Talk:Sulbutiamine

Sulbutiamine structure
Can someone that understands this better look at the 'mechanisms of action' section and fix the wording of this sentence?:

"Sulbutiamine is a thiamine derivative which has two different properties in comparison with vitamin B1 as a result of structural modification of free thiamine, namely opening of the thiazole ring, esterification of the alcohol groups and dimerization, with formation of a disulfide bridge." 209.63.116.205 (talk) 16:51, 2 October 2008 (UTC)
 * I completely reworded that sentence and moved it to the article opening where it makes more sense. The structural characteristics of sulbutiamine should not be included in the "Mechanism of action" section unless a structure-activity relationship (SAR) is being discussed. Firewall62 (talk) 04:59, 23 December 2008 (UTC)
 * I just revised the article again and removed the wordy discussion about the structural characteristics of sulbutiamine. Those characteristics are obvious when comparing the structures of sulbutiamine and thiamine. Pointing them out isn't necessary. In my opinion, the article should focus more on the biochemistry and clinical pharmacology of sulbutiamine--information that can't be obtained simply by looking at the structure. Firewall62 (talk) 20:09, 30 March 2009 (UTC)

Excuse me if this is a dumb question, but I notice that the systematic name doesn't seem to take account of the fact that sulbutiamine is a dimer: the two aromatic groups are listed as "[4-[(4-amino-2-methyl-pyrimidin-5-yl]" and "3-[2-[(etc." despite being identically placed. I don't do this at all often, but I would render sulbutiamine as S-S'-5-aza-N-formyl-6-(4-amino-2-methyl-pyrimidin-5-yl)-3-thio-3-hexenyl 2-methylpropionate, or even S-bis- etc. If the suffix conflicts with the dimerization, then a 2-methylpropoxycarbonyl could be stuck in before the pyrimidinyl, or could it? Scutigera (talk) 18:10, 4 July 2012 (UTC)

Article development and assessment change
Over the past week, I have made numerous content additions and improvements to the article. At this point, practically every published source on sulbutiamine has been incorporated into the article and cited. Compared to other drugs, there is not a lot of information on sulbutiamine, and the length of the article will invariably be limited by the number of reliable sources. However, I believe that the article is currently B quality on the assessment scale, and I would like to see it reach GA quality in the future. Firewall62 (talk) 19:39, 6 April 2009 (UTC)

Adverse effects
The abstract used for source 5 doesn't seem to really support the wording used in the adverse events portion about the bipolar person. It doesn't seem to mention anything about a prescription being written, and, in fact, speaks of the dangers of over the counter medications. This section of the article seems to imply more of a medical distinction on sulbatiamine than is warranted by the source cited. Maybe this is in the full-text, but I doubt it based upon how the abstract is worded (i.e. "his psychiatric care was severely compromised through him defaulting appointments and frequent changes of psychiatrists")

71.2.123.68 (talk) 19:22, 25 August 2009 (UTC)

We need more adverse effects mentioned. So far, I'm just finding anecdotes and conjecture, but what I find are many reports of addiction or discontinuation side-effects. The rationale seems to be that it makes dopamine receptors more sensitive but causes there to be less of them. There are articles in journals that make you wonder this, but they are too technical for me to understand. There are even people using sulbutiamine recreationally. They claim they quit taking it after 4 days and feel lethargy and headache. There has to be some real information on this out there.72.11.53.145 (talk) 05:13, 26 May 2014 (UTC)

Erectile and memory claim
Is a reference available for the erectile dysfunction and memory claim? Or is it included in the bi-polar article of reference 5? Access to the full article requires a paid subscription. From the abstract it doesn't sound like it would cover erectile dysfunction or memory aspects of Sulbutiamine. —Preceding unsigned comment added by 184.77.198.218 (talk) 18:17, 15 June 2010 (UTC)

