Talk:Sunifiram

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Side effect of chronic headaches[edit]

Word to the wise - be aware that numerous users have reported pressure headaches, often lasting weeks or even indefinitely in one case from the use of sunifiram in combination with other agents. The symptoms may likely include tinnitus and worsening of sleep. Of concern is the fact that it was the addition of sunifiram that initiated the symptoms. This information was removed from the article because it was not backed up by a scientific article, but it nevertheless ought to be of significant concern. --IO Device (talk) 07:21, 25 November 2013 (UTC)

Removed section contents: Safety[edit]

OK, this speculation has got to stop. Can we please keep this page factual? I.E. anything not demonstrated by a study does not belong here. I see absolutely nothing unreasonable about what I am proposing but do see what people like IO_Device are adding to the page as damaging. 2.30.51.94 (talk) 13:54, 20 June 2013 (UTC)

Your claim of "speculation" is bogus because no speculation was ever added to the Safety section. Each statement there was well sourced, and is validated by multiple journal articles and studies. No one said or even suggested that sunifiram causes excitotoxicity or cancer. The facts were presented simply as they are. Since you are not familiar with editing Wikipedia, I will advise you that it is completely normal for related statements to be presented in an article, as long as they're referenced and are presented neutrally. The fact that you don't like a particular statement is not an acceptable reason to remove it. I know you will disagree, but before you do, I advise you to consult a Wikipedia administrator. Why do you think that having safety related information is damaging? Because you have been basically censoring the article, which is a peculiar thing to do, it is required that you declare your financial connections to sunifiram. You have 24 hours, after which the content will be reinserted into the article. --IO Device (talk) 16:26, 20 June 2013 (UTC)
I'm the DRN volunteer who closed the request there for lack of talk page discussion. I do want to comment on this matter, however. I've not looked back through all the reverts, but am going to assume that this edit encapsulates the issue. I have to agree that the material should not be included in the article, not due to lack of sourcing, but because its inclusion violates the WP:SYNTHESIS section of the No Original Research policy, which says:

"Do not combine material from multiple sources to reach or imply a conclusion not explicitly stated by any of the sources."

(Emphasis added.) This information is clearly being included to imply or suggest that there safety issues connected with Sunifiram, but the deleted material only says that there are safety issues connected with PKC alpha. Unless the sources in the removed material specifically discuss Sunifiram, then to suggest or imply that there are safety issues with Sunifiram because it activates PKC alpha and there are safety issues with PKC alpha is prohibited original research via implication under Wikipedia policy. Even if that is not the intent of the editor who wishes for it to be included, it clearly has that effect and appearance and is improper for that reason. Regards, TransporterMan (TALK) 14:53, 21 June 2013 (UTC)
PS: At the DRN listing IO Device said, "As with any drug, readers are very interested in knowing any possible safety concerns. The removal of these concerns by 2.30.51.94 potentially places the readers in jeopardy if they, in their ignorance, choose to use the drug." It is a well-established principle that Wikipedia is not a soapbox and does not raise or imply safety issues which have not specifically been first raised in reliable sources. — TransporterMan (TALK) 15:14, 21 June 2013 (UTC)

For the record, the removed content is saved below, in case more appropriate evidence presents itself in the future. --IO Device (talk) 16:41, 21 June 2013 (UTC)

Safety

Overactivation[1] of glutamate receptors, especially NMDA[2][3][4] but also AMPA[2][3] receptors, induces excitotoxic neurotoxicity.

Sunifiram, like galantamine,[5] activates PKC-α.[6] PKC-α activation has various cellular functions,[7] and can enhance learning and memory.[8] Increased activation of PKC-α is also associated with the growth and invasion of cancers.[9][10] High levels of PKCα are linked to malignant brain cancer.[11] Moreover, a high proliferation rate of glioma tumor cells is the result of overexpression of isozyme PKC-α.[12]

