Talk:Theralizumab/Archive 1

message: Cytokine storm: The Wikipedia article Cytokine storm mentions that the drug OX40-Ig may be used to treat this condition. Does anyone know if this was used in the treatment of these patients? While OX40-Ig is in itself an experimental drug, in this extraordinary situation it might be worth trying it in the critically ill patients, if they did indeed suffer a cytokine storm. 12:59, 19 March 2006 (UTC)
replies: text: As an admin I can edit the main page but I'm just looking up the criteria. Secretlondon 21:41, 16 March 2006 (UTC)

text: I've added it to the main page In the news section. It may get swapped out again by someone else. It's pretty rare that science stories get in there and it may not be obvious why it belongs there. Secretlondon 21:53, 16 March 2006 (UTC)

text: Well we need both - we need a general para for the non-science literate. Secretlondon 22:33, 16 March 2006 (UTC)

text: A Reuters article from today   quotes an expert, Dr. David Glover, "I suspect the antibody was designed to work against human CD28 and because it was designed to work best in humans its performance in different animals may fall short of what you might have expected in humans".  Just remember you heard it here first.  ;) Mike Serfas 19:36, 19 March 2006 (UTC)

text: A Daily Mail article from March 20  says:  "Professor Trevor Smart, head of pharmacology at University College London, said that as well as any permanent damage to their organs, there could be long-term disruption to their immune systems."Mike Serfas 08:19, 22 March 2006 (UTC)
replies: text: Can someone wikify this comment? --Chl 13:43, 22 March 2006 (UTC)
thread_title: Cytokine storm, MoA, etc

message: How much is the media playing up the "we have no clue how to treat this" "we're totally in the dark" angle of the doctors in this case? It would seem that if they know that this isn't a case of overdosing then they have general reason to believe that the drug really did 'hyperstimulate' the immune system to attack it's own body. Knowing that, wouldn't it be reasonable to turn to immunosuppressants such as Cyclosporine as a next course of action? Not knowing much about how clinical trials for pharmaceuticals like these go, I have to say it is rather shocking that they are allowed to tinker so freely with something as horrendously complex as the immune system. You would think that one would be more careful about not conjuring demons which one doesn't know how to cage. scary.--Deglr6328 04:11, 17 March 2006 (UTC)
thread_title: Media etc.

message: Any conjecture in this article must be made by a third party otherwise it is Original Research. We can report facts (such as the difference between rodent and primate biology, etc) but postulating as to the cause of error must be attributable to some other source, preferrably with a citation/reference to online material that can be verified.
Also, this talk page is for discussion regarding this article, and how to improve it. It is not a forum for general discussion/speculation about this drug and the clinical trial.
Colin°Talk 11:34, 17 March 2006 (UTC)
replies: text: That rule only applies to the article itself. Talk pages can and do contain whatever people want to talk about regarding the subject. With a story like this one, especially since it's still ongoing, it is only natural that this page will be full of conjecture like so many others. --Deglr6328 13:39, 17 March 2006 (UTC)
replies: text: See What may talk pages be used for?. Whilst talk pages have relaxed some rules (e.g. you can express a POV), they are not a substitute for an Internet forum or blog. This is just a Guideline, not a Rule. I'm not trying to stop any discussion here, just to keep it focussed on the article. Colin°Talk 14:40, 17 March 2006 (UTC)
thread_title: Conjecture

message: The article presently states something like "this is the only academic reference" in connection with  an abstract. What about the articles returned from Google Scholar: , e.g., 
Sorry Dude #1 isn't academic (i.e) peer reviewed #2 is about the antibody before it got humanized.Mxpule 15:38, 17 March 2006 (UTC)
thread_title:  Only academic reference? 

