Talk:Azathioprine/GA1

GA Review

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Reviewer: I plan to review this article, which is likely to take me a few days due to patchy editing time. Jfdwolff (talk · contribs) 13:50, 31 August 2012 (UTC)

I will continue making additions as I go along, and will let you know when I'm finished. JFW | T@lk 15:14, 2 September 2012 (UTC)

• General:
  • Referencing style seems consistent but I'm not sure whether we need quite so many commas and periods in the lists of authors.
  • Some sections are very short and would benefit from either expanding or merging with others. JFW | T@lk 15:14, 2 September 2012 (UTC)
• Intro:
  • The introduction is quite short and doesn't fully summarise the remaining sections of the article.
  • The list of drug names in other countries is not found elsewhere in the article, and is thus not referenced. While I agree that this information is easily verifiable, I appreciate it might be tricky finding a single source that lists these names in a reliable fashion. JFW | T@lk 15:14, 2 September 2012 (UTC)
    • Thanks for finding the source, but it doesn't say which name is used in which country. It is not a breaking point.
  • I'm not entirely convinced that the average reader understands the word "prodrug", which may require a brief explanation.
    • Done. --ἀνυπόδητος (talk) 13:17, 11 September 2012 (UTC)
  • The reference titled "ahf" needs a page number or range. I have no access to the source, so can't do it for you.
    • For the "ahf", it's a online book without any page numbers...it only has section names. You can find it here if you have the right to access it.--Jsjsjs1111 (talk) 23:36, 11 September 2012 (UTC)
  • The phrase "Cancer is the major long term side effect" suggests that a lot of people who take azathioprine develop cancer. It would be good to give an idea about percentages, provided a good secondary source is available. JFW | T@lk 21:21, 10 September 2012 (UTC)
    • Deleted.--Jsjsjs1111 (talk) 23:49, 11 September 2012 (UTC)
  • The source used to discuss TPMT deficiency (Konstantopoulou) is a case report that doesn't really meet the requirements of WP:MEDRS. While it is an educational source, I imagine better sources are available for these particular assertions. In fact, the Patel source seems to discuss the topic in some detail.
    • Replaced.--Jsjsjs1111 (talk) 03:08, 13 September 2012 (UTC)

• Medical uses
  • I would suggest rephrasing "which are generally considered as autoimmune diseases as well" to "which are immune-mediated as well". The conditions listed are not classical autoimmune diseases.
    • Done.--Jsjsjs1111 (talk) 03:10, 13 September 2012 (UTC)
  • It might be an idea to add the licence data for other English-speaking countries. From the British National Formulary it would appear that azathioprine is licensed for RA and transplant rejection, and not licensed for other conditions.
  • The sources for "kidney transplantation" are less than ideal. Referring to UK guidelines, mycophenolate is possibly better. We need secondary sources to reflect these developments.
  • With regards to rheumatoid arthritis, I have been puzzled by the fact that azathioprine is much less popular than methotrexate as a DMARD. When I search Pubmed on the subject, very little has been written on the subject in the last 10 years. I have no idea whether my suspicions are correct, and whether they need to be reflected here.
  • With regards to IBD, the header currently only mentions Crohn's but I would broaden this to "Inflammatory bowel disease". Some of the references are a bit rusty (1998 is 14 years ago). A very strong source is the 2011 British guideline for IBD (doi:10.1136/gut.2010.224154). There are Cochrane reviews in both Crohn's and UC (quoted in Mowat et al) that would deserve mention here. The paediatric section is currently partially based on a primary source, and ideally a secondary source should be used if possible.
  • With regards to other conditions, I think we should only mention clinical uses that can be supported with secondary sources. For MS, we should be citing the Cochrane review rather than a derivative source (doi:10.1002/14651858.CD003982.pub2). JFW | T@lk 15:49, 12 September 2012 (UTC)

• Reply:
  • Reference -- It's because most of them are from {{cite doi}} or {{cite pmid}}.
  • Sections -- I've merged some of them.
  • Introduction -- can you give me some advice on improving that?
  • List of drug names -- I've added the refs, not sure they're suitable or not though.
• Thanks!--Jsjsjs1111 (talk) 07:08, 3 September 2012 (UTC)