References
  1. ^ Szydlowska, K.; Tymianski, M. (2010). "Calcium, ischemia and excitotoxicity". Cell Calcium 47 (2): 122–129. doi:10.1016/j.ceca.2010.01.003. PMID 20167368.  edit
  2. ^ a b Frandsen, A.; Drejer, J.; Schousboe, A. (1989). "Direct evidence that excitotoxicity in cultured neurons is mediated via N-methyl-D-aspartate (NMDA) as well as non-NMDA receptors". Journal of neurochemistry 53 (1): 297–299. doi:10.1111/j.1471-4159.1989.tb07327.x. PMID 2566655.  edit
  3. ^ a b Choi, D. W. (1992). "Excitotoxic cell death". Journal of Neurobiology 23 (9): 1261–1276. doi:10.1002/neu.480230915. PMID 1361523.  edit
  4. ^ Mody, I.; MacDonald, J. F. (1995). "NMDA receptor-dependent excitotoxicity: The role of intracellular Ca2+ release". Trends in pharmacological sciences 16 (10): 356–359. doi:10.1016/S0165-6147(00)89070-7. PMID 7491714.  edit
  5. ^ Moriguchi, S.; Shioda, N.; Han, F.; Yeh, J. Z.; Narahashi, T.; Fukunaga, K. (2009). "Galantamine enhancement of long-term potentiation is mediated by calcium/calmodulin-dependent protein kinase II and protein kinase C activation". Hippocampus 19 (9): 844–854. doi:10.1002/hipo.20572. PMID 19253410.  edit
  6. ^ Cite error: The named reference pmid23733502 was invoked but never defined (see the help page).
  7. ^ Nakashima, S. (2002). "Protein kinase C alpha (PKC alpha): Regulation and biological function". Journal of biochemistry 132 (5): 669–675. doi:10.1093/oxfordjournals.jbchem.a003272. PMID 12417014.  edit
  8. ^ Hongpaisan, J.; Alkon, D. L. (2007). "A structural basis for enhancement of long-term associative memory in single dendritic spines regulated by PKC". Proceedings of the National Academy of Sciences 104 (49): 19571–19576. doi:10.1073/pnas.0709311104. PMC 2148330. PMID 18073185.  edit
  9. ^ Koivunen, J.; Aaltonen, V.; Peltonen, J. (2006). "Protein kinase C (PKC) family in cancer progression". Cancer Letters 235 (1): 1–10. doi:10.1016/j.canlet.2005.03.033. PMID 15907369.  edit
  10. ^ Haughian, J. M.; Bradford, A. P. (2009). "Protein kinase C alpha (PKCα) regulates growth and invasion of endometrial cancer cells". Journal of Cellular Physiology 220 (1): 112–118. doi:10.1002/jcp.21741. PMID 19235902.  edit
  11. ^ Yazaki, T.; Ahmad, S.; Chahlavi, A.; Zylber-Katz, E.; Dean, N. M.; Rabkin, S. D.; Martuza, R. L.; Glazer, R. I. (1996). "Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxynucleotide". Molecular pharmacology 50 (2): 236–242. PMID 8700129.  edit
  12. ^ Baltuch, G. H.; Dooley, N. P.; Rostworowski, K. M.; Villemure, J. G.; Yong, V. W. (1995). "Protein kinase C isoform alpha overexpression in C6 glioma cells and its role in cell proliferation". Journal of neuro-oncology 24 (3): 241–250. doi:10.1007/BF01052840. PMID 7595754.  edit

Ampakine or not?[edit]

I think the AMPA PAM claim, considering it's uncited, must not be kept in the article. I find there is inadequate substantiation thus far for an allosteric effect. --IO Device (talk) 22:31, 21 June 2013 (UTC)

Doi 10.1111/j.1527-3458.2006.00039.x clearly hypothesizes ampakine modulation. E.g. p.46: "NBQX, inactive on its own, antagonizes the unifiram reversal of the KYNA antagonism of the NMDA-evoked tritium release (Fig. 4A) as well as the sunifiram-mediated effect (Fig. 4B), suggesting involvement of AMPA receptors in the effects of both compounds (11)". Also p.49: "The hypothesis that unifiram and sunifiram exert their antiamnesic effect through the activation of AMPA-mediated effects is also supported by in vitro results in which both compounds produced a NBQX-sensitive reversal of the kynurenate-induced antagonism in the 'kynurenate test.'" I have therefore restored the cut text but have added "appears to" with the reference. — Preceding unsigned comment added by GKantaris (talkcontribs) 06:43, 24 June 2013 (UTC)

Replying to your deleted comments:

There are two things you need to know: 1. Ampakine requires ALLOSTERIC modulation. Until you find a sourced statement stating that sunifiram is allosteric in its effect, or until you show a direct sourced statement that sunifiram is an ampakine, you cannot call it an ampakine. 2. An agonist doesn't have to be allosteric. --IO Device (talk) 07:01, 24 June 2013 (UTC)