Therapeutic claims
I have removed fairly extensive claims of therapeutic benefit that were based on sources failing our sourcing requirements for such claims. Please don't restore that content without high-quality, recent secondary sources. -- Scray (talk) 09:04, 15 March 2013 (UTC)
 * Sulbutiamine is an approved drug (i.e. not sold as a dietary supplement/nootropic) in several countries, so that shouldn't be too hard. The Drugs Today citation you removed (Van Reeth, 1999) was a review article, so perhaps it can be used to restore/modify some content. (I don't have access to the full text, though.) Fvasconcellos (t·c) 13:00, 15 March 2013 (UTC)
 * A 14-year-old article in a top journal would fail WP:MEDRS for claims like these; exacerbating the problem, Drugs Today is far from a top journal. -- Scray (talk) 02:02, 18 March 2013 (UTC)
 * It's a narrative review in a respected, peer-reviewed journal and is the most recent secondary source available. I wouldn't interpret that as failing MEDRS—quite the contrary—and if we have an article on sulbutiamine at all, it's probably (I say probably because, again, I have no full-text access) the best reference we can use. Fvasconcellos (t·c) 22:11, 25 March 2013 (UTC)
 * Here are some links to Russian web pages that Google Chrome can translate.
 * http://kornyenko.com/klinicheskaya-effektivnost-eneriona.html
 * http://health.mail.ru/drug/enerion/
 * http://www.apteka.ua/article/1408
 * http://www.medlinks.ru/article.php?sid=24311
 * http://medi.ru/doc/a0210602.htm
 * http://uronews.ru/2012/08/lechenie-erektilnoj-disfunkcii-enerion-sialis-2/
 * And in English, on PubMed: http://www.ncbi.nlm.nih.gov/pubmed/15776829
 * They might not count as "high-quality", but might as well leave them here, eh?
 * --Clevera (talk) 02:58, 16 March 2013 (UTC)
 * Leave them here on the talk page? Fine.  If you mean to restore therapeutic claims based on sources failing WP:MEDRS - then no, that would violate our standards for health-related content.  -- Scray (talk) 15:12, 16 March 2013 (UTC)


 * You have deleted a good deal of the article but made little effort to explain how it violated Wikipedia's guidelines. That is not to say that it did not, but if the reason you deleted such a large amount of information was on the basis of there being too many references to primary studies then note the following from WP:MEDRS: 'All Wikipedia articles should be based on reliable, published secondary sources. Reliable primary sources may occasionally be used with care as an adjunct to the secondary literature, but there remains potential for misuse. For that reason, edits that rely on primary sources should only describe the conclusions of the source, and should describe these findings clearly so the edit can be checked by editors with no specialist knowledge. This at least seems to suggest that edits can rely on primary sources as long as they describe the conclusions and do so clearly; the ideal would be to rely only on secondary sources (which the article is based on). Wikipedia's guidelines only make sense if it is understood that it is at least possible to refer to primary sources in the way that was done with sulbutiamine. A quote from WP:MEDRS again, on primary sources without accompanying secondary material: 'If the conclusions of the research are worth mentioning, they should be described as being from a single study, for example: "A 2009 U.S. study found the average age of formal autism spectrum diagnosis was 5.7 years"'. This is what was done, as the conclusions were of interest and published in reliable journals (see below on my comment relating to 'Drugs Today').


 * It is true that if, in a particular subject area, no timely review was performed then it should be deleted. But studies supporting the initial findings of one study are not necessarily making new claims - they may simply be more evidence in favour of the original claim (the asthenia studies seem to be of this kind). Therefore a secondary source preceding them is allowable, for 'reliable primary sources may occasionally be used with care as an adjunct to the secondary literature'. Wikipedia's guidelines on this area state as a rule of thumb that one should look for information in the last five years or so. It would be wrong to say that this is an inviolable command (after all, it is a 'rule of thumb') - especially so in contexts where research on something is hard to come by. Also, why is 'Drugs Today (Barc)' not an acceptable journal? It is not the crème-de-la-crème but Wikipedia’s guidelines only seem to require that we use a reliable source that is the best and most reliable available; this is the best available for sulbutiamine, and its reliability is not such that it should not be referred to, for after all, the respected 'Meyler's Side Effects of Drugs' is quite happy to refer to 'Drugs Today (Barc)' many times over. So why can't we?