message: "The critical point here is whether investigators gave 1/500th of the murinae LD50 or a safe dose in primates."
LD50 is the dose that has a 50% chance of having death as a side effect.  LD50 is an unsafe dose.  Don't talk about it like it's a safe dose.  It isn't, the whole point of labelling it such is that it isn't.
:Er did you actually read the sentence? What it is trying to say is we don't know whether it is 1/500th of the murinae LD50 which would be a very serious mistake OR 1/500th of the safe dose in primates. I believe the original quote is something like 1/500th of the maximal dose in animals. We cannot conclude from this quote what exactly they mean by 1/500th of the maximal dose in animals, it could be the LD50, it could be the safe dose... A number of people including me find it unlikely that anyone would be stupid enough to give 1/500th of the LD50 in murines as the starting dose given that the people administring this trial were dumb enough to give it to 6 people in a short space of time, who knows? Nil Einne 17:10, 17 March 2006 (UTC)
thread_title:  Since when is LD50 "safe"??? 

message: This article links to multicentre trial. Was this intended to be a multicentre trial and were there other centres going to test the drug in a few days or hours time? If so, I would guess the people recruited in the other centres must be thanking their lucky stars that they weren't the first Nil Einne 17:10, 17 March 2006 (UTC)
thread_title:  Multicentre trial 

message: Does anyone have any idea what the time frame is like? This article supports what I think many of us not knowledgable in clinical testing thought, that it is not standard practice to give the drug to 8 different people (although 2 received the placebo of course) in such a short space of time but what kind of time frame are we talking about. Did they administer doses within minutes? Hours? How long is it normal to wait? Nil Einne 17:16, 17 March 2006 (UTC)
replies: text: Criticism has been raised that six participants were given the drug in such a short time, which is against the recommendations of standard literature
Could anyone more medical-literate find a citation to support the "recommendations of standard literature"? - Eric 17:03, 18 March 2006 (UTC)
thread_title:  Time frame 

message: I think what this article needs is a diagram on the mechanism of action - even if it is just a molecule binding to a  T Cell. Do we know enough about the mechanism to be able to pull it off? Secretlondon 21:09, 17 March 2006 (UTC)
replies: text: * Agreed. 4.232.195.49 01:19, 18 March 2006 (UTC)
thread_title: Diagram

message: What sort of compo are they looking at if they make it? Presumably they took part in these trials to earn a bit of extra dosh. They should be able to sue after this. Probably never need to work again. ;-). 
Sounds like some of these subjects will be lucky to make it out of ICU alive, probably won't be able to ever work again. Mxpule 11:20, 18 March 2006 (UTC)
replies: text: I've been wondering about this too and it's something that should be added somewhere IMHO. Since this is the UK were talking about not the US and given that the people taking part in the trial must have signed some agreement severely restricting their ability to claim compensation, I would guess it'll depends a LOT on whether anyone was actually neglegent or not and how neglegent they were. From the story as it stands, it appears they may have been at least partially neglegent if they did violate the supposed agreed protocol of 2 hours between treatments. Does anyone know if it's standard practice to insure test paticipants against ongoing medical complications/costs from negative reactions? Nil Einne 13:18, 20 March 2006 (UTC)
thread_title:  MOST importantly... 

message: While this is an interesting article it doesn't really seem to me to be front page news; other media don't seem to be covering it intensively.  Phr 23:15, 18 March 2006 (UTC)
replies: text: I don't think the front page of wikipedia is an appropriate mechanism for telling media outlets what the news should be.  Wikinews is a better choice and was created for that purpose. Phr 05:44, 19 March 2006 (UTC)
replies: text: The UK media have been covering it intensely. The question is - why have the in the news section - to tell people what's in the news (they can get this anywhere) or to link to good articles on current topics. We still have the best article on this subject - much better than the UK media despite it having been on their front pages. This is an encyclopedia article - not a current affairs article. Discussion on "in the news" is probably best placed at Template talk:In the news. Secretlondon 08:28, 19 March 2006 (UTC)
thread_title:  front page news? 