You're the one deleting things and adding things without evidence (like all the stuff about Sunifiram and cancer), and generally impoverishing and damaging the article. A number of the careful studies undertaken by Galeotti and team show "AMPA-mediated" effects. Sure, the word "allosteric" isn't used by that team, but they're showing indirect AMPA activation, not claiming direct binding to receptors. The statement that sunifiram is a PAM of AMPA has been in the article from before you were involved in editing it. You coming in and just removing it needs a bit more research and sifting through evidence than you seem to have done. And try to keep things civilized -- accusing me of being "lame" because I tried in a bit of a hurry to *restore* content you arbitrarily deleted (you've never made a typo, huh?) and threatening to "report" me because you don't see the evidence I see in the article I read and cited in good faith (i.e. over a matter of interpretation), suggests you're getting unhealthily possessive about this article. GKantaris (talk) 10:22, 25 June 2013 (UTC)

Why would you reply to my deleted comments? Clearly I deleted them for a reason, i.e. I didn't mean them. Are you feeling sane? I am not stopping anyone from making sourced, relevant, and constructive edits to the article. For now, all I am saying is that I too have read the reference, and it does not say that sunifiram is a PAM, yet you continue to lie about it. I acknowledge that it is a dirty ampakine (dirty in that it also affects NMDAR activation). In your comment above, you also lied about me linking sunifiram and cancer. The truth is that I only linked PKCa and cancer. Let's move on and continue to improve the article with justified claims. --IO Device (talk) 17:03, 25 June 2013 (UTC)

Removed section: Alternatives[edit]

The section quoted below was removed by an editor. It is saved here.

Alternatives

Nefiracetam is a drug with similar effects.[1] Lithium potentiates AMPAR[2] and LTP[3][4][5] while inactivating Src kinase[6] and protecting[6][7][8][9] against NMDAR excitotoxicity.

References
  1. ^ Moriguchi, S.; Shioda, N.; Han, F.; Narahashi, T.; Fukunaga, K. (2008). "CaM kinase II and protein kinase C activations mediate enhancement of long-term potentiation by nefiracetam in the rat hippocampal CA1 region". Journal of neurochemistry 106 (3): 1092–1103. doi:10.1111/j.1471-4159.2008.05440.x. PMID 18445137.  edit
  2. ^ Gebhardt, C.; Cull-Candy, S. G. (2010). "Lithium acts as a potentiator of AMPAR currents in hippocampal CA1 cells by selectively increasing channel open probability". The Journal of Physiology 588 (20): 3933–3941. doi:10.1113/jphysiol.2010.195115. PMC 3000583. PMID 20807790.  edit
  3. ^ Shim, S. S.; Hammonds, M. D.; Tatsuoka, C.; Jung Feng, I. (2012). "Effects of 4-weeks of treatment with lithium and olanzapine on long-term potentiation in hippocampal area CA1". Neuroscience Letters 524 (1): 5–9. doi:10.1016/j.neulet.2012.06.047. PMID 22750162.  edit
  4. ^ Son, H.; Yu, I. T.; Hwang, S. J.; Kim, J. S.; Lee, S. H.; Lee, Y. S.; Kaang, B. K. (2003). "Lithium enhances long-term potentiation independently of hippocampal neurogenesis in the rat dentate gyrus". Journal of neurochemistry 85 (4): 872–881. doi:10.1046/j.1471-4159.2003.01725.x. PMID 12716419.  edit
  5. ^ Voytovych, H.; Kriváneková, L.; Ziemann, U. (2012). "Lithium: A switch from LTD- to LTP-like plasticity in human cortex". Neuropharmacology 63 (2): 274–279. doi:10.1016/j.neuropharm.2012.03.023. PMID 22507665.  edit
  6. ^ a b Hashimoto, R.; Fujimaki, K.; Jeong, M. R.; Christ, L.; Chuang, D. M. (2003). "Lithium-induced inhibition of Src tyrosine kinase in rat cerebral cortical neurons: A role in neuroprotection against N-methyl-D-aspartate receptor-mediated excitotoxicity". FEBS letters 538 (1–3): 145–148. doi:10.1016/S0014-5793(03)00167-4. PMID 12633868.  edit
  7. ^ Chen, R. W.; Chuang, D. M. (1999). "Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity". The Journal of biological chemistry 274 (10): 6039–6042. doi:10.1074/jbc.274.10.6039. PMID 10037682.  edit
  8. ^ Nonaka, S.; Hough, C. J.; Chuang, D. M. (1998). "Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx". Proceedings of the National Academy of Sciences of the United States of America 95 (5): 2642–2647. doi:10.1073/pnas.95.5.2642. PMC 19446. PMID 9482940.  edit
  9. ^ Hashimoto, R.; Hough, C.; Nakazawa, T.; Yamamoto, T.; Chuang, D. M. (2002). "Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: Involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation". Journal of neurochemistry 80 (4): 589–597. doi:10.1046/j.0022-3042.2001.00728.x. PMID 11841566.  edit

--IO Device (talk) 15:47, 24 September 2014 (UTC)