 * The removal of all this information on sulbutiamine is overkill, as now someone looking at this page would be under the impression that science has had almost no interest in it at all in so far as it relates to health. We should at least be able to point out that it has not been completely neglected. Therefore I have put the information back to where it was, added warning messages, and we should make sure it states clearly on each claim when single studies were used (if necessary as I am pretty sure it was clear anyway) and where animal studies were being referred to (this is something that needs changing in the information relating to its mechanism of action). I was responsible for a negligible part of the original page, so my view is not based on over-attachment to my own work. It is just that at the moment improvements should focus on highlighting the lack of certainty on these topics, in keeping with Wikipedia’s guidelines, rather than ignoring them altogether. I believe that a much briefer section on its possible therapeutic uses should be developed in the long run.


 * Dutyworth (talk) 19:21, 24 March 2013 (UTC)

Mechanism
This will require some heavy citation but I feel the mechanism section does not address the fundamental issue of how sulbutiamine is transformed into thiamine. It should be added that the disulfide bond is cleaved in vitro, likely after entering the CNS where the thiol monomers are deprotonated to the thiolate anions leading to an intramolecular attack on the amide carbonyl, which is followed by ring closure and dehydration to the thiazolium cation. Or something like that.Glucuronide (talk) 05:59, 20 March 2015 (UTC)

First synthesis
DE1620538 is a valid granted patent with a priority date of 1965-03-18 and a granted date of 1977-12-31 that contains a composition of matter claim for the chemical structure that corresponds to sulbutiamine and process claims for synthesizing it. If the structure of sulbutiamine had previously been reported in the patent or scientific literature, this would have been regarded as prior art and a patent would never have been granted. Furthermore it is obvious that if the structure had never been reported before, then a synthesis for could not have been previously described either. Hence to say this is the first reported synthesis of sulbutiamine is not original research. This is implicit in the patent. What we are relying on is the patent examiners doing their job to identify relevant prior art and not on any original research on our part. Boghog (talk) 12:48, 15 March 2015 (UTC)

For reference, GB1089475 is in the same patent family (essentially the same patent filed in a different country): Both claim a priority date of 1965-03-18 from Japanese patent application JP19650015344.

Also for reference, the Chemical Abstract Service reports that the following citations are the first publications of sulbutiamine by the same group. These were published shortly after the Japanese patent application filed:


 * Patents are generally not reliable sources, per WP:SPS which is policy. Also with regard to reliability,  to the best of my knowledge patent examiners don't actually pick apart data and methods that are presented in patent applications - if it looks plausible they go with it.  Many things are patented that turn out not to work in real life.  More importantly for the claim of "first" -  for all you or I know, the company or a competitor published the same, or a different, synthesis somewhere in the scientific literature after the priority date of the patent application, but before the patent application was published.  The claim  of "first" is completely WP:OR and if what you write above is your OR reasoning, poor OR at that.  You need a secondary source saying what the "first" was. Jytdog (talk) 15:45, 15 March 2015 (UTC)
 * What I wrote above is really poor OR because it is not OR. Once again, you are overstating Wikipedia policy. Per WP:SPS, if a self-published source such as a patent has been authored by an established expert, that patent may be considered a reliable source. The inventors of this patent are not crack pots.  Quite to the contrary, they have an extensive publication record in the same field (see publication list above) and therefore qualify as established experts.  Furthermore while patent examiners cannot verify that an invention works, they can verify priority and inventorship.  The priority date and the fact that the patent has granted doesn't confirm that the synthesis works, but it does confirm that it was the first reported synthesis.  Finally since the inventors are experts and the inventors subsequently published the same synthesis in a peer reviewed journal, it is highly that they synthesis that they reported does work. Boghog (talk) 19:27, 15 March 2015 (UTC)