message: From the Times:
:EXPERTS knew that drugs similar to the one that nearly killed six men at a London hospital last week could have had dangerous side effects.
 Nomen Nescio 00:41, 19 March 2006 (UTC)
thread_title: Oops

message: Can someone update the article please. http://news.bbc.co.uk/1/hi/england/london/4823992.stm for example. I don't have time right now. Rich   Farmbrough 14:00 20  March 2006 (UTC).
:It was done earlier. Last para. Secretlondon 05:00, 21 March 2006 (UTC)
thread_title: Update

message: I've removed the link to multicentre trial since AFAIK, this was never intended ot be a multicentre trial (no one answered my q above and I've seen no suggestion elsewhere it was). In fact, I think someone just copied the references from or perhaps used the Clinical trial article as a template. Clinical trial was not linked further proving my theory so I added it. Nil Einne 16:04, 1 April 2006 (UTC)
thread_title:  Further reading 

message: :However, it appears the MHRA approved a protocol involving the doses being given within 2 hours whereas one of the placebo-receiving participants has explained the doses were given with 2-minute intervals
Has anyone seen the issue of dosage frequency raised in any newspaper or whatever discussing the story? We've discussed it earlier and although it did seem a bit bizarre to me, the fact that I haven't seen any discussion/mention of it in any media discussion and the fact that the report doesn't discuss it makes me wonder whether this isn't really an issue. Perhaps they we're planning to administer the actual primary doses within 2 hours of each other however the initial 1/500 dose was going to be administered at abouy the same time. I guess since this was such a minute dose, the expectation was that absolutely nothing would happen and even if something did happen, they weren't in their wildest dreams expecting anything this severe... Nil Einne 11:36, 6 April 2006 (UTC)
replies: text: Thanks. The interim report and other documents have lots of information. The interim report says the 6 volunteers experienced a life threatening incident of "cytokine release syndrome" (page 2). Clinical trial protocol 6.3.2 (page 33 in the pdf file) says a "cytokine burst" or anaphylactic reactions theoretically could occur within the first few hours. My reading is that the trial documentation covered the possibilty of the reaction occuring. (I'm presuming that cytokine burst and cytokine release syndrome are the same). The documents contain lots of info about the trial protocol, dosing, and previous studies. We should be able to add lots to the article from this. Secretlondon 16:31, 7 April 2006 (UTC)
thread_title:  The dosage frequency issue 

message: Firstly, my apologies, I initially placed this in the wrong position. 
Immunological activity of TGN1412 at low doses was known. According to the IB and the IMPD available on the MHRA website, rats receiving an equivalent monoclonal had immunological effects at 0.3mg/kg - but no no observed effect level was stated. The primates in the 28 day study showed T cell activation and increases in some cytokines at 5mg/kg. Again, it is not known at what dose this effect ceases. Unfortunately, most of the in vitro activity data were deleted. These can give some clue as to what tissue/plasma concentrations might be active. However, it is clear that immunological changes would reasonably have been expected in volunteers at the starting dose of 0.1mg/kg. In calculating a safe starting dose TeGenero disregarded the immunological effects and MHRA endorsed this. Their reasoning seems to have been that the T cell and cytokine changes were not in themselves adverse and no cytokine release syndrome had been detected in the primates. Note, the primate study was not robust - two animals were killed because of diarrhoea and it is likely many others were affected but less so. 
Was it reasonable to disregard the immunological changes likely to be present when calculating the starting dose? If I had been doing this assessment (and I have done dozens)I would have wanted a lot more information than was apparent from the released documentation before recommending such a high dose to volunteers - we know all too well the serious adverse reactions that can accompany T cell and cytokine stimulation and TeGenero appreciated this. And why they started with 6 volunteers apparently to be dosed within a total of 2 hours defeats me. Sandy Wilson 14:31, 10 April 2006 (UTC)
thread_title:  Immunological changes at trial doses were expected 

message: I don't wish to split hairs, but if the transient swelling of the lymph nodes is the consequence of the increased T cell production which is the drug's objective, then this swelling is not, strictly speaking, a "side effect" (as it is referred to in this section) but evidence of the drug's mode of action.  Any objection to my changing this? Rrburke 04:29, 11 April 2006 (UTC)
thread_title: [[TGN1412#Criticism_and_controversy|Criticism and controversy]]