Talk:Zidovudine

Mode of Action

Should we be making it clear in the article that the mechanism behind AZT’s stated affinity for HIV's reverse-transcription enzyme is cell division -- that AZT has no affinity for any kind of non-dividing cell, HIV-infected or not? BruceSwanson (talk) 16:35, 16 December 2010 (UTC)

AZT doesn't have an affinity for cells. It has an affinity for various forms of DNA polymerase, a family of enzymes essential in DNA replication, which in turn is a necessary step in cell division. Unlike bacteria, viruses cannot replicate on their own, so they are dependent upon cellular DNA replication machinery to reproduce and spread. Many modern antivirals act at the level of DNA polymerase.

I'm not sure I see that we need to emphasize this aspect here when this is an issue common to many antiviral medicines. It creates the impression that AZT is somehow unique in this regard, which is misleading and false. Do you think we need to belabor this point on, say, acyclovir, cidofovir, ganciclovir, and ribavirin? Or is there something unique about AZT in your view? MastCell ^Talk 17:42, 16 December 2010 (UTC)

I don't see an issue with it (phrased as MastCell explains), particularly if the words "Like all/most antiviral medications..." but there needs to be a source for it. It's a reasonable and interesting part of the mechanism that needs to be contextualized within the family of antiviral drugs. WLU (t) (c) Wikipedia's rules:^simple/_complex 18:14, 16 December 2010 (UTC)

This might be a useful review article. [1] Graham Colm (talk) 19:20, 16 December 2010 (UTC)

So the mechanism enabling AZT, acyclovir, cidofovir, ganciclovir, and ribavirin is cell division alone, not the presence of a drug's viral target inside a cell. And the absence of that viral target will not prevent each drug from terminating DNA/RNA synthesis during cellular replication. Is this correct? BruceSwanson (talk) 22:43, 16 December 2010 (UTC)

No. Graham Colm (talk) 23:25, 16 December 2010 (UTC)

Bruce, if you need some general education about virology and antiviral pharmacology, then you should ask at the reference desk, read some of the articles that have been suggested here, or check out a few college-level textbooks. If you're just feigning ignorance to post ridiculous "gotcha" questions, then please don't waste everyone's time. Either way, you're in the wrong venue. MastCell ^Talk 05:28, 17 December 2010 (UTC)

Here are two studies dated 1995 and 2000 respectively. 1; 2.

And now consider this sentence, taken from the Modes of Action section of the article:

The triphosphate form also inhibits DNA polymerase used by human cells to undergo cell division, but has approximately 100-fold greater affinity for viral reverse transcriptase.[26] Because of this selectivity, in vitro studies have shown that AZT inhibits HIV replication without affecting the function of normal T cells.[8]

The two footnotes [26, 8] are from 1986 and 1985, respectively. I move that the above statement be amended as follows:

Early studies [26, 8] indicated that in vitro the triphosphate form of AZT inhibited DNA polymerase used by human cells to undergo cell division, but had approximately 100-fold greater affinity for viral reverse transcriptase; and that because of that affinity AZT inhibited HIV replication without affecting the function of normal T cells. Later in vitro studies [insert ref's 1&2 above] indicate that AZT's cytotoxic interaction with cellular metabolism both in vitro and in vivo may be more complex and powerful than previously thought.

Comments, anyone? BruceSwanson (talk) 05:10, 18 December 2010 (UTC)

The papers discuss the mechanisms by which AZT suppresses bone marrow function and causes anemia. You seem to want to juxtapose with information about AZT's binding affinity and the function of mature T cells. Thus, your proposed text is vague and misleading. So no. As an aside, this will probably be the last time I address efforts to cherry-pick the medical literature and misrepresent this subject; see WP:SHUN. MastCell ^Talk 05:16, 19 December 2010 (UTC)

The full text of the two papers in question is here and here. BruceSwanson (talk) 07:35, 19 December 2010 (UTC)

Those are primary sources, so are inappropriate. WLU (t) (c) Wikipedia's rules:^simple/_complex 01:54, 20 December 2010 (UTC)

The Internet contains many forums for the discussion of idiosyncratic views on HIV/AIDS. This is not one of them.