 * The OR lies in the claim of "first reported".  The following sequence is totally plausible.
 * 1) company files a patent application on inventors' work
 * 2) some other group publishes a synthesis of the same compound in a journal article
 * 3) inventors publish their synthesis in a journal article. (or show it at a conference)
 * 4) patent application publishes
 * 5) patent issues and publishes.
 * the first published synthesis is 2), not 3) nor 4) nor 5).  Even if 2) doesn't happen, the inventors' own scientific publication can come out before the patent application published or the patent issues.  It is OR to say that the issued patent (date of issuance) is the first publication.  It is even OR to say that the published patent application is the first published synthesis.  You need a secondary source that says what the first published synthesis is.  You ~could~ do a search yourself, but that would be OR.  You cannot just assume the published patent application or issued patent is the first; the assumption is OR and poor at that.  You can say the inventors invented that synthesis, based on a patent.  Sure, that is OK generally but still dangerous as the patent is both a primary source and a SPS.   But inventing is not publishing.  Jytdog (talk) 19:55, 15 March 2015 (UTC)
 * Even if someone else published a sulbutiamine synthesis before the patent application published but after the priority date, it would still not be considered first. The priority claim of "first" is based on first disclosure, not first publication. This is true for both patents (when first filed) and the scientific literature (when first submitted for publication).  Furthermore patents applications are more than abstract inventions.  Sufficiency of disclosure requires that sufficient detail is given for someone else to carry out the invention. In this case, the initially filed patent application gave a complete description of how sulbutiamine was prepared.  Hence this patent application as first filed is the first reported synthesis of sulbutiamine and it is not OR to state that. In this particular case, the inventors own publication did appear before the patent published but after the priority date. Per WP:CALC, it is not OR to state that the first disclosure of the patent preceded the publication. Boghog (talk) 21:14, 15 March 2015 (UTC)
 * i took issue with your use of "reported". As I am sure you know patent applications don't publish until 18 months after their priority date, and scientists often publish elsewhere before that; whatever that publication is becomes the first actual report. If you want to talk about who invented the specific synthesis described in issued claims, that is another discussion - the issue there is just primary/SPS and using the patent is marginally OK if you limit the content to just what the source says and don't give it too much WEIGHT.  This is kind of a stupid/petty argument we are in. If you change the content from "The synthesis of sulbutiamine was first reported" to "A synthesis of sulbutiamine was reported" my objection goes away, or even better: "Taiho, which invented sulbutiamine, also patented a method to make it" or the like.  Jytdog (talk) 21:21, 15 March 2015 (UTC)

OK so change it to "A synthesis of sulbtiamine was reported..." although I find it very unlikely there is a synthesis that predates the one I posted, it is the earliest synthesis indexed by scifinder and reaxys. It's amazing how outright errors can persist on wikipedia for so long (like the version the preceded my edit) but the moment well cited information is introduced everyone is up in arms.Glucuronide (talk) 05:58, 20 March 2015 (UTC)


 * According to Scifinder, the earliest published synthesis was also authored by chemists at Taisho Pharma. This synthesis was published before the Taisho Pharma patent published but after the patent was filed. However you look at it, Taisho Pharma disclosed/published the first synthesis. Per WP:CALC, why can't we simply state that Taisho Pharma reported the first synthesis? All we are doing is comparing the dates of sulbutiamine publications indexed by Scifinder. In any case, I restored the text minus "first" and included both the patent and scientific publication. Boghog (talk) 07:00, 20 March 2015 (UTC)

Problems with universal statements based on animal studies
The following makes definitive statements in the content about how this drug that people take, works in people. It is invalid to make blanket statements like this for CNS drugs (cancer is one thing, where we can pull a tumor out of somebody and get a decent idea of what it is doing to human tissue. can't do that with a human brain). This needs to be way, way toned down and it made clear this is rodent work.