Sorry, been very busy these days. Will be back next week.--Jsjsjs1111 (talk) 16:59, 23 September 2012 (UTC)

Suggestions

I recently rewrote the Thioguanine entry, then unfortunately suffered over-enthusiasm and began editing Azathioprine without checking to see it was already being edited. All my changes deleted. Suggest the following be considered:

• • Aza is the pro-drug for 6-mercaptopurine so virtually everything that applies to Aza also applies to 6MP.
    • There is an old claim that the nitroimidazole might contribute to its action; not sure whether this is still up-to-date so I didn't add it. --ἀνυπόδητος (talk) 08:54, 10 September 2012 (UTC)
      • As I am one of the co-authors on the oft-quoted paper on this, I humbly suggest that it be passed over - it relates only to minor effects in small proportion of patients. But I am not THAT old! (well, less than 70) Johnaduley (talk) 07:20, 11 September 2012 (UTC)
  • Under Adverse Events, the common dose-dependent adverse events should be listed - they include flu-like symptoms (myalgia, tiredness, fever) and generalised hepatotoxicity which are not noted, and bone marrow suppression (with its symptoms including neutropenia and lymphopenia - not noted). Other toxicity is idiosyncratic, considered to be of immune origin, and include (more rarely) rash and pancreatitis, and (more commonly) nausea. The latter is quite common and is a major cause of non-compliance.
  • Overdose is not an adverse event, it is misuse - deliberate or otherwise.
    • Overdose is in its own section according to WP:MOSMED. --ἀνυπόδητος (talk) 08:54, 10 September 2012 (UTC)
  • TPMT is a central feature of all thiopurine PK and as such determines both the correct dosing and the likelihood of adverse events, it is not an adverse event in itself.
    • Does the article say it's an adverse event? Sorry, can't see that. --ἀνυπόδητος (talk) 08:54, 10 September 2012 (UTC)
  • TPMT activity is not measured in serum - this is incorrect, it is measured in red blood cells.
    • This statement has been fixed. --ἀνυπόδητος (talk) 08:54, 10 September 2012 (UTC)
  • The frequency of TPMT polymorphism is 5%, which means that the activity is 'low' in 10% of patients and 'absent or completely deficient' in 0.3%.
    • My mistake. Will fix. --ἀνυπόδητος (talk) 08:54, 10 September 2012 (UTC)
  • TPMT deficiency is associated with both bone marrow suppression and nausea, as shown by the only prospective study performed (Ansari A, Arenas M, Greenfield S, Morris D, Lindsay J, Smith M, Lewis C, Marinaki A, Duley J, Sanderson J (2008). Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 28(8):973-83).
  • TPMT does not explain all bone marrow suppression - this is incorrectly stated - attributed to Reuther et al. TPMT explains only 30% of neutropenia, the rest is considered to be caused by co-therapies and infections (CMV etc).
    • Hm, interesting one. The neutropenia caused by infections and co-medication is not caused by azathioprine, so TMPT deficiency explains all azathioprine-related neutropenia?? --ἀνυπόδητος (talk) 08:54, 10 September 2012 (UTC)
      • Poorly explained by me (late-night brain-fog). Everyone quotes the study from Colombel which concluded: "Twenty-seven percent of patients with CD and myelosuppression during azathioprine therapy had mutant alleles of the TPMT gene associated with enzyme deficiency. Myelosuppression is more often caused by other factors. Continued monitoring of blood cell counts remains mandatory in patients treated with azathioprine." - Gastroenterology. 2000 Jun;118(6):1025-30. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy. Colombel JF, Ferrari N, Debuysere H, Marteau P, Gendre JP, Bonaz B, Soulé JC, Modigliani R, Touze Y, Catala P, Libersa C, Broly F. PMID:10833476. So while patients with TPMT deficiency have a high risk of myelosuppression (not just neutropenia, as my fogged brian remembered) if improperly dosed, the proportion of patients with myelosuppression and TPMT deficiency is less than 30% overall. Johnaduley (talk) 07:20, 11 September 2012 (UTC)