They are definitely primary. Primary sources are to be used with care as they are subject to abuse, and it is a violation to base articles on primary sources. (I have commented on primary sources on my user and talk pages.) WLU has deleted the two primary sources I recently placed (they are here and here). I have no problem with that, provided certain other primary sources in the article are deleted as well. I have identified the following as primary sources and nominate them for deletion [The numbers are not the footnote-numbers]: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20. After giving the above refs a look, read WLU's remarks regarding them, made in the second paragraph of the Templates section of my Talk page. I have excerpted those remarks below: The article contains many, many sources (28 as of my reading), the sources are reliable and third-party, and there are very vew primary sources used in the page. Those few that are used are appropriately used - primary sources are permitted if not misused. The statements they source are quite basic, they are accurate, they report the scientific consensus that AZT is a useful and safe (relative to dying from AIDS) treatment for HIV infection, and present no synthesis. Consensus for the statement was established on talk:Zidovudine in July of this year. The fact that you think AZT causes more harm than HIV is irrelevant, the scientific community agrees it is an extremely useful treatment for HIV infection to prevent AIDS. Note especially two of WLU's assertions: . .. [the sources] report the scientific consensus . . . and . . . the scientific community agrees . . . . Now look over again the two primary sources he deleted. They are here and here. Note certain terms in the titles, such as inhibits, potently inhibits dramatically alters, and clinically relevant concentrations. Are such terms the reason WLU feels that the papers are unacceptable as primary sources, as opposed to the other primary sources long in place? Does he feel that the papers actually support AZT's use as treatment but is afraid their titles will mislead lay readers? Or is WLU's generalization about the scientific consensus regarding the safety and efficacy of AZT simply an inaccurate one? BruceSwanson (talk) 19:43, 20 December 2010 (UTC) It's not the source that's problematic, it's how it is used. Those two sources were used to represent strong general risks due to specific mechanisms based on primary sources. For that you would need a secondary source. The first source, Horowitz, is the first documentation of AZT being synthesized and the text is accompanied by two other sources. That would be an acceptable use of a primary source in my mind, in particular because no interpretation is needed. The second source is Horowitz again. The third similarly reports only the results of the primary source with no interpretation. Same with the fourth. And the fifth. And the sixth and seventh. Yep, you're wasting our time. If you can't tell the difference between an obviously appropriately used primary source that is not used to present a conclusion that bucks the scientific consensus and one that's cherry-picked towards a slanted agenda, there's not much point in continuing the conversation. WLU (t) (c) Wikipedia's rules:simple/complex 21:05, 20 December 2010 (UTC) Numbered the links; they're not permalinks so any changes to the references in the main page will break about three quarters of them. This is the version I believe is being worked from. WLU (t) (c) Wikipedia's rules:simple/complex 22:59, 20 December 2010 (UTC) Real name editors! Are you willing to let your supervisors, colleagues, co-workers, family, and friends view your thoughts on this dispute? Maybe some of those people would care to weigh in with their real names too? So let's start at the beginning with my original question: Should we be making it clear in the article that the mechanism behind AZT’s stated affinity for HIV's reverse-transcription enzyme is cell division -- that AZT has no affinity for any kind of non-dividing cell, HIV-infected or not? A pseudonym answered that AZT, a thymidine analog, has no affinity for cells at all. Meanwhile the article states that AZT penetrates cell walls by diffusion. What isn't stated clearly is that once inside, AZT's sole originally-designed chemotherapeutic purpose is to destroy the cell during replication, regardless of what kind of cell it is and certainly whether or not it contains reverse transcriptase. My concern is that casual readers may go away with a vague impression that AZT somehow targets HIV specifically and not dividing cells in general -- in other words, that it shares HIV's stated affinity for T-cells. BruceSwanson (talk) 23:10, 20 December 2010 (UTC) Wow, what a spectacular waste of time. There are certainly some primary sources referred to in Bruce's above post. There are also numerous non-primary sources, perhaps a third. I've looked over the uses of the primary sources and found none that were used inappropriately. They reference the type of basic information that primary sources are useful for (raw numbers, initial studies, large and early clinical trials, unsurprising results that are corroborated by later studies and were not contradicted by later evidence). I didn't find any that were outright inappropriately used, though some could be supplemented by reference to secondary sources. In many cases they were. So, I think we're done, it's shun time. Yeah, Bruce, allow me to yet again point out that your call for "real name" is just a red herring and really just underscores your ability to substantiate your postings with anything remotely close to an appropriate use of a reference or policy. If you want to edit under your real name, I suggest Citizendium, where you will doubtless find a hostile reception. Oh, and your point "What isn't stated clearly is that once inside, AZT's sole originally-designed chemotherapeutic purpose is to destroy the cell during replication, regardless of what kind of cell it is and certainly whether or not it contains reverse transcriptase" is pretty stupid considering the reason it failed to be used as a chemotherapeutic agent is because it was wildly, wildly unsuccessful at destroying body cells during replication. That's why it's toxicity is quite low - it tends to interfere with viral and mitochondrial ability to replicate, not the eukaryotic cells that comprise much of the human body. Also, your concern is that people might go away with the impression that AZT is safer than dying of AIDS. WLU (t) (c) Wikipedia's rules:simple/complex 23:21, 20 December 2010 (UTC) No one told you to re-number the references. You chose to waste your own time there. I'm curious about your statement that AZT "tends to interfere with viral and mitochondrial ability to replicate, not the eukaryotic cells that comprise much of the human body." BruceSwanson (talk) 02:30, 21 December 2010 (UTC) Given your ignorance of basic biology, I'm not surprised. WLU (t) (c) Wikipedia's rules:simple/complex 04:15, 21 December 2010 (UTC)