 * Mechanism of action

Sulbutiamine is a lipophilic molecule that crosses the blood–brain barrier more easily than thiamine. Its metabolism in the brain leads to an increase in the levels of thiamine and thiamine phosphate esters. While the exact mechanism of action of sulbutiamine is unknown, it is thought to occur through the upregulation of the reticular activating system, which is the center of arousal and motivation in the brain. The administration of sulbutiamine potentiates glutamatergic activity in the prefrontal cortex through a reduction in the density of kainate glutamate receptors, which may occur in response to a modulation of intrasynaptic glutamate. The facilitation of central glutamatergic transmission is a likely explanation for the ability of sulbutiamine to improve memory. In addition to its action on cholinergic and glutamatergic transmission, the administration of sulbutiamine reduces the release of dopamine in the prefrontal cortex, which increases the density of D1 dopamine receptors through a compensatory mechanism. The modulation of dopaminergic transmission may also contribute to the ability of sulbutiamine to improve memory. A possible explanation for the pharmacodynamics of sulbutiamine is the increased availability of thiamine triphosphate (ThTP). Although the full physiological role of ThTP is unknown, it is an integral component of synaptosomal membranes, participates in the phosphorylation of proteins, and activates chloride channels that have a large unit conductance. The activation of chloride channels by ThTP may be involved in the modulation of receptor binding.

- Jytdog (talk) 10:30, 24 April 2016 (UTC)

scam
This whole page is a commercial for sulbutiamine. Having taken sulbutiamine a while, and gotten really sick from it, as did other people on amazon reviews I can say it does not have thiamine activity. It is chemically similar to thiamine disulfide which is a known thiamine transporter inhibitor in several studies. So it induces thiamine deficiency in the user. How about a section about this. Canyouguessmyname (talk) 23:23, 23 January 2018 (UTC)

sulbutiamin is a thiamine transporter inhibitor
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1192637/pdf/jphysiol00562-0096.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC235561/pdf/jbacter00304-0307.pdf

I will change the page accordingly to something like "Sulbutiamine is a thiamine transporter inhibitor that is marketed as a nootropic" Canyouguessmyname (talk) 01:08, 27 January 2018 (UTC)
 * These refs are not OK. Please do read WP:MEDRS. There is link to recent reviews in pubmed in one of the beige boxes at the top of this page. Jytdog (talk) 02:59, 27 January 2018 (UTC)

Sourcing
So
 * only one review in pubmed, in french, from 1999
 * nothing at EMA
 * nothing at UK electronic medicines compendium
 * search at FDA yields one hit, a big list that includes "|Arkaliox|Proprietary|n/a|sulbutiamine 200 MG Oral Tablet [Arkaliox]".

Going to need to dig for books and other stuff it seems starting to dig through various books... will post things as I find them...Jytdog (talk) 03:46, 27 January 2018 (UTC)
 * got its INN in 1980 in list 20


 * This ref, says the following:
 * "Arcalion is a brand of sulbutiamine 200 mg per tablet. Sulbutiamine was first marketed by Servier in France in 1973, with the name Arcalion. The tablet doses at 100 mg were discontinued in January 1989, leaving only 200 mg tablets in the market. The product has since undergone a 'validation procedure', as required by European directive 75/319/EEC, in the 1983 to 1994 editions of the French data slheet compendium (Vidal), the licenced indication was 'proposed for symptomatic treatmnent of functional fatigue'. According to a statement by the French medicine agency the expression 'proposed for' means that, despite pharmacological properties. the clinical indications for a given drug have not been validated in comparative clinical trials. In the conclusion it says 'The wording of the indications for sulbutiamine is unacceptable. The term 'certain inhibitory states' is meaningless' (Prescrire International, August 1996, vol 5, no 24). Mental and physical inhibition can correspond to a variety of conditions, ranging from exhaustion due to overwork to depression or psychosis. When a patient complains of fatigue, every attempt must be made to identify the precise cause: it is not enough simply to rule out depression. There are no clinical trial data on which health professionals can base their judgment on sulbutiamine. The only published clinical trial is totally worthless. Neither Servier group nor the French medicines agency should be proud of this affair."
 * -- useful for the history section perhaps... Jytdog (talk) 04:07, 27 January 2018 (UTC)