• • Happy to supply reference list - it is long because thiopurines are hugely studied, especially as a model for pharmacogenetics. it would be ideal to write up all of the thiopurine drugs and TPMT with cross-referencing and cross-copied text, with exceptions for the peculiarities for each drug (e.g. VOD for thioguanine). Johnaduley (talk) 14:12, 9 September 2012 (UTC)

Thanks for the advices. I'm busy these days, so I'll look in to it later. More inputs would be welcomed.--Jsjsjs1111 (talk) 23:55, 9 September 2012 (UTC)

Thanks from me as well. --ἀνυπόδητος (talk) 08:54, 10 September 2012 (UTC)

• • I realise that at least one editor is uncomfortable with the seeming accent on side effects, but hepatitis really should be noted - The only prospective study of azathioprine (a large London-based project) found the following proportions of adverse drug reaction (ADRs) to Aza:
    • Gastric intolerance (incl nausea) 41%
    • Flu-like symptoms 13.3%
    • Pancreatitis 9.6%
    • Hepatitis 9.6%
    • Rash 9.6%
    • Myelotoxicity (bone marrow suppression) 8.4%
    • Other 8.4%
    • Ref: Aliment. Pharmacol. Ther. 2008 Oct 15;28(8):973-83. PMID:18616518. Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease. Ansari A, Arenas M, Greenfield SM, Morris D, Lindsay J, Gilshenan K, Smith M, Lewis C, Marinaki A, Duley J, Sanderson J. (Table 1). (Gastric intolerance/Nausea is generally regarded as being higher in IBD patients probably because of their gastric sensitivity. Sorry to quote one of my one publications - you can also check papers from other 'heavies' in the field: anything by W Sandborn, W Evans & M Relling, J Colombel, L Lennard, R Weinshilboum is bound to be ok. It's a large and complex topic, but considering that any one time there would be ~50,000 patients in Australia and ~150,000 in Britain on thiopurines, it is important.Johnaduley (talk) 07:20, 11 September 2012 (UTC)
  • As regarding Indications... Azathioprine is an old drug (50+ years) but is still front-line therapy for Crohn's Disease and many other diseases, as well as being an invaluable steroid-sparing drug, so it has been widely used - not quite for "coughs, colds, warts and moles". Anyhow, good luck with it! And yes, Jsjsjs1111, it must have been fun living in the West End/South Brisbane area, no doubt missing jogging along the Southbank and swimming in the subtropical pools there? On the other hand I miss some aspects of life in London, where I lived 100 yards from the Thames at Rotherhithe, for almost 16 years. As my young son said at the time, when asked if he liked living in central London, "Yes it's quite nice, in the Spring all the birds start coughing in the trees" Johnaduley (talk) 07:20, 11 September 2012 (UTC)

Minor Intro error

Intro section has minor typo - The main adverse effect of azathioprine is bone marrow suppression, and in case of people [insert something like: who are genetically deficient for the enzyme] thiopurine S-methyltransferase...

It's looking good. Mercaptopurine could be virtually merged with Azathioprine, with minor difference. -Jad — Preceding unsigned comment added by 203.27.62.92 (talk) 23:29, 9 September 2012 (UTC)

It's now fixed, and thank you very much, dear fellow from Brisbane! I used to live in South Bank last year, just 5 minutes from Mater Health Services :)--Jsjsjs1111 (talk) 23:58, 9 September 2012 (UTC)

• What's the status on this review? No comments in a month+. Wizardman 20:37, 14 October 2012 (UTC)
  • Both the reviewer and the lead editor seem snowed under with work. I am happy to continue reviewing, but I suspect this may need to fail for the time being. JFW | T@lk 21:34, 14 October 2012 (UTC)

    The editor seems to be active, so if there hasn't been progress then a fail would be appropriate. Wizardman 22:19, 14 October 2012 (UTC)

• Another twelve days have gone by. BlueMoonset (talk) 07:25, 27 October 2012 (UTC)

• Still no action by the editor after two more weeks, though there has been some activity by another editor. JFW, it's well past time to take some definitive action here. BlueMoonset (talk) 15:55, 11 November 2012 (UTC)

• I agree. We can always have a go when Jsjsjs1111 has more time. JFW | T@lk 22:00, 13 November 2012 (UTC)