)

---

To the Editor: Kleinschmidt-DeMasters and Tyler described a patient with multiple sclerosis and PML that developed after she received natalizumab treatment. However, some of the findings in this patient are uncommon in multiple sclerosis. The absence of contrast enhancement in the MRI studies that were performed — almost a rule in patients with PML — is uncommon in multiple sclerosis. The lack of intrathecal synthesis of IgG is unusual in multiple sclerosis, although it is frequent in PML. Moreover, an autopsy study found no multiple sclerosis plaques but only PML lesions. Therefore, the pathological findings did not support a diagnosis of multiple sclerosis, which raises some questions. Can initial PML mimic multiple sclerosis? Was PML the only disease in this patient? To our knowledge, PML with a relapsing–remitting course has not been described. To clarify whether PML may have a relapsing–remitting course, it is necessary to study the cerebrospinal fluid in patients with relapsing neurologic disorders to rule out this disease. This seems particularly important for patients with suspected multiple sclerosis with atypical findings, such as early mental symptoms or an absence of oligoclonal bands. If it is demonstrated that PML can have an initial relapsing–remitting course, the risks of natalizumab treatment should be reevaluated.

José C. Álvarez-Cermeño, M.D. Jaime Masjuan, M.D. Luisa M. Villar, Ph.D. Hospital Ramón y Cajal 28034 Madrid, Spain

Note that these letters raise the possibility that, not only did one or both patients never had MS, but may have had "sub-clinical" PML. Perhaps in recognition of this (because the anomaly was raised at the FDA Advisory Committee Hearings - reference available), patients "who already have PML" are contra-indicated on the label for N treatment....io_editor (talk) 13:23, 29 March 2008 (UTC)

In actual practice, both in all trials and in 2 years of widespread availability, no MS patient (real or disgnosed) has contracted PML while on N alone - http://www.biogenidec.com/site/tysabri-information-center.html (by Dec '07, there were 21,000 MS patients on N)....io_editor (talk) 14:16, 29 March 2008 (UTC)

---

I'm posting the third letter on that page, for completeness' sake: Drs. Kleinschmidt-Demasters and Tyler reply: We appreciate the comments of Drs. Berger and Deisenhammer and Dr. Álvarez-Cermeño and colleagues. Our involvement with this case began only post mortem; we were not involved in this patient's initial clinical evaluation, diagnosis, and treatment. The clinical and laboratory data presented were supplied by the patient's treating physician and supplemented by the Biogen company representative. Unfortunately, in some instances only the original MRI reports, not the actual scans, were available for independent review.

A variety of diagnostic criteria for multiple sclerosis have been proposed, including the widely accepted criteria of McDonald et al.1 These criteria do allow for the diagnosis of multiple sclerosis to be made solely on clinical grounds in a patient with two or more attacks and objective clinical evidence of two or more lesions. Criteria specific to MRI can provide supportive evidence of the dissemination of lesions over time; this criterion can be satisfied by the appearance of new T2-weighted lesions on appropriately spaced sequential scans. Oligoclonal bands on evaluation of the cerebrospinal fluid and enhancing lesions as shown on MRI are found in the majority of patients with definite multiple sclerosis; however, their presence is not absolutely required for diagnosis, nor does their absence completely rule out a diagnosis of multiple sclerosis.

We cannot resolve whether the absence of multiple sclerosis lesions at autopsy reflects obliteration of a limited number of multiple sclerosis plaques by the widespread and extremely destructive PML lesions, sampling error, or the presence of an alternative disease process. With regard to this last possibility, we believe it is unlikely that a chronic indolent or relapsing–remitting form of PML was the sole disease that this patient had or that it was responsible for this patient's symptoms early in her clinical course.

Our report, in combination with the others published in the same issue of the Journal,2,3 clearly indicates that natalizumab is associated with an increased risk of PML in patients without other recognized risk factors for this disease. The common denominator in all three reported cases, regardless of the underlying disease, was treatment with natalizumab.2,3

We hope that ongoing studies will clarify the pathogenesis of this disorder, including the viral factors and specific host factors responsible, and also the mechanisms by which natalizumab facilitates induction of PML.

B.K. Kleinschmidt-DeMasters, M.D. Kenneth L. Tyler, M.D. University of Colorado Health Sciences Center Denver, CO 80262 - Antelan^talk 16:14, 29 March 2008 (UTC)

Their long-winded excuses, for failing to note the strange diagnosis in their single-patient paper, doesnt help ths page much - but here is part of their conclusion - "we believe it is unlikely that a chronic indolent or relapsing–remitting form of PML was the sole disease that this patient had" - all the more remarkable given that all they had was an autopsy....io_editor (talk) 16:32, 29 March 2008 (UTC)

Today's MS Society (UK) 12-page pull-out on MS in London Times

N mentioned twice, including general descriptions of efficacy and safety - http://doc.mediaplanet.com/projects/papers/Multiplesclerosis.pdf - notice that PML & Deaths are not mentioned at all - io_editor (talk) 17:24, 29 March 2008 (UTC)

So an article by the New York Times isn't appropriate, but an advertisement in the London Times is? Antelan^talk 17:47, 29 March 2008 (UTC)

I have alreaady dealt with the NYT - even this month they think N is "back in clinical trials" and appear to borrow the term "the sixth drug is Tysabri" http://query.nytimes.com/gst/fullpage.html?res=9C03E0DC123BF937A35750C0A96E9C8B63&sec=&spon=&pagewanted=2 - from the Wikipedia (Multiple sclerosis page) - but to call the London Times piece an advertisement is intellectually dishonest because there is no other a way that a national MS society can advance its agenda in so prominent a manner, and what they write reflects their policies...io_editor (talk) 18:53, 29 March 2008 (UTC)

No, to call it an advertisement is intellectually and in all other ways candid, since an advertisement is what that is. The fact that a robust and respected institution took out the advertisement doesn't change the fact that it is an advertisement. Antelan^talk 19:04, 29 March 2008 (UTC)

Well, if you have a point relative to N - any point at all - say what it is. I will leave it you and others to determine which has more relevance to encyclopedic-writing on N - this 12-page ad by the "robust and respected institution" or the current NYT article which appears to borrow from Wiki itself, and and get other basic facts wrong....io_editor (talk) 19:22, 29 March 2008 (UTC